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1. Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy : not all AIDS-defining conditions are created equal

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Antiretroviral Therapy Cohort Collaboration Mocroft A, Sterne JA, Egger M, May M, Grabar S, Furrer H, Sabin C, Fatkenheuer G, Justice A, Reiss P, d'Arminio Monforte A, Gill J, Hogg R, Bonnet F, Kitahata M, Staszewski S, Casabona J, Harris R, Saag M, Chêne G, Costagliola D, Dabis F, D'Arminio Monforte A, de Wolf F, Ledergerber B, Mocroft A, Phillips A, Weller I, Sterne J, Abgrall S, Barin F, Bentata M, Billaud E, Boué F, Burty C, Cabié A, Cotte L, De Truchis P, Duval X, Duvivier C, Enel P, Fredouille Heripret L, Gasnault J, Gaud C, Gilquin J, Katlama C, Khuong MA, Lang JM, Lascaux AS, Launay O, Mahamat A, Mary Krause M, Matheron S, Meynard JL, Pavie J, Pialoux G, Pilorgé F, Poizot Martin I, Pradier C, Reynes J, Rouveix E, Simon A, Tattevin P, Tissot Dupont H, Viard JP, Viget N, Pariente Khayat A, Salomon V, Jacquemet N, Rivet A, Guiguet M, Kousignian I, Lanoy E, Lièvre L, Potard V, Selinger Leneman H, Bouvet E, Crickx B, Ecobichon JL, Leport C, Picard Dahan C, Yeni P, Tisne Dessus D, Weiss L, Salmon D, Sicard D, Auperin I, Roudière L, Fior R, Delfraissy JF, Goujard C, Jung C, Lesprit P, Desplanque N, Meyohas MC, Picard O, Cadranel J, Mayaud C, Bricaire F, Herson S, Clauvel JP, Decazes JM, Gerard L, Molina JM, Diemer M, Sellier P, Berthé H, Dupont C, Chandemerle C, Mortier E, Honoré P, Jeantils V, Tassi S, Mechali D, Taverne B, Gourdon F, Laurichesse H, Fresard A, Lucht F, Eglinger P, Faller JP, Bazin C, Verdon R, Boibieux A, Peyramond D, Livrozet JM, Touraine JL, Trepo C, Ravaux I, Delmont JP, Moreau J, Gastaut JA, Retornaz F, Soubeyrand J, Allegre T, Blanc PA, Galinier A, Ruiz JM, Lepeu G, Granet Brunello P, Esterni JP, Pelissier L, Cohen Valensi R, Nezri M, Chadapaud S, Laffeuillade A, May T, Rabaud C, Raffi F, Arvieux C, Michelet C, Borsa Lebas F, Caron F, Fraisse P, Rey D, Arlet Suau E, Cuzin L, Massip P, Thiercelin Legrand MF, Yasdanpanah Y, Pradinaud R, Sobesky M, Contant M, Montroni M, Scalise G, Braschi MC, Riva A, Tirelli U, Martellotta F, Pastore G, Ladisa N, Suter F, Arici C, Chiodo F, Colangeli V, Fiorini C, Carosi G, Cristini G, Torti C, Minardi C, Bertelli D, Quirino T, Manconi PE, Piano P, Cosco L, Scerbo A, Vecchiet J, D'Alessandro M, Santoro D, Pusterla L, Carnevale G, Lorenzotti S, Viganò P, Mena M, Ghinelli F, Sighinolfi L, Leoncini F, Mazzotta F, Pozzi M, Lo Caputo S, Grisorio B, Ferrara S, Grima P, Grima PF, Pagano G, Cassola G, Alessandrini A, Piscopo R, Toti M, Trezzi M, Soscia F, Tacconi L, Orani A, Perini P, Scasso A, Vincenti A, Chiodera F, Castelli P, Scalzini A, Palvarini L, Moroni M, Lazzarin A, Rizzardini G, Caggese L, Cicconi P, Galli A, Merli S, Pastecchia C, Moioli MC, Esposito R, Mussini C, Abrescia N, Chirianni A, Izzo CM, Piazza M, De Marco M, Viglietti R, Manzillo E, Colomba A, Abbadessa V, Prestileo T, Mancuso S, Ferrari C, Pizzaferri P, Filice G, Minoli L, Bruno R, Novati S, Baldelli F, Camanni G, Petrelli E, Cioppi A, Alberici F, Ruggieri A, Menichetti F, Martinelli C, De Stefano C, La Gala A, Ballardini G, Rizzo E, Magnani G, Ursitti MA, Arlotti M, Ortolani P, Cauda R, Dianzani F, Ippolito G, Antinori A, Antonucci G, Ciardi M, Narciso P, Petrosillo N, Vullo V, De Luca A, Zaccarelli M, Acinapura R, De Longis P, Trotta MP, Noto P, Lichtner M, Capobianchi MR, Carletti F, Girardi E, Pezzotti P, Rezza G, Mura MS, Mannazzu M, Caramello P, Di Perri G, Orofino GC, Sciandra M, Grossi PA, Basilico C, Poggio A, Bottari G, Raise E, Ebo F, Pellizzer G, Buonfrate D, Resta F, Loso K, Cozzi Lepri A, Battegay M, Bernasconi E, Böni J, Bucher H, Bürgisser P, Cattacin S, Cavassini M, Dubs R, Elzi L, Erb P, Fischer M, Flepp M, Fontana A, Francioli P, Gorgievski M, Günthard H, Hirsch H, Hirschel B, Hösli I, Kahlert C, Kaiser L, Karrer U, Kind C, Klimkait T, Martinetti G, Martinez B, Müller N, Nadal D, Opravil M, Paccaud F, Pantaleo G, Rickenbach M, Rudin C, Schmid P, Schultze D, Schüpbach J, Speck R, Taffé P, Tarr P, Telenti A, Trkola A, Vernazza P, Weber R, Yerly S, Gras LA, van Sighem AI, Smit C, Bronsveld W, Hillebrand Haverkort ME, Prins JM, Branger J, Eeftinck Schattenkerk JK, Gisolf J, Godfried MH, Lange JM, Lettinga KD, van der Meer JT, Nellen FJ, van der Poll T, Ruys TA, Steingrover R, Vermeulen JN, Vrouenraets SM, van Vugt M, Wit FW, Kuijpers TW, Pajkrt D, Scherpbier HJ, van Eeden A, Brinkman K, van den Berk GE, Blok WL, Frissen PH, Roos JC, Schouten WE, Mulder JW, van Gorp EC, Wagenaar J, Veenstra J, Danner SA, Van Agtmael MA, Claessen FA, Perenboom RM, Rijkeboer A, van Vonderen MG, Richter C, van der Berg J, Vriesendorp R, Jeurissen FJ, Kauffmann RH, Pogány K, Bravenboer B, ten Napel CH, Kootstra GJ, Sprenger HG, van Assen S, van Leeuwen JT, Doedens R, Scholvinck EH, ten Kate RW, Soetekouw R, van Houte D, Polée MB, Kroon FP, van den Broek PJ, van Dissel JT, Schippers EF, Schreij G, van der Geest S, Lowe S, Verbon A, Koopmans PP, Van Crevel R, de Groot R, Keuter M, Post F, van der Ven AJ, Warris A, van der Ende ME, Gyssens IC, van der Feltz M, Nouwen JL, Rijnders BJ, de Vries TE, Driessen G, van der Flier M, Hartwig NG, Juttman JR, van Kasteren ME, Van de Heul C, Hoepelman IM, Schneider MM, Bonten MJ, Borleffs JC, Ellerbroek PM, Jaspers CA, Mudrikove T, Schurink CA, Gisolf EH, Geelen SP, Wolfs TF, Faber T, Tanis AA, Groeneveld PH, den Hollander JG, Duits AJ, Winkel K, Back NK, Bakker ME, Berkhout B, Jurriaans S, Zaaijer HL, Cuijpers T, Rietra PJ, Roozendaal KJ, Pauw W, van Zanten AP, Smits PH, von Blomberg BM, Savelkoul P, Pettersson A, Swanink CM, Franck PF, Lampe AS, Jansen CL, Hendriks R, Benne CA, Veenendaal D, Storm H, Weel J, van Zeijl JH, Kroes AC, Claas HC, Bruggeman CA, Goossens VJ, Galama JM, Melchers WJ, Poort YA, Doornum GJ, Niesters MG, Osterhaus AD, Schutten M, Buiting AG, Swaans CA, Boucher CA, Schuurman R, Boel E, Jansz AF, Veldkamp A, Beijnen JH, Huitema AD, Burger DM, Hugen PW, van Kan HJ, Losso M, Duran A, Vetter N, Karpov I, Vassilenko A, Mitsura VM, Suetnov O, Clumeck N, De Wit S, Poll B, Colebunders R, Kostov K, Begovac J, Machala L, Rozsypal H, Sedlacek D, Nielsen J, Lundgren J, Benfield T, Kirk O, Gerstoft J, Katzenstein T, Hansen AB, Skinhøj P, Pedersen C, Oestergaard L, Zilmer K, Ristola M, Girard PM, Vanhems P, Rockstroh J, Schmidt R, van Lunzen J, Degen O, Stellbrink HJ, Bogner J, Kosmidis J, Gargalianos P, Xylomenos G, Perdios J, Panos G, Filandras A, Karabatsaki E, Sambattakou H, Banhegyi D, Mulcahy F, Yust I, Turner D, Burke M, Pollack S, Hassoun G, Maayan S, Chiesi A, Mazeu I, Pristera R, Gabbuti A, Montesarchio E, Gargiulo M, Iacomi F, Vlassi C, Finazzi R, Galli M, Ridolfo A, Rozentale B, Aldins P, Chaplinskas S, Hemmer R, Staub T, Bruun J, Maeland A, Ormaasen V, Knysz B, Gasiorowski J, Horban A, Prokopowicz D, Wiercinska Drapalo A, Boron Kaczmarska A, Pynka M, Beniowski M, Mularska E, Trocha H, Antunes F, Valadas E, Mansinho K, Maltez F, Duiculescu D, Rakhmanova A, Vinogradova E, Buzunova S, Jevtovic D, Mokrás M, Staneková D, González Lahoz J, Soriano V, Martin Carbonero L, Labarga P, Clotet B, Jou A, Conejero J, Tural C, Gatell JM, Miró JM, Domingo P, Gutierrez M, Mateo G, Sambeat MA, Karlsson A, Persson PO, Flamholc L, Boffi E, Kravchenko E, Chentsova N, Barton S, Johnson AM, Mercey D, Johnson MA, Murphy M, Weber J, Scullard G, Fisher M, Brettle R, Gatell J, Gazzard B, Friis Møller N, Bannister W, Ellefson M, Borch A, Podlekareva D, Holkmann Olsen C, Kjaer J, Peters L, Reekie J, Raffanti S, Dieterch D, Becker S, Scarsella A, Fusco G, Most B, Balu R, Rana R, Beckerman R, Ising T, Fusco J, Irek R, Johnson B, Hirani A, DeJesus E, Pierone G, Lackey P, Irek C, Johnson A, Burdick J, Leon S, Arch J, Helm EB, Carlebach A, Müller A, Haberl A, Nisius G, Lennemann T, Stephan C, Bickel M, Mösch M, Gute P, Locher L, Lutz T, Klauke S, Knecht G, Khaykin P, Doerr HW, Stürmer M, Babacan E, von Hentig N, Beylot J, Dupon M, Longy Boursier M, Pellegrin JL, Ragnaud JM, Salamon R, Thiébaut R, Lewden C, Lawson Ayayi S, Mercié P, Moreau JF, Morlat P, Bernard N, Lacoste D, Malvy D, Neau D, Blaizeau MJ, Decoin M, Delveaux S, Hannapier C, Labarrère S, Lavignolle Aurillac V, Uwamaliya Nziyumvira B, Palmer G, Touchard D, Balestre E, Alioum A, Jacqmin Gadda H, Bonarek M, Coadou B, Gellie P, Nouts C, Bocquentin F, Dutronc H, Lafarie S, Aslan A, Pistonne T, Thibaut P, Vatan R, Chambon D, De La Taille C, Cazorla C, Ocho A, Viallard JF, Caubet O, Cipriano C, Lazaro E, Couzigou P, Castera L, Fleury H, Lafon ME, Masquelier B, Pellegrin I, Breilh D, Blanco P, Loste P, Caunègre L, Bonnal F, Farbos S, Ferrand M, Ceccaldi J, Tchamgoué S, De Witte S, Buy E, Alexander C, Barrios R, Braitstein P, Brumme Z, Chan K, Cote H, Gataric N, Geller J, Guillemi S, Harrigan PR, Harris M, Joy R, Levy A, Montaner J, Montessori V, Palepu A, Phillips E, Phillips P, Press N, Tyndall M, Wood E, Yip B, Bhagani S, Breen R, Byrne P, Carroll A, Cuthbertson Z, Dunleavy A, Geretti AM, Heelan B, Johnson M, Kinloch de Loes S, Lipman M, Madge S, Marshall N, Nair D, Nebbia G, Prinz B, Shah S, Swader L, Tyrer M, Youle M, Chaloner C, Grabowska H, Holloway J, Puradiredja J, Ransom D, Tsintas R, Bansi L, Fox Z, Harris E, Hill T, Lampe F, Lodwick R, Smith C, Amoah E, Booth C, Clewley G, Garcia Diaz A, Gregory B, Janossy G, Labbett W, Thomas M, Read R, Krentz H, Beckthold B, Schmeisser N, Alquézar A, Esteve A, Podzamczer D, Murillas J, Romero A, Agustí C, Agüero F, Ferrer E, Riera M, Segura F, Navarro G, Force L, Vilaró J, Masabeu A, García I, Guadarrama M, Montoliu A, Ortega N, Lazzari E, Puchol E, Sanchez M, Blanco JL, Garcia Alcaide F, Martinez E, Mallolas J, López Dieguez M, García Goez JF, Sirera G, Romeu J, Negredo E, Miranda C, Capitan MC, Olmo M, Barragan P, Saumoy M, Bolao F, Cabellos C, Peña C, Sala M, Cervantes M, Jose Amengual M, Navarro M, Penelo E, Barrufet P, Raper JL, Mugavero MJ, Willig JH, Schumacher J, Chang PW, Westfall AO, Cloud G, Lin HY, Acosta EP, Colette Kempf M, Allison JJ, Pisu M., NAPPA, SALVATORE, Mocroft, A, Mancuso, S, Antiretroviral Therapy Cohort Collaboration Mocroft, A, Sterne, Ja, Egger, M, May, M, Grabar, S, Furrer, H, Sabin, C, Fatkenheuer, G, Justice, A, Reiss, P, d'Arminio Monforte, A, Gill, J, Hogg, R, Bonnet, F, Kitahata, M, Staszewski, S, Casabona, J, Harris, R, Saag, M, Chêne, G, Costagliola, D, Dabis, F, D'Arminio Monforte, A, de Wolf, F, Ledergerber, B, Phillips, A, Weller, I, Sterne, J, Abgrall, S, Barin, F, Bentata, M, Billaud, E, Boué, F, Burty, C, Cabié, A, Cotte, L, De Truchis, P, Duval, X, Duvivier, C, Enel, P, Fredouille Heripret, L, Gasnault, J, Gaud, C, Gilquin, J, Katlama, C, Khuong, Ma, Lang, Jm, Lascaux, A, Launay, O, Mahamat, A, Mary Krause, M, Matheron, S, Meynard, Jl, Pavie, J, Pialoux, G, Pilorgé, F, Poizot Martin, I, Pradier, C, Reynes, J, Rouveix, E, Simon, A, Tattevin, P, Tissot Dupont, H, Viard, Jp, Viget, N, Pariente Khayat, A, Salomon, V, Jacquemet, N, Rivet, A, Guiguet, M, Kousignian, I, Lanoy, E, Lièvre, L, Potard, V, Selinger Leneman, H, Bouvet, E, Crickx, B, Ecobichon, Jl, Leport, C, Picard Dahan, C, Yeni, P, Tisne Dessus, D, Weiss, L, Salmon, D, Sicard, D, Auperin, I, Roudière, L, Fior, R, Delfraissy, Jf, Goujard, C, Jung, C, Lesprit, P, Desplanque, N, Meyohas, Mc, Picard, O, Cadranel, J, Mayaud, C, Bricaire, F, Herson, S, Clauvel, Jp, Decazes, Jm, Gerard, L, Molina, Jm, Diemer, M, Sellier, P, Berthé, H, Dupont, C, Chandemerle, C, Mortier, E, Honoré, P, Jeantils, V, Tassi, S, Mechali, D, Taverne, B, Gourdon, F, Laurichesse, H, Fresard, A, Lucht, F, Eglinger, P, Faller, Jp, Bazin, C, Verdon, R, Boibieux, A, Peyramond, D, Livrozet, Jm, Touraine, Jl, Trepo, C, Ravaux, I, Delmont, Jp, Moreau, J, Gastaut, Ja, Retornaz, F, Soubeyrand, J, Allegre, T, Blanc, Pa, Galinier, A, Ruiz, Jm, Lepeu, G, Granet Brunello, P, Esterni, Jp, Pelissier, L, Cohen Valensi, R, Nezri, M, Chadapaud, S, Laffeuillade, A, May, T, Rabaud, C, Raffi, F, Arvieux, C, Michelet, C, Borsa Lebas, F, Caron, F, Fraisse, P, Rey, D, Arlet Suau, E, Cuzin, L, Massip, P, Thiercelin Legrand, Mf, Yasdanpanah, Y, Pradinaud, R, Sobesky, M, Contant, M, Montroni, M, Scalise, G, Braschi, Mc, Riva, A, Tirelli, U, Martellotta, F, Pastore, G, Ladisa, N, Suter, F, Arici, C, Chiodo, F, Colangeli, V, Fiorini, C, Carosi, G, Cristini, G, Torti, C, Minardi, C, Bertelli, D, Quirino, T, Manconi, Pe, Piano, P, Cosco, L, Scerbo, A, Vecchiet, J, D'Alessandro, M, Santoro, D, Pusterla, L, Carnevale, G, Lorenzotti, S, Viganò, P, Mena, M, Ghinelli, F, Sighinolfi, L, Leoncini, F, Mazzotta, F, Pozzi, M, Lo Caputo, S, Grisorio, B, Ferrara, S, Grima, P, Grima, Pf, Pagano, G, Cassola, G, Alessandrini, A, Piscopo, R, Toti, M, Trezzi, M, Soscia, F, Tacconi, L, Orani, A, Perini, P, Scasso, A, Vincenti, A, Chiodera, F, Castelli, P, Scalzini, A, Palvarini, L, Moroni, M, Lazzarin, A, Rizzardini, G, Caggese, L, Cicconi, P, Galli, A, Merli, S, Pastecchia, C, Moioli, Mc, Esposito, R, Mussini, C, Abrescia, N, Chirianni, A, Izzo, Cm, Piazza, M, De Marco, M, Viglietti, R, Manzillo, E, Nappa, Salvatore, Colomba, A, Abbadessa, V, Prestileo, T, Ferrari, C, Pizzaferri, P, Filice, G, Minoli, L, Bruno, R, Novati, S, Baldelli, F, Camanni, G, Petrelli, E, Cioppi, A, Alberici, F, Ruggieri, A, Menichetti, F, Martinelli, C, De Stefano, C, La Gala, A, Ballardini, G, Rizzo, E, Magnani, G, Ursitti, Ma, Arlotti, M, Ortolani, P, Cauda, R, Dianzani, F, Ippolito, G, Antinori, A, Antonucci, G, Ciardi, M, Narciso, P, Petrosillo, N, Vullo, V, De Luca, A, Zaccarelli, M, Acinapura, R, De Longis, P, Trotta, Mp, Noto, P, Lichtner, M, Capobianchi, Mr, Carletti, F, Girardi, E, Pezzotti, P, Rezza, G, Mura, M, Mannazzu, M, Caramello, P, Di Perri, G, Orofino, Gc, Sciandra, M, Grossi, Pa, Basilico, C, Poggio, A, Bottari, G, Raise, E, Ebo, F, Pellizzer, G, Buonfrate, D, Resta, F, Loso, K, Cozzi Lepri, A, Battegay, M, Bernasconi, E, Böni, J, Bucher, H, Bürgisser, P, Cattacin, S, Cavassini, M, Dubs, R, Elzi, L, Erb, P, Fischer, M, Flepp, M, Fontana, A, Francioli, P, Gorgievski, M, Günthard, H, Hirsch, H, Hirschel, B, Hösli, I, Kahlert, C, Kaiser, L, Karrer, U, Kind, C, Klimkait, T, Martinetti, G, Martinez, B, Müller, N, Nadal, D, Opravil, M, Paccaud, F, Pantaleo, G, Rickenbach, M, Rudin, C, Schmid, P, Schultze, D, Schüpbach, J, Speck, R, Taffé, P, Tarr, P, Telenti, A, Trkola, A, Vernazza, P, Weber, R, Yerly, S, Gras, La, van Sighem, Ai, Smit, C, Bronsveld, W, Hillebrand Haverkort, Me, Prins, Jm, Branger, J, Eeftinck Schattenkerk, Jk, Gisolf, J, Godfried, Mh, Lange, Jm, Lettinga, Kd, van der Meer, Jt, Nellen, Fj, van der Poll, T, Ruys, Ta, Steingrover, R, Vermeulen, Jn, Vrouenraets, Sm, van Vugt, M, Wit, Fw, Kuijpers, Tw, Pajkrt, D, Scherpbier, Hj, van Eeden, A, Brinkman, K, van den Berk, Ge, Blok, Wl, Frissen, Ph, Roos, Jc, Schouten, We, Mulder, Jw, van Gorp, Ec, Wagenaar, J, Veenstra, J, Danner, Sa, Van Agtmael, Ma, Claessen, Fa, Perenboom, Rm, Rijkeboer, A, van Vonderen, Mg, Richter, C, van der Berg, J, Vriesendorp, R, Jeurissen, Fj, Kauffmann, Rh, Pogány, K, Bravenboer, B, ten Napel, Ch, Kootstra, Gj, Sprenger, Hg, van Assen, S, van Leeuwen, Jt, Doedens, R, Scholvinck, Eh, ten Kate, Rw, Soetekouw, R, van Houte, D, Polée, Mb, Kroon, Fp, van den Broek, Pj, van Dissel, Jt, Schippers, Ef, Schreij, G, van der Geest, S, Lowe, S, Verbon, A, Koopmans, Pp, Van Crevel, R, de Groot, R, Keuter, M, Post, F, van der Ven, Aj, Warris, A, van der Ende, Me, Gyssens, Ic, van der Feltz, M, Nouwen, Jl, Rijnders, Bj, de Vries, Te, Driessen, G, van der Flier, M, Hartwig, Ng, Juttman, Jr, van Kasteren, Me, Van de Heul, C, Hoepelman, Im, Schneider, Mm, Bonten, Mj, Borleffs, Jc, Ellerbroek, Pm, Jaspers, Ca, Mudrikove, T, Schurink, Ca, Gisolf, Eh, Geelen, Sp, Wolfs, Tf, Faber, T, Tanis, Aa, Groeneveld, Ph, den Hollander, Jg, Duits, Aj, Winkel, K, Back, Nk, Bakker, Me, Berkhout, B, Jurriaans, S, Zaaijer, Hl, Cuijpers, T, Rietra, Pj, Roozendaal, Kj, Pauw, W, van Zanten, Ap, Smits, Ph, von Blomberg, Bm, Savelkoul, P, Pettersson, A, Swanink, Cm, Franck, Pf, Lampe, A, Jansen, Cl, Hendriks, R, Benne, Ca, Veenendaal, D, Storm, H, Weel, J, van Zeijl, Jh, Kroes, Ac, Claas, Hc, Bruggeman, Ca, Goossens, Vj, Galama, Jm, Melchers, Wj, Poort, Ya, Doornum, Gj, Niesters, Mg, Osterhaus, Ad, Schutten, M, Buiting, Ag, Swaans, Ca, Boucher, Ca, Schuurman, R, Boel, E, Jansz, Af, Veldkamp, A, Beijnen, Jh, Huitema, Ad, Burger, Dm, Hugen, Pw, van Kan, Hj, Losso, M, Duran, A, Vetter, N, Karpov, I, Vassilenko, A, Mitsura, Vm, Suetnov, O, Clumeck, N, De Wit, S, Poll, B, Colebunders, R, Kostov, K, Begovac, J, Machala, L, Rozsypal, H, Sedlacek, D, Nielsen, J, Lundgren, J, Benfield, T, Kirk, O, Gerstoft, J, Katzenstein, T, Hansen, Ab, Skinhøj, P, Pedersen, C, Oestergaard, L, Zilmer, K, Ristola, M, Girard, Pm, Vanhems, P, Rockstroh, J, Schmidt, R, van Lunzen, J, Degen, O, Stellbrink, Hj, Bogner, J, Kosmidis, J, Gargalianos, P, Xylomenos, G, Perdios, J, Panos, G, Filandras, A, Karabatsaki, E, Sambattakou, H, Banhegyi, D, Mulcahy, F, Yust, I, Turner, D, Burke, M, Pollack, S, Hassoun, G, Maayan, S, Chiesi, A, Mazeu, I, Pristera, R, Gabbuti, A, Montesarchio, E, Gargiulo, M, Iacomi, F, Vlassi, C, Finazzi, R, Galli, M, Ridolfo, A, Rozentale, B, Aldins, P, Chaplinskas, S, Hemmer, R, Staub, T, Bruun, J, Maeland, A, Ormaasen, V, Knysz, B, Gasiorowski, J, Horban, A, Prokopowicz, D, Wiercinska Drapalo, A, Boron Kaczmarska, A, Pynka, M, Beniowski, M, Mularska, E, Trocha, H, Antunes, F, Valadas, E, Mansinho, K, Maltez, F, Duiculescu, D, Rakhmanova, A, Vinogradova, E, Buzunova, S, Jevtovic, D, Mokrás, M, Staneková, D, González Lahoz, J, Soriano, V, Martin Carbonero, L, Labarga, P, Clotet, B, Jou, A, Conejero, J, Tural, C, Gatell, Jm, Miró, Jm, Domingo, P, Gutierrez, M, Mateo, G, Sambeat, Ma, Karlsson, A, Persson, Po, Flamholc, L, Boffi, E, Kravchenko, E, Chentsova, N, Barton, S, Johnson, Am, Mercey, D, Johnson, Ma, Murphy, M, Weber, J, Scullard, G, Fisher, M, Brettle, R, Gatell, J, Gazzard, B, Friis Møller, N, Bannister, W, Ellefson, M, Borch, A, Podlekareva, D, Holkmann Olsen, C, Kjaer, J, Peters, L, Reekie, J, Raffanti, S, Dieterch, D, Becker, S, Scarsella, A, Fusco, G, Most, B, Balu, R, Rana, R, Beckerman, R, Ising, T, Fusco, J, Irek, R, Johnson, B, Hirani, A, Dejesus, E, Pierone, G, Lackey, P, Irek, C, Johnson, A, Burdick, J, Leon, S, Arch, J, Helm, Eb, Carlebach, A, Müller, A, Haberl, A, Nisius, G, Lennemann, T, Stephan, C, Bickel, M, Mösch, M, Gute, P, Locher, L, Lutz, T, Klauke, S, Knecht, G, Khaykin, P, Doerr, Hw, Stürmer, M, Babacan, E, von Hentig, N, Beylot, J, Dupon, M, Longy Boursier, M, Pellegrin, Jl, Ragnaud, Jm, Salamon, R, Thiébaut, R, Lewden, C, Lawson Ayayi, S, Mercié, P, Moreau, Jf, Morlat, P, Bernard, N, Lacoste, D, Malvy, D, Neau, D, Blaizeau, Mj, Decoin, M, Delveaux, S, Hannapier, C, Labarrère, S, Lavignolle Aurillac, V, Uwamaliya Nziyumvira, B, Palmer, G, Touchard, D, Balestre, E, Alioum, A, Jacqmin Gadda, H, Bonarek, M, Coadou, B, Gellie, P, Nouts, C, Bocquentin, F, Dutronc, H, Lafarie, S, Aslan, A, Pistonne, T, Thibaut, P, Vatan, R, Chambon, D, De La Taille, C, Cazorla, C, Ocho, A, Viallard, Jf, Caubet, O, Cipriano, C, Lazaro, E, Couzigou, P, Castera, L, Fleury, H, Lafon, Me, Masquelier, B, Pellegrin, I, Breilh, D, Blanco, P, Loste, P, Caunègre, L, Bonnal, F, Farbos, S, Ferrand, M, Ceccaldi, J, Tchamgoué, S, De Witte, S, Buy, E, Alexander, C, Barrios, R, Braitstein, P, Brumme, Z, Chan, K, Cote, H, Gataric, N, Geller, J, Guillemi, S, Harrigan, Pr, Harris, M, Joy, R, Levy, A, Montaner, J, Montessori, V, Palepu, A, Phillips, E, Phillips, P, Press, N, Tyndall, M, Wood, E, Yip, B, Bhagani, S, Breen, R, Byrne, P, Carroll, A, Cuthbertson, Z, Dunleavy, A, Geretti, Am, Heelan, B, Johnson, M, Kinloch de Loes, S, Lipman, M, Madge, S, Marshall, N, Nair, D, Nebbia, G, Prinz, B, Shah, S, Swader, L, Tyrer, M, Youle, M, Chaloner, C, Grabowska, H, Holloway, J, Puradiredja, J, Ransom, D, Tsintas, R, Bansi, L, Fox, Z, Harris, E, Hill, T, Lampe, F, Lodwick, R, Smith, C, Amoah, E, Booth, C, Clewley, G, Garcia Diaz, A, Gregory, B, Janossy, G, Labbett, W, Thomas, M, Read, R, Krentz, H, Beckthold, B, Schmeisser, N, Alquézar, A, Esteve, A, Podzamczer, D, Murillas, J, Romero, A, Agustí, C, Agüero, F, Ferrer, E, Riera, M, Segura, F, Navarro, G, Force, L, Vilaró, J, Masabeu, A, García, I, Guadarrama, M, Montoliu, A, Ortega, N, Lazzari, E, Puchol, E, Sanchez, M, Blanco, Jl, Garcia Alcaide, F, Martinez, E, Mallolas, J, López Dieguez, M, García Goez, Jf, Sirera, G, Romeu, J, Negredo, E, Miranda, C, Capitan, Mc, Olmo, M, Barragan, P, Saumoy, M, Bolao, F, Cabellos, C, Peña, C, Sala, M, Cervantes, M, Jose Amengual, M, Navarro, M, Penelo, E, Barrufet, P, Raper, Jl, Mugavero, Mj, Willig, Jh, Schumacher, J, Chang, Pw, Westfall, Ao, Cloud, G, Lin, Hy, Acosta, Ep, Colette Kempf, M, Allison, Jj, Pisu, M., Amsterdam institute for Infection and Immunity, Amsterdam Public Health, Infectious diseases, Other departments, General Internal Medicine, Graduate School, Global Health, Paediatric Infectious Diseases / Rheumatology / Immunology, and Medical Microbiology and Infection Prevention

Subjects
Male, Infectious diseases and international health [NCEBP 13], Lymphoma, 030312 virology, Esophageal candidiasis, Cohort Studies, 0302 clinical medicine, Interquartile range, 030212 general & internal medicine, AIDS-Related, Lymphoma, AIDS-Related, 0303 health sciences, Mortality rate, Progressive multifocal leukoencephalopathy, Hazard ratio, Prognosis, 3. Good health, Pathogenesis and modulation of inflammation [N4i 1], Infectious Diseases, Combination, Drug Therapy, Combination, Female, Infection and autoimmunity [NCMLS 1], Human, Microbiology (medical), Adult, medicine.medical_specialty, Prognosi, Anti-HIV Agents, antiretroviral therapy, Infectious Disease, Article, AIDS-Related Opportunistic Infection, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Drug Therapy, Internal medicine, medicine, Humans, AIDS-defining event, Proportional Hazards Models, AIDS-Related Opportunistic Infections/diagnosis/ mortality, Acquired Immunodeficiency Syndrome/complications/diagnosis/drug, therapy/ mortality, Anti-HIV Agents/ therapeutic use, AIDS-Related/diagnosis/mortality, Acquired Immunodeficiency Syndrome, AIDS-Related Opportunistic Infections, business.industry, Proportional hazards model, Poverty-related infectious diseases [N4i 3], Anti-HIV Agent, medicine.disease, mortality, Confidence interval, Immunology, Proportional Hazards Model, Cohort Studie, business
Abstract

Contains fulltext : 80963.pdf (Publisher’s version ) (Open Access) BACKGROUND: The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. METHODS: We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in

Published
2009
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4. Role of IL-10 in transplantation tolerance

Author

RONCAROLO , MARIA GRAZIA, Bacchetta R, Touraine JL, de Waal Malefyt R, de Vries JE, J.L. Touraine, J. Traeger, H. Bétuel, J.M. Dubernard, J.P. Revillard and C. Dupuy, Roncarolo, MARIA GRAZIA, Bacchetta, R, Touraine, Jl, de Waal Malefyt, R, and de Vries, Je

Published
1994

5. FETAL LIVER-TRANSPLANTATION - BIOLOGY AND CLINICAL-RESULTS

Author

TOURAINE JL, BACCHETTA R, RAUDRANT D, REBAUD A, LAPLACE S, CESBRON P, GEBUHRER L, ZABOT MT, TOURAINE F, FRAPPAZ D, SOUILLET G, VULLO C., RONCAROLO , MARIA GRAZIA, Touraine, Jl, Roncarolo, MARIA GRAZIA, Bacchetta, R, Raudrant, D, Rebaud, A, Laplace, S, Cesbron, P, Gebuhrer, L, Zabot, Mt, Touraine, F, Frappaz, D, Souillet, G, and Vullo, C.

Abstract

Over the last 18 years, we have developed the transplantation of fetal liver cells to treat severe immunodeficiencies, hematological disorders and inborn errors of metabolism. Post-natally, this treatment is successful in two-third of patients and it is therefore very valuable, especially when there is no perfectly matched donor for a bone marrow transplant. Since 1 988 we have carried out these fetal liver transplants (FLTs) in utero, immediately after prenatal diagnosis. Engraftment and reconstitution have been obtained, and several advantages appear to be associated with in utero FLT : increased probability of graft take, ideal isolation of the patient (in the maternal uterus) and optimal environment for the differentiation of the transplanted fetal liver cells (in the fetal host).

Published
1993

6. INUTERO TRANSPLANTATION OF STEM-CELLS IN HUMANS - IMMUNOLOGICAL ASPECTS AND CLINICAL FOLLOW-UP OF PATIENTS

Author

TOURAINE JL, RAUDRANT D, REBAUD A, LAPLACE S, GEBUHRER L, BETUEL H, FRAPPAZ D, FREYCON F, ZABOT MT, TOURAINE F, SOUILLET G, PHILIPPE N, VULLO C., RONCAROLO , MARIA GRAZIA, Touraine, Jl, Raudrant, D, Rebaud, A, Roncarolo, MARIA GRAZIA, Laplace, S, Gebuhrer, L, Betuel, H, Frappaz, D, Freycon, F, Zabot, Mt, Touraine, F, Souillet, G, Philippe, N, and Vullo, C.

Abstract

Four human fetuses were treated by transplantation of human fetal liver stem cells. Two of them had severe immunodeficiency disease and thc two other ones had thalassemia major. Three of these in utero transplants were followed by engraftment. The three patients are now born : the first one is now very healthy thanks to the reconstitution of cell-mediated immunity associated with this transplant, and he lives normally at home ; the two other ones, who have been more recently treated, have a significant improvement of their condition and they also live normally at home. This procedure, for the first time used in humans, has therefore demonstrated its feasibility and its efficacy : during early fetal development, foreign cells engraft readily and may result in cure or significant correction of a large variety of inherited diseases.

Published
1992

7. INUTERO TRANSPLANTATION OF HEMATOPOIETIC STEM-CELLS IN HUMANS

Author

TOURAINE JL, RAUDRANT D, ROYO C, REBAUD A, BARBIER F, TOURAINE F, LAPLACE S, GEBUHRER L, BETUEL H, FRAPPAZ D, FREYCON F, VULLO C., RONCAROLO , MARIA GRAZIA, Touraine, Jl, Raudrant, D, Royo, C, Rebaud, A, Barbier, F, Roncarolo, MARIA GRAZIA, Touraine, F, Laplace, S, Gebuhrer, L, Betuel, H, Frappaz, D, Freycon, F, and Vullo, C.

Published
1991

8. A SCID PATIENT RECONSTITUTED WITH HLA-INCOMPATIBLE FETAL STEM-CELLS AS A MODEL FOR STUDYING TRANSPLANTATION TOLERANCE

Author

RONCAROLO , MARIA GRAZIA, BACCHETTA R, BIGLER M, TOURAINE JL, DEVRIES JE, SPITS H., Roncarolo, MARIA GRAZIA, Bacchetta, R, Bigler, M, Touraine, Jl, Devries, Je, and Spits, H.

Abstract

We studied a severe combined immunodeficiency (SCID) patient who received transplantations with completely HLA-mismatched fetal liver and thymus from two different donors. The patient is now 14 years old, healthy and shows normal immunoresponses to recall antigens. His T cells are of donor origin, whereas the monocytes, B cells, and natural killer (NK) cells are of the recipient. The successful immunological reconstitution raised questions as to how T and B cells could collaborate across an HLA barrier and how tolerance was achieved. We have shown that tetanus toxin-specific T cell clones isolated from this patient recognized this antigen in the context of host and not of donor HLA-DR, indicating that those cells were educated in the host environment, presumably the thymus. Despite this, an unexpectedly high frequency of host-reactive clones was found that could recognize MHC antigens of the host. It was particularly striking that CD8+ CTL clones were obtained that recognized class I MHC antigens on the host cells. Nevertheless, the patient did not show any sign of acute or chronic graft-versus-host disease (GVHD). These data indicated that no or only incomplete clonal deletion had taken place in this patient and suggest the presence of a peripheral suppressor mechanism. Thus far, we have no indication for the existence of suppressor T cells. Inasmuch as it was found that host-reactive T cells fail to produce IL-4, which is exceptional for CD4+ T cells, we are exploring the possibility that abnormal cytokine production patterns of host-reactive T cells are associated with suppression of these cells in vivo.

Published
1991

9. ENDOCRINOMETABOLIC EFFECTS OF WHOLE VERSUS SEGMENTAL PANCREAS ALLOTRANSPLANTATION IN DIABETIC-PATIENTS - A 2-YEAR FOLLOW-UP

Author

SECCHI , ANTONIO, DUBERNARD JM, LAROCCA E, LEFRANCOIS N, MELANDRI M, MARTIN X, TOURAINE JL, TRAEGER J, POZZA G., Secchi, Antonio, Dubernard, Jm, Larocca, E, Lefrancois, N, Melandri, M, Martin, X, Touraine, Jl, Traeger, J, and Pozza, G.

Abstract

We have investigated the metabolic effects of segmental (neoprene-injected) pancreas transplantation versus whole (enteric-diverted) pancreas transplantation. Seventeen uremic insulin-dependent diabetes mellitus (IDDM) patients received a simultaneous pancreaticorenal transplant: in a prospective, randomized study, 9 patients received a segmental neoprene-injected graft (group A) while 8 patients received a total pancreatico-duodenal graft, with enteric diversion (group B). The immunosuppressive therapy was based on ALG, CsA, azathioprine, and steroids. Three months after surgery, patients were submitted to the following metabolic investigation: i.v. and oral glucose tolerance tests, Hba 1, i.v. arginine test, and a 24-hr metabolic profile. The OGTT, HbA1, and metabolic profile were repeated 12 and 24 months after transplantation. At 3 months after transplantation, the OGTT showed delayed insulin secretion and higher blood glucose levels in group A. Serum insulin levels after IVGTT or arginine were higher in group B than in group A. OGTT at 12 and 24 months were unchanged in group B, while in group A a higher incidence of impaired glucose tolerance (IGT) and diabetes mellitus response were observed. HbA1 and blood glucose levels during the 24-hr profile showed good metabolic control in both groups at 3, 12, and 24 months. We can conclude that both the segmental and total pancreas transplantation restore a good metabolic control in IDDM patients, though a higher incidence of IGT and DM responses were observed after OGTT in the patients receiving a segmental graft. These abnormalities do not seem to interfere with metabolic control in everyday life. These results seem to be the consequence of the different B cell masses transplanted with these two techniques.

Published
1991

10. NEW DEVELOPMENTS IN STEM-CELL TRANSPLANTATION WITH SPECIAL REFERENCE TO THE 1ST INUTERO TRANSPLANTS IN HUMANS

Author

TOURAINE JL, RAUDRANT D, VULLO C, FRAPPAZ D, FREYCON F, REBAUD A, BARBIER F, GEBUHRER L, BETUEL H, ZABOT MT, RONCAROLO , MARIA GRAZIA, Touraine, Jl, Raudrant, D, Vullo, C, Frappaz, D, Freycon, F, Rebaud, A, Barbier, F, Roncarolo, MARIA GRAZIA, Gebuhrer, L, Betuel, H, and Zabot, Mt

Abstract

Based on the experience acquired in post-natal liver transplantation since 1974, we recently initiated pre-natal, in utero stem cell transplantation from the human fetal liver. The first two fetuses that we treated had immunodeficiencies, the third one had thalassemia major. Donors and recipients were not matched. The fetal cells were infused in the umbilical vein of the first two patients and injected intraperitoneally into the third one, under ultrasonic visualization. The first patient, born in 1988, has both engraftment of donor cells and reconstitution of cell-mediated immunity. This child, who had bare lymphocyte syndrome, has no clinical manifestation of the disease and he lives normally at home. The second child, born in 1989, has not yet developed a significant reconstitution of immunity although donor cell engraftment has been proven (Y chromosome in this female patient). The third patient has also evidence of donor cell take (Y chromosome in a female patient) but the effect on thalassemia has not yet been fully analyzed (donor hemoglobin present in small quantity). In all 3 cases, no side-effect of any kind developed in the mother nor in the fetus. Several advantages appear to be associated with in utero FLT: increased probability of graft take, ideal isolation of patient (in the uterus), optimal environment for fetal cell development (in the fetal host).

Published
1991

11. HERV-W envelope is significantly expressed in Multiple Sclerosis and causes neuroinflammation in animal models with specific antibody inhibition

Author

Bernard, Corinne, primary, Bertrand, Jean-Baptiste, additional, Stefas, Ilias, additional, Veas, Francisco, additional, Lang, Alois B, additional, Popa, I, additional, Sanhadji, Kamel, additional, Mancuso, Roberta, additional, Saresella, Marina, additional, Clerici, M, additional, Touraine, JL, additional, Portoukalian, J, additional, and Perron, Hervé, additional

Published
2009
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13. Multiple Sclerosis-Associated Retrovirus Particles Cause T Lymphocyte-Dependent Death with Brain Hemorrhage in Humanized SCID Mice Model

Author

Firouzi, R, primary, Rolland, A, additional, Michel, M, additional, Jouvin-Marche, E, additional, Hauw, JJ, additional, Malcus-Vocanson, C, additional, Lazarini, F, additional, Gebuhrer, L, additional, Seigneurin, JM, additional, Touraine, JL, additional, Sanhadji, K, additional, Marche, PN, additional, and Perron, H, additional

Published
2003
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16. An overview on clinical organ transplantation under FK 506

Author

Touraine, JL, Traeger, J, Beutuel, H, Dubernard, JM, Revillard, JP, Dupuy, C, Alessiani, M, Jain, A, Abu-Elmagd, K, Todo, S, Fung, J, Starzl, TE, Touraine, JL, Traeger, J, Beutuel, H, Dubernard, JM, Revillard, JP, Dupuy, C, Alessiani, M, Jain, A, Abu-Elmagd, K, Todo, S, Fung, J, and Starzl, TE

Published
1991

17. Present status of the cluster transplantation and its variants

Author

Touraine, JL, Traeger, J, Beutuel, H, Dubernard, JM, Revillard, JP, Dupuy, C, Alessiani, M, Ricordi, C, Todo, S, Tzakis, A, Fung, J, Starzl, TE, Touraine, JL, Traeger, J, Beutuel, H, Dubernard, JM, Revillard, JP, Dupuy, C, Alessiani, M, Ricordi, C, Todo, S, Tzakis, A, Fung, J, and Starzl, TE

Published
1991

19. Influence of immunosuppressive treatment on the endocrine function of segmental pancreatic allografts

Author

Traeger J, Dubernard JM, Pozza G, SECCHI, ANTONIO, Pontiroli AE, Touraine JL, Betuel H, El Yafi S, Da Ponte F, Cantarovich D, Diab N, Cardozo C, Martin X, Kamel G, Gelet A., BOSI , EMANUELE, Traeger, J, Dubernard, Jm, Pozza, G, Bosi, Emanuele, Secchi, Antonio, Pontiroli, Ae, Touraine, Jl, Betuel, H, El Yafi, S, Da Ponte, F, Cantarovich, D, Diab, N, Cardozo, C, Martin, X, Kamel, G, and Gelet, A.

Published
1983

23. Fetal tissue transplantation, bone marrow transplantation and prospective gene therapy in severe immunodeficiencies and enzyme deficiencies

Author

Touraine JL, Royo C, Touraine F., RONCAROLO , MARIA GRAZIA, Touraine, Jl, Roncarolo, MARIA GRAZIA, Royo, C, and Touraine, F.

Subjects
Male, Fetus, Liver, Bone Marrow, Immunologic Deficiency Syndromes, Humans, Female, Thymus Gland, Genetic Engineering, Metabolism, Inborn Errors, Bone Marrow Transplantation, Follow-Up Studies, Liver Transplantation
Abstract

The successful development of fetal tissue transplantation has resulted in therapeutical solutions for patients with a variety of diseases. Fetal liver transplants as well as bone marrow transplants, can completely cure patients with severe combined immunodeficiency disease. These transplants can also be applied to treat other types of immunodeficiency, hemopathies, and inborn errors of metabolism, in association with immunosuppressive therapy. Despite complete HLA incompatibility between transplanted stem cells and host cells, functional activities of donor-derived T-lymphocytes are not restricted. In severe forms of Di George syndrome, immunological reconstitution can be obtained by fetal thymus transplantation. It is expected that, in the near future, pure stem cell transplants and gene transplants will develop and will provide remarkable solutions for the therapy of a large number of diseases.

Published
1987

26. Human organ transplantation under cyclosporin A and steroids

Author

Touraine, JL, Traeger, J, Betuel, H, Brochier, J, Dubernard, JM, Revillard, JB, Triau, R, Starzl, TE, Iwatsuki, S, Klintmalm, GBG, Porter, KA, Fernandez-Bueno, C, Touraine, JL, Traeger, J, Betuel, H, Brochier, J, Dubernard, JM, Revillard, JB, Triau, R, Starzl, TE, Iwatsuki, S, Klintmalm, GBG, Porter, KA, and Fernandez-Bueno, C

Published
1981

27. Reappraisal of in utero Stem Cell Transplantation Based on Long-Term Results

Author

Rachel Sembeil, Roseline d'Oiron, L Gebuhrer, Thierry Lambert, Rosa Bacchetta, Albert Rebaud, Maria Grazia Roncarolo, Jean Louis Touraine, Daniel Raudrant, François Golfier, Touraine, Jl, Raudrant, D, Golfier, F, Rebaud, A, Sembeil, R, Roncarolo, MARIA GRAZIA, Bacchetta, R, D'Orion, R, Lambert, T, and Gebuhrer, L.

Subjects
Embryology, Thalassemia, Prenatal diagnosis, In utero transplantation, Time, Pregnancy, Prenatal Diagnosis, medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, Fetal Stem Cells, Immunodeficiency, Ultrasonography, Fetal Therapies, business.industry, Obstetrics and Gynecology, General Medicine, medicine.disease, Hemoglobinopathies, Transplantation, Fetal Diseases, In utero, Pediatrics, Perinatology and Child Health, Immunology, Female, Stem cell, business, Stem Cell Transplantation
Abstract

The therapeutic field of in utero transplantation of stem cells, into human fetuses, has developed since 1988 with the hope of improved probability of engraftment and tolerance, due to immune immaturity of the host. Fifteen years later, it is possible to evaluate the results that we and others have obtained in the treatment of several fetal diseases. Seven fetal patients have been treated in Lyon: In 2 cases, pregnancy termination was induced by the in utero injection; in the 5 other cases, engraftment was obtained and repeatedly documented with presence of donor HLA antigens and/or Y chromosome in recipients. In the 2 patients with combined immunodeficiency disease, a sustained reconstitution of immunity was obtained as a result of the transplant but other complications occurred thereafter. In patients with thalassemia major, Niemann-Pick disease or hemophilia, a very partial and very transitory benefit was only obtained. Approximately 33 other patients with immunodeficiencies, hemoglobinopathies or inborn errors of metabolism have been treated worldwide, over the last 13 years, with a comparable method, using parental or fetal stem cells transplanted in utero. Successful treatment has usually been recorded in immunodeficiencies, and insufficient results have been obtained in the other cases. This form of treatment can therefore be recommended after prenatal diagnosis of combined immunodeficiency but additional research is required to improve the degree of engraftment, the lack of resistance of the host and the ‘space’ available for hematopoiesis in the other conditions.

Published
2004
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28. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells

Author

R de Waal Malefyt, Pier-Angelo Tovo, Maria Grazia Roncarolo, Robertson Parkman, Rosa Bacchetta, M. Bigler, Jean Louis Touraine, John S. Abrams, J E de Vries, Bacchetta, R, Bigler, M, Touraine, Jl, Parkman, R, Tovo, Pa, Abrams, J, Malefyt, Rd, Devries, Je, and Roncarolo, MARIA GRAZIA

Subjects
CD4-Positive T-Lymphocytes, Male, T cell, Immunology, Molecular Sequence Data, Biology, Polymerase Chain Reaction, Monocytes, TCIRG1, Interleukin 21, HLA Antigens, medicine, Immune Tolerance, Immunology and Allergy, Cytotoxic T cell, Humans, Antigen-presenting cell, Interleukin 3, Severe combined immunodeficiency, Base Sequence, Hematopoietic Stem Cell Transplantation, Articles, DNA, HLA-DR Antigens, medicine.disease, Hematopoietic Stem Cells, Molecular biology, Clone Cells, Interleukin-10, medicine.anatomical_structure, Liver, Interleukin-2, Severe Combined Immunodeficiency, Stem cell, Cell Division
Abstract

Transplantation of HLA mismatched hematopoietic stem cells in patients with severe combined immunodeficiency (SCID) can result in a selective engraftment of T cells of donor origin with complete immunologic reconstitution and in vivo tolerance. The latter may occur in the absence of clonal deletion of donor T lymphocytes able to recognize the host HLA antigens. The activity of these host-reactive T cells is suppressed in vivo, since no graft-vs. -host disease is observed in these human chimeras. Here it is shown that the CD4+ host-reactive T cell clones isolated from a SCID patient transplanted with fetal liver stem cells produce unusually high quantities of interleukin 10 (IL-10) and very low amounts of IL-2 after antigen-specific stimulation in vitro. The specific proliferative responses of the host-reactive T cell clones were considerably enhanced in the presence of neutralizing concentrations of an anti-IL-10 monoclonal antibody, suggesting that high levels of endogenous IL-10 suppress the activity of these cells. These in vitro data correlate with observations made in vivo. Semi-quantitative polymerase chain reaction analysis carried out on freshly isolated peripheral blood mononuclear cells (PBMC) of the patient indicated that the levels of IL-10 messenger RNA (mRNA) expression were strongly enhanced, whereas IL-2 mRNA expression was much lower than that in PBMC of healthy donors. In vivo IL-10 mRNA expression was not only high in the T cells, but also in the non-T cell fraction, indicating that host cells also contributed to the high levels of IL-10 in vivo. Patient-derived monocytes were found to be major IL-10 producers. Although no circulating IL-10 could be detected, freshly isolated monocytes of the patient showed a reduced expression of class II HLA antigens. However, their capacity to stimulate T cells of normal donors in primary mixed lymphocyte cultures was within the normal range. Interestingly, similar high in vivo IL-10 mRNA expressions in the T and non-T cell compartment were also observed in three SCID patients transplanted with fetal liver stem cells and in four SCID patients transplanted with T cell-depleted haploidentical bone marrow stem cells. Taken together, these data indicate that high endogenous IL-10 production is a general phenomenon in SCID patients in whom allogenic stem cell transplantation results in immunologic reconstitution and induction of tolerance. Both donor T cells and host accessory cells contribute to these high levels of IL-10, which would suppress the activity of host-reactive T cell in vivo.

Published
1994

29. Immunological lessons learnt from patients transplanted with fully mismatched stem cells

Author

Rosa Bacchetta, Jean Louis Touraine, Hélène Plotnicky, Maria Grazia Roncarolo, L Gebuhrer, Touraine, Jl, Plotnicky, H, Roncarolo, MARIA GRAZIA, Bacchetta, R, Gebuhrer, L., and Inconnu

Subjects
Cytotoxicity, Immunologic, Male, [SDV]Life Sciences [q-bio], T-Lymphocytes, Immunology, Human leukocyte antigen, Biology, Clonal deletion, Antigen, HLA Antigens, Living Donors, Humans, Cytotoxic T cell, Clonal Anergy, Clonal anergy, Histocompatibility Testing, Hematopoietic Stem Cell Transplantation, Infant, Hematopoietic Stem Cells, Virology, In vitro, Transplantation, Treatment Outcome, Female, Severe Combined Immunodeficiency, Transplantation Tolerance, Stem cell, T-Lymphocytes, Cytotoxic
Abstract

Fully HLA-mismatched stem cells from human fetal livers were transplanted into 17 infants and two fetuses to treat severe combined immunodeficiency disease in 1976-2000. Donor cell engraftment and immunological reconstitution were obtained in 14/ 19 patients, three of whom have been extensively and repeatedly studied immunologically during prolonged follow-up. T-cells were derived totally from donor cells; B-cells and antigen-presenting cells (APC) remained mainly of host origin. Due to class I and 11 mismatches between T-cells and all other cells (APC, B-cells, virus-infected target cells), limitations in the defense against infections in vivo and in T-cell functions in vitro (helper and cytotoxic activities) were predicted; however, these did not occur. Anti-tetanus toxoid responses (including specific antibody production) developed despite HLA disparities between T-cells and B-cells or APC in the chimeric children. Similarly, cytotoxic T-cells (of donor HLA phenotype) recognized host Epstein-Barr virus-infected target cells. Recognition of antigenic peptide by T-cells under these conditions involved presentation by host allogeneic HLA molecules and not by self HLA antigens. Tolerance to donor antigens was acquired by clonal deletion; tolerance to host antigens existed despite the presence of many host-reactive T-cells and involved clonal anergy.

Published
2007
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30. CHIMERISM AND TOLERANCE TO HOST AND DONOR IN SEVERE COMBINED IMMUNODEFICIENCIES TRANSPLANTED WITH FETAL LIVER STEM-CELLS

Author

Rosa Bacchetta, J. E. De Vries, L Gebuhrer, Hergen Spits, Bart Vandekerckhove, Jean Louis Touraine, Maria Grazia Roncarolo, M. Bigler, Silvana Martino, Bacchetta, R, Vandekerckhove, Bae, Touraine, Jl, Bigler, M, Martino, S, Gebuhrer, L, Devries, Je, Spits, H, Roncarolo, MARIA GRAZIA, and Other departments

Subjects
Cytotoxicity, Immunologic, Male, Adolescent, T-Lymphocytes, T cell, Biology, Clonal deletion, Cell Line, Immunophenotyping, Interleukin 21, Fetal Tissue Transplantation, HLA Antigens, T-Lymphocyte Subsets, Immune Tolerance, medicine, Humans, Cytotoxic T cell, IL-2 receptor, Antigen-presenting cell, Interleukin 3, B-Lymphocytes, Chimera, Histocompatibility Testing, Stem Cells, Immunologic Deficiency Syndromes, Receptors, Antigen, T-Cell, gamma-delta, General Medicine, Natural killer T cell, Immunoglobulin A, Liver Transplantation, medicine.anatomical_structure, Child, Preschool, Immunoglobulin G, Immunology, Female, Stem Cell Transplantation, Research Article
Abstract

We have studied the peripheral T cell repertoire of two patients with severe combined immunodeficiency who were successfully treated with human histocompatibility leukocyte antigen (HLA)-mismatched fetal liver stem cell transplantation. The patients presented a split chimerism. T cells were of donor origin, whereas the B cells/monocytes were of the host phenotype. Interestingly, the natural killer (NK) cells in one patient were donor derived and in the other patient of host origin. The NK cells were functional but did not have antihost or donor reactivity. Despite the HLA mismatch between donor and host cells, complete tolerance was achieved in vivo, and a specific unresponsiveness of peripheral blood mononuclear cells from both patients toward the host cells was demonstrated in vitro. Nevertheless, we could isolate T cell receptor (TCR)alpha beta, CD4+ or CD8+, T cell clones specifically reacting with HLA class I and II molecules of the host. The CD4+ host-reactive T cell clones from both patients produced interleukins 2 and 5, interferon-gamma, granulocyte/macrophage colony-stimulating factor but are specifically defective in interleukin 4 production. The frequencies of CD8+ host-reactive T cells were high, and were in the same range as those observed for CD8+ alloreactive T cells. In contrast, no donor-reactive CD8+ T cells or host or donor-reactive TCR gamma delta + T cells were detected. These data indicate that, after fetal stem cell transplantation, donor-reactive, but not host-reactive cells, are deleted from the T cell repertoire. Therefore, a peripheral mechanism of suppression or clonal anergy, rather than clonal deletion, is involved in maintaining in vivo tolerance toward the host.

Published
1993

31. Immunological tolerance following stem cell transplantation in human fetuses in utero

Author

Daniel Raudrant, Maria Grazia Roncarolo, Jean Louis Touraine, S. Laplace, Touraine, Jl, Raudrant, D, Laplace, S, and Roncarolo, MARIA GRAZIA

Subjects
Transplantation, Fetus, business.industry, medicine.medical_treatment, Hematopoietic Stem Cell Transplantation, Hematopoietic stem cell transplantation, Liver transplantation, Clonal deletion, In utero transplantation, Immune tolerance, Pregnancy, Immunology, Immune Tolerance, Humans, Medicine, Female, Surgery, Stem cell, business
Abstract

FOLLOWING 19 years of experience in postnatal fetal liver transplantation (FLT), we have developed a new therapeutic method, namely the in utero transplantation of stem cells from the human fetal liver. This early transplant takes advantage of the immunological tolerance that exists in young fetal recipients. The six fetuses that we treated were 28, 26, 17, 14, and 12 weeks postfertilization. Three patients had immunodeficiencies, two others had thalassemia major and the last one had Niemann-Pick disease (type A). Donor cells were obtained from 7- to 13-week-old fetuses, with conditions approved by the National Committee for Bioethics. Donors and recipients were not matched. Under ultrasonic visualization, the fetal cells were infused through the umbilical vein of four patients and injected intraperitoneally into the 2 other ones. The first patient, born in 1988, has evidence of engraftment (T lymphocytes of donor origin expressing donor HLA specificities, in the host peripheral blood) and reconstitution of cell-mediated immunity. This child, who had bare lymphocyte syndrome,1 has no clinical manifestation of the disease and lives normally at home. The second child was born in 1989; donor cell engraftment has been proven (distinct HLA phenotype) and the severe immunodeficiency has been corrected to a large degree. One fetus with chronic granulomatous disease developed fatal bradycardia after a second in utero FLT. One fetal patient with thalassemia major had cardiac arrest following the intravenous infusion. The fifth patient, transplanted intraperitoneally at 12 weeks of fetal age, to treat thalassemia major, has evidence of donor cell take (Y chromosome in a female patient) and a partial effect on thalassemia has been obtained (HbA increased up to 30%, 1 year after birth); the proportion of donor versus host cells however tended to decrease over the following years suggesting that, in contrast with immunodeficient patients, thalassemic patients exhibit a selective advantage for the development of host, rather than donor, stem cells. The last patient treated by in utero FLT had Niemann-Pick disease. Engraftment was again obtained (donor HLA phenotype) but due to either the limited number of donor cells or the blood-brain barrier, moderate clinical and metabolic effects were seen, especially in the CNS. In all four patients who were born, no side-effect developed in the mother nor in the fetus. Several advantages appear to be associated with in utero FLT2: increased probability of graft take with development of specific immunological tolerance, ideal isolation of patient (in the uterus), and optimal environment for fetal cell development (in the fetal host). Immunological tolerance, in T cells deriving from donor stem cells, after education within host thymus, was shown to involve clonal deletion for donor antigens (deletion induced by donor dendritic cells and macrophages), and clonal anergy for host antigens (anergy induced by host thymic epithelial cells).3 High IL-10 production persisted for many years and was likely to play a role in the stable chimerism and tolerance maintenance.2

Published
1997
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32. Islet Cell Autoimmunity in Type I Diabetic Patients After HLA-Mismatched Pancreas Transplantation

Author

Antonio Secchi, Emanuele Bosi, Marion Shattock, Jules Traeger, Guido Pozza, Gian Franco Bottazzo, Albert Gelet, Jean Louis Touraine, Anna Saunders, Jean-Michel Dubernard, Bosi, Emanuele, Bottazzo, Gf, Secchi, Antonio, Pozza, G, Shattock, M, Saunders, A, Gelet, A, Touraine, Jl, Traeger, J, and Dubernard, Jm

Subjects
Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Azathioprine, Pancreas transplantation, medicine.disease_cause, Gastroenterology, Autoimmunity, Islets of Langerhans, HLA Antigens, Prednisone, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Autoantibodies, geography, geography.geographical_feature_category, business.industry, Histocompatibility Testing, Complement Fixation Tests, Immunosuppression, Middle Aged, Islet, medicine.disease, Kidney Transplantation, Diabetes Mellitus, Type 1, medicine.anatomical_structure, Immunology, Female, Pancreas Transplantation, business, Pancreas, medicine.drug
Abstract

The aim of this study was to investigate a possible reenhancement of islet cell autoimmunity in type I (insulin-dependent) diabetic patients who received HLA-mismatched pancreas transplants from cadaveric donors and who underwent generalized immunosuppression. Circulating islet cell antibodies (ICA) and complement-fixing ICAs (CF-ICAs) have been tested at 1, 2, 3, 6, and 12 mo and at least once a year posttransplantation in 23 recipients of 25 transplants (22 simultaneous with kidney, 2 retransplants, 1 isolated; 23 segmentai neoprene injected, 2 whole with enteric drainage). Patients were aged 35.3 ± 1.9 yr with a duration of diabetes of 20.6 ±1.1 yr. Immunosuppression consisted of double or triple association of azathioprine, cyclosporin, and prednisone with or without temporary antilymphocyte globulins. The number of HLA-A and HLA-B compatibilities was none in 8 patients, one in 12 patients, two in 4 patients, and three in 1 patient. The mean follow-up was 4.0 ± 0.4 yr/patient (range 0.4–7.2). ICAs were positive pretransplantation in 2 of 25 patients and reappeared 1–42 mo posttransplantation in another 7. In 6 patients, CF-ICAs were also positive. In 7 of 9 ICA+ patients the pancreas transplant failed; in 1 patient this occurred 4 mo before ICA reappearance, and in 6 patients it occurred 2–35 mo after the first detection of ICAs. Pancreas-transplant failure was significantly associated with the positivity for ICAs (P < .05) and particularly for CF-ICAs (P < .005). ICA positivity was transitory in 4 patients (2–27 mo) and persistent in the remaining 5 (up to 61 mo). These findings suggest a possible reenhancement of islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation, which could contribute to some cases of transplant failure.

Published
1989
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33. Cooperation between major histocompatibility complex mismatched mononuclear cells from a human chimera in the production of antigen-specific antibody

Author

Maria Grazia Roncarolo, Jean Louis Touraine, J Banchereau, Roncarolo, MARIA GRAZIA, Touraine, Jl, and Banchereau, J.

Subjects
Lymphocyte Cooperation, Human leukocyte antigen, Lymphocyte Activation, Major histocompatibility complex, Monocytes, Immunoglobulin G, Immune system, Antigen, HLA Antigens, Tetanus Toxoid, Humans, Lymphocytes, biology, Chimera, Histocompatibility Antigens Class II, General Medicine, HLA Mismatch, Virology, Immunoglobulin M, Antibody Formation, Immunology, biology.protein, Antibody, Research Article
Abstract

Fetal liver and thymus transplantation can be successfully employed for the treatment of severe combined immunodeficiency disease. In virtually all cases, donor and recipient cells are HLA mismatched. In a patient suffering from a severe combined immunodeficiency disease, full immunological reconstitution was obtained after fetal liver and thymus transplantation. HLA typing revealed that the patient's T cells were of donor origin, while the B cells and monocytes were of host origin. Despite this complete HLA mismatch, the patient was found to mount a subnormal to normal antibody response in vivo. This finding is in contrast with the concept that antigen recognition by T cells is major histocompatibility complex (MHC) restricted. To define the mechanism responsible for this in vivo antibody response, antibody production by peripheral blood mononuclear cells from the patient was tested in vitro after in vivo booster. The in vitro anti-tetanus toxoid antibody production was similar to that of the control group. In addition, specific proliferative responses to tetanus toxoid were obtained. Immunoglobulin allotype determination showed that antibodies were synthetized by host B cells. The results of the present study indicate that transplanted T lymphocytes and recipient cells cooperate despite complete HLA mismatch.

Published
1986

34. Interleukin-4 suppresses immunoglobulin production by peripheral blood lymphocytes of patients with common variable immunodeficiency (CVI) induced by supernatants of T cell clones

Author

G, Pastorelli, M G, Roncarolo, J L, Touraine, F, Rousset, J, Pene, J E, de Vries, Pastorelli, G, Roncarolo, MARIA GRAZIA, Touraine, Jl, Rousset, F, Pene, J, and de Vries, J. E.

Subjects
Adult, Antigens, Differentiation, T-Lymphocyte, CD4-Positive T-Lymphocytes, Male, B-Lymphocytes, Lymphokines, Adolescent, T-Lymphocytes, Immunoglobulins, chemical and pharmacologic phenomena, Lymphocyte Activation, Recombinant Proteins, Clone Cells, Immunoglobulin A, Immunoglobulin M, Agammaglobulinemia, Immunoglobulin G, Humans, Female, Interleukin-4, Child, Cells, Cultured, Aged, Research Article
Abstract

Supernatants of both CD4+ and CD8+ alloreactive T cell clones induced IgM, IgG and IgA synthesis by peripheral blood lymphocytes (PBL) of healthy donors in vitro. These supernatants were also tested on their capacity to induce immunoglobulin production by PBL of four patients with CVI and one patient with CVI and thymoma. A low degree of IgM, IgG and IgA production was induced in one patient with CVI. In the patient with CVI and thymoma, induction of IgG and IgA synthesis was in the normal range, whereas IgM production was reduced. In the three other patients only a low production of IgM was induced. Interestingly, pre-incubation of the PBL for 24 h with interleukin-4 (IL-4) suppressed immunoglobulin production both by PBL of the patients with CVI and healthy donors. The strongest inhibitory effects were observed on IgA synthesis. These data indicate that B cells of three patients with CVI can not be induced to switch to IgG or IgA producing cells in vitro. In contrast, B cells of the patient with CVI and thymoma were able to respond to the relevant B cell growth and differentiation factors present in the T cell clone supernatants, suggesting that the T cells of this patient may fail to produce these factors. However, the proliferative responses of the T cells to phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM), were normal in all five patients tested. In addition, the interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production by PBL of the five patients was also in the normal range. Although only a small number of patients was tested, these results support the view that defects in both regulatory T cell functions and/or intrinsic B cell defects may contribute to the pathogenesis of CVI.

Published
1989

35. Thirty months experience with cyclosporin in human pancreatic transplantation

Author

Emanuele Bosi, Piermarco Piatti, J. Traeger, J. M. Dubernard, Jean Louis Touraine, Albert Gelet, Guido Pozza, Antonio Secchi, Traeger, J, Bosi, Emanuele, Dubernard, Jm, Touraine, Jl, Piatti, Pm, Secchi, Antonio, Gelet, A, and Pozza, G.

Subjects
Adult, medicine.medical_specialty, Globulin, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Cyclosporins, Azathioprine, Internal Medicine, medicine, Humans, Pancreatic graft, Kidney, Type 1 diabetes, biology, business.industry, Incidence (epidemiology), Graft Survival, Immunosuppression, medicine.disease, Kidney Transplantation, Surgery, Transplantation, Diabetes Mellitus, Type 1, medicine.anatomical_structure, biology.protein, Pancreas Transplantation, business, medicine.drug
Abstract

Between September 1978 and December 1983, 33 simultaneous kidney plus pancreatic transplantations were performed in Type 1 (insulin-dependent) diabetic patients with uraemia at the Herriot Hospital, Lyon. In eight patients grafted before June 1981, immunosuppressive treatment consisted of azathioprine, steroids and a temporary course with anti-lymphocyte globulins (protocol A). Since June 1981, the immunosuppressive treatment has consisted of cyclosporin administered according to two protocols: from the day of transplantation with temporary anti-lymphocyte globulins with or without steroids (protocol B, seven patients), or after an initial course with protocol A, with or without steroids (protocol C, 18 patients). Only slight differences in patient and pancreatic graft survival between the three protocols were observed at 3, 6 and 12 months, while an improved survival rate for both patients and pancreatic grafts was observed in protocols B and C at 2 years. Moreover the incidence of pancreatic rejection as a cause of loss of pancreatic function seemed to be reduced under protocols B and C.

Published
1984

36. An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes.

Author

Levet S, Medina J, Joanou J, Demolder A, Queruel N, Réant K, Normand M, Seffals M, Dimier J, Germi R, Piofczyk T, Portoukalian J, Touraine JL, and Perron H

Subjects
Animals, Antiviral Agents therapeutic use, Cohort Studies, Diabetes Mellitus, Type 1 complications, Endogenous Retroviruses genetics, Endogenous Retroviruses pathogenicity, Female, Humans, Hyperglycemia complications, Insulin metabolism, Insulin Antagonists pharmacology, Islets of Langerhans metabolism, Male, Mice, Mice, Transgenic, RNA, Viral blood, Viral Envelope Proteins drug effects, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 virology, Endogenous Retroviruses drug effects, Viral Envelope Proteins physiology
Abstract

Human endogenous retroviruses (HERVs), remnants of ancestral viral genomic insertions, are known to represent 8% of the human genome and are associated with several pathologies. In particular, the envelope protein of HERV-W family (HERV-W-Env) has been involved in multiple sclerosis pathogenesis. Investigations to detect HERV-W-Env in a few other autoimmune diseases were negative, except in type-1 diabetes (T1D). In patients suffering from T1D, HERV-W-Env protein was detected in 70% of sera, and its corresponding RNA was detected in 57% of peripheral blood mononuclear cells. While studies on human Langerhans islets evidenced the inhibition of insulin secretion by HERV-W-Env, this endogenous protein was found to be expressed by acinar cells in 75% of human T1D pancreata. An extensive immunohistological analysis further revealed a significant correlation between HERV-W-Env expression and macrophage infiltrates in the exocrine part of human pancreata. Such findings were corroborated by in vivo studies on transgenic mice expressing HERV-W-env gene, which displayed hyperglycemia and decreased levels of insulin, along with immune cell infiltrates in their pancreas. Altogether, these results strongly suggest an involvement of HERV-W-Env in T1D pathogenesis. They also provide potentially novel therapeutic perspectives, since unveiling a pathogenic target in T1D.

Published
2017
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37. First international workshop on human endogenous retroviruses and diseases, HERVs & disease 2015.

Author

Nath A, Küry P, Sciascia do Olival G, Dolei A, Karlsson H, Groc L, Schneider M, Kriesel J, Touraine JL, Mallet F, Marche PN, Arnaud F, Feschotte C, and Perron H

Abstract

The First International Scientific Conference on Human Endogenous Retroviruses (HERVs) and Disease, Lyon-France, May 26-27 th 2015, brought together scientific and medical specialists from around the world investigating the involvement of human endogenous retroviruses (HERVs) in complex human diseases.

Published
2015
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38. Human endogenous retrovirus protein activates innate immunity and promotes experimental allergic encephalomyelitis in mice.

Author

Perron H, Dougier-Reynaud HL, Lomparski C, Popa I, Firouzi R, Bertrand JB, Marusic S, Portoukalian J, Jouvin-Marche E, Villiers CL, Touraine JL, and Marche PN

Subjects
Adjuvants, Immunologic administration & dosage, Animals, Cells, Cultured, Central Nervous System, Dendritic Cells, Encephalomyelitis, Autoimmune, Experimental chemically induced, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental immunology, Gene Expression, Gene Products, env immunology, Humans, Lipopolysaccharide Receptors genetics, Lipopolysaccharide Receptors immunology, Mice, Inbred C57BL, Mice, Knockout, Multiple Sclerosis genetics, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Myelin-Oligodendrocyte Glycoprotein administration & dosage, Peptide Fragments administration & dosage, Pregnancy Proteins immunology, Recombinant Proteins administration & dosage, Recombinant Proteins immunology, Toll-Like Receptor 4 deficiency, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 immunology, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental pathology, Gene Products, env administration & dosage, Immunity, Innate drug effects, Mice, Pregnancy Proteins administration & dosage
Abstract

Multiple sclerosis (MS) is a complex multifactorial disease of the central nervous system (CNS) for which animal models have mainly addressed downstream immunopathology but not potential inducers of autoimmunity. In the absence of a pathogen known to cause neuroinflammation in MS, Mycobacterial lysate is commonly used in the form of complete Freund's adjuvant to induce autoimmunity to myelin proteins in Experimental Allergic Encephalomyelitis (EAE), an animal model for MS. The present study demonstrates that a protein from the human endogenous retrovirus HERV-W family (MSRV-Env) can be used instead of mycobacterial lysate to induce autoimmunity and EAE in mice injected with MOG, with typical anti-myelin response and CNS lesions normally seen in this model. MSRV-Env was shown to induce proinflammatory response in human macrophage cells through TLR4 activation pathway. The present results demonstrate a similar activation of murine dendritic cells and show the ability of MSRV-Env to trigger EAE in mice. In previous studies, MSRV-Env protein was reproducibly detected in MS brain lesions within microglia and perivascular macrophages. The present results are therefore likely to provide a model for MS, in which the upstream adjuvant triggering neuroinflammation is the one detected in MS active lesions. This model now allows pre-clinical studies with therapeutic agents targeting this endogenous retroviral protein in MS.

Published
2013
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39. High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vgamma9Vdelta2 T-cell chemotaxis and cytotoxicity in vivo.

Author

Benzaïd I, Mönkkönen H, Stresing V, Bonnelye E, Green J, Mönkkönen J, Touraine JL, and Clézardin P

Subjects
Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate metabolism, Animals, Antigens, Neoplasm immunology, Breast Neoplasms metabolism, Cell Line, Tumor, Cytotoxicity, Immunologic, Female, Hemiterpenes metabolism, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Organophosphorus Compounds metabolism, Phosphorylation, T-Lymphocytes drug effects, Zoledronic Acid, Antigens, Neoplasm metabolism, Breast Neoplasms drug therapy, Breast Neoplasms immunology, Diphosphonates pharmacology, Imidazoles pharmacology, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocytes immunology
Abstract

The nitrogen-containing bisphosphonate zoledronic acid (ZOL), a potent inhibitor of farnesyl pyrophosphate synthase, blocks the mevalonate pathway, leading to intracellular accumulation of isopentenyl pyrophosphate/triphosphoric acid I-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (IPP/ApppI) mevalonate metabolites. IPP/ApppI accumulation in ZOL-treated cancer cells may be recognized by Vγ9Vδ2 T cells as tumor phosphoantigens in vitro. However, the significance of these findings in vivo remains largely unknown. In this study, we investigated the correlation between the anticancer activities of Vγ9Vδ2 T cells and the intracellular IPP/ApppI levels in ZOL-treated breast cancer cells in vitro and in vivo. We found marked differences in IPP/ApppI production among different human breast cancer cell lines post-ZOL treatment. Coculture with purified human Vγ9Vδ2 T cells led to IPP/ApppI-dependent near-complete killing of ZOL-treated breast cancer cells. In ZOL-treated mice bearing subcutaneous breast cancer xenografts, Vγ9Vδ2 T cells infiltrated and inhibited growth of tumors that produced high IPP/ApppI levels, but not those expressing low IPP/ApppI levels. Moreover, IPP/ApppI not only accumulated in cancer cells but it was also secreted, promoting Vγ9Vδ2 T-cell chemotaxis to the tumor. Without Vγ9Vδ2 T-cell expansion, ZOL did not inhibit tumor growth. These findings suggest that cancers-producing high IPP/ApppI levels after ZOL treatment are most likely to benefit from Vγ9Vδ2 T-cell-mediated immunotherapy., (©2011 AACR.)

Published
2011
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40. Transplantation tolerance induced in humans at the fetal or the neonatal stage.

Author

Touraine JL and Sanhadji K

Abstract

Patients transplanted with HLA-mismatched stem cells from fetal livers develop transplantation tolerance to donor antigens. Engraftment needs no conditioning regimen prior to transplantation in neonates with severe combined immunodeficiency disease or in human fetal patients having not yet developed any immune maturity, especially T-cell differentiation. The chimeric patients have donor-derived T lymphocytes which progressively demonstrate positive interactions with other host cells. They also can be shown to be tolerant toward both host and donor antigens. The latter tolerance relies upon clonal deletion from the T-cell repertoire, and it results from the contact between thymocytes of donor origin and dendritic cells or macrophages also deriving from donor stem cells. The former tolerance does not imply clonal deletion of T-cells with host reactivity. Numerous T-cells recognizing the allogeneic, host-type antigens are identified in these patients, but these cells are anergized, following interaction with epithelial cells of the host thymus. Induction of transplantation tolerance at the fetal stage requires minimal engraftment only; in the future it will be possible to further amplify the clinical benefit, using additional cell transplants after birth.

Published
2011
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41. HIV-1 infection: functional competition between gp41 and interleukin-2.

Author

Sanhadji K, Tardy JC, and Touraine JL

Subjects
AIDS Vaccines, Binding, Competitive physiology, CD4-Positive T-Lymphocytes metabolism, Cell Line, Cell Proliferation, Humans, Molecular Mimicry, Receptors, Interleukin-2 metabolism, HIV Envelope Protein gp41 metabolism, HIV Infections physiopathology, HIV-1, Interleukin-2 metabolism
Abstract

To determine whether the gp41 of HIV-1 could adhere to the interleukin (IL)-2 receptor at the surface of target cells in vitro, we analysed in vitro the possible functional competition between various forms of the HIV-1 gp41 molecule (i.e. peptides, trimeric or primary structures) and IL-2. This competition has been analysed in a test involving the proliferation of an IL-2-dependent cell line (CTLL2). The putative interaction between the IL-2 molecule and HIV-1 has also been assayed on MT4 cells (CD4(+) T lymphocytes) in culture. The gp41 trimeric molecule and an HIV-1 gp41 peptide (578-590 aminoacid sequence) dramatically inhibited CTLL2 cell proliferation, despite the presence of IL-2. The addition of serum, containing anti-gp41 antibodies, from HIV-1 patients resulted in a significant abolition of this inhibition. The concomitant incubation of IL-2 and HIV-1 with MT4 cells resulted in a strong decrease (70%) in HIV-1 p24 release. These data suggest that the gp41 of HIV-1 can use the IL-2 receptor during the process of HIV-1 infection and that there is some functional mimesis between gp41 and IL-2., (Copyright 2010 Académie des sciences. Published by Elsevier SAS. All rights reserved.)

Published
2010
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42. Telmisartan inhibits human urological cancer cell growth through early apoptosis.

Author

Matsuyama M, Funao K, Kuratsukuri K, Tanaka T, Kawahito Y, Sano H, Chargui J, Touraine JL, Yoshimura N, and Yoshimura R

Abstract

Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agents. In addition, studies have provided evidence that ARBs have the potential to inhibit the growth of several types of cancer cells. It was reported that telmisartan (a type of ARB) has peroxisome proliferator-activated receptor (PPAR)-γ activation activity. We previously reported that the PPAR-γ ligand induces growth arrest in human urological cancer cells through apoptosis. In this study, we evaluated the effects of telmisartan and other ARBs on cell proliferation in renal cell carcinoma (RCC), bladder cancer (BC), prostate cancer (PC) and testicular cancer (TC) cell lines. The inhibitory effects of telmisartan and other ARBs (candesartan, valsartan, irbesartan and losartan) on the growth of the RCC, BC, PC and TC cell lines was investigated using an MTT assay. Flow cytometry and Hoechst staining were used to determine whether the ARBs induced apoptosis. Telmisartan caused marked growth inhibition in the urological cancer cells in a dose- and time-dependent manner. Urological cancer cells treated with 100 μM telmisartan underwent early apoptosis and DNA fragmentation. However, the other ARBs had no effect on cell proliferation in any of the urological cancer cell lines. Telmisartan may mediate potent anti-proliferative effects in urological cancer cells through PPAR-γ. Thus, telmisartan is a potent target for the prevention and treatment of human urological cancer.

Published
2010
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43. Different mechanisms are involved in apoptosis induced by melanoma gangliosides on human monocyte-derived dendritic cells.

Author

Bennaceur K, Popa I, Chapman JA, Migdal C, Péguet-Navarro J, Touraine JL, and Portoukalian J

Subjects
Antigens, CD immunology, Caspase Inhibitors, Caspases biosynthesis, Ceramides metabolism, Cysteine Proteinase Inhibitors pharmacology, Dendritic Cells drug effects, Dendritic Cells enzymology, Enzyme Activation, G(M3) Ganglioside chemistry, G(M3) Ganglioside pharmacology, Gangliosides chemistry, Gangliosides pharmacology, Humans, Lactosylceramides immunology, Monocytes immunology, Oligopeptides pharmacology, Apoptosis immunology, Dendritic Cells immunology, G(M3) Ganglioside metabolism, Gangliosides metabolism, Melanoma immunology, Tumor Escape
Abstract

Tumor escape is linked to multiple mechanisms, notably the liberation, by tumor cells, of soluble factors that inhibit the function of dendritic cells (DC). We have shown that melanoma gangliosides impair DC differentiation and induce their apoptosis. The present study was aimed to give insight into the mechanisms involved. DC apoptosis was independent of the catabolism of gangliosides since lactosylceramide did not induce cell death. Apoptosis induced by GM3 and GD3 gangliosides was not blocked by inhibitors of de novo ceramide biosynthesis, whereas the acid sphingomyelinase inhibitor desipramine only prevented apoptosis induced by GM3. Furthermore, our results suggest that DC apoptosis was triggered via caspase activation, and it was ROS dependent with GD3 ganglioside, suggesting that GM3 and GD3 induced apoptosis through different mechanisms.

Published
2009
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44. The incidence of herpes zoster is less likely than other opportunistic infections to be reduced by highly active antiretroviral therapy.

Author

Vanhems P, Voisin L, Gayet-Ageron A, Trepo C, Cotte L, Peyramond D, Chidiac C, Touraine JL, Livrozet JM, Fabry J, and Voirin N

Subjects
AIDS-Related Opportunistic Infections epidemiology, Adult, Cohort Studies, Female, Follow-Up Studies, France epidemiology, HIV Infections drug therapy, HIV Infections immunology, HIV-1, Herpes Zoster epidemiology, Herpes Zoster prevention & control, Humans, Male, AIDS-Related Opportunistic Infections prevention & control, Antiretroviral Therapy, Highly Active, Herpes Zoster complications
Published
2005
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45. Molecular evidence of interhuman transmission of Pneumocystis pneumonia among renal transplant recipients hospitalized with HIV-infected patients.

Author

Rabodonirina M, Vanhems P, Couray-Targe S, Gillibert RP, Ganne C, Nizard N, Colin C, Fabry J, Touraine JL, van Melle G, Nahimana A, Francioli P, and Hauser PM

Subjects
Adult, Cluster Analysis, Female, France epidemiology, HIV Infections complications, Humans, Male, Middle Aged, Molecular Epidemiology, Mycological Typing Techniques, Pneumonia, Pneumocystis complications, Pneumonia, Pneumocystis epidemiology, Time Factors, Cross Infection epidemiology, Kidney Transplantation, Pneumocystis carinii, Pneumonia, Pneumocystis transmission
Abstract

Ten Pneumocystis jirovecii pneumonia (PCP) cases were diagnosed in renal transplant recipients (RTRs) during a 3-year period. Nosocomial transmission from HIV-positive patients with PCP was suspected because these patients shared the same hospital building, were not isolated, and were receiving suboptimal anti-PCP prophylaxis or none. P. jirovecii organisms were typed with the multitarget polymerase chain reaction-single-strand conformation polymorphism method. Among the 45 patients with PCP hospitalized during the 3-year period, 8 RTRs and 6 HIV-infected patients may have encountered at least 1 patient with active PCP within the 3 months before the diagnosis of their own PCP episode. In six instances (five RTRs, one HIV-infected patient), the patients harbored the same P. jirovecii molecular type as that found in the encountered PCP patients. The data suggest that part of the PCP cases observed in this building, particularly those observed in RTRs, were related to nosocomial interhuman transmission.

Published
2004
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46. The recent increase of syphilis cases in Lyon University hospitals Is mainly observed in HIV-infected patients: descriptive data from a laboratory-based surveillance system.

Author

Giard M, Queyron PC, Ritter J, Peyramond D, Trépo C, Miailhes P, Chidiac C, Touraine JL, Livrozet JM, Boibieux A, Fabry J, Allard R, and Vanhems P

Subjects
Adult, Aged, Aged, 80 and over, Female, France epidemiology, HIV Infections epidemiology, Humans, Male, Middle Aged, Syphilis epidemiology, HIV Infections complications, HIV-1, Syphilis complications, Treponema pallidum
Published
2003
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47. Gene therapy for human immunodeficiency virus infection in the humanized SCID mouse model.

Author

Touraine JL, Sanhadji K, and Sembeil R

Subjects
Animals, Disease Models, Animal, Genes, rev, Genes, tat, Humans, Interferons therapeutic use, Mice, Mice, SCID, RNA-Directed DNA Polymerase metabolism, Transformation, Genetic genetics, CD4 Immunoadhesins therapeutic use, Genetic Therapy methods, HIV Infections therapy, Interferons genetics
Abstract

Background: The humanized SCID mouse model is an attractive tool for testing gene therapy to combat human immunodeficiency virus infection in vivo., Objectives: To devise a more specific gene therapy directed against HIV, replacing the formerly used interferon with either soluble CD4 molecule immunoadhesin (sCD4-IgG) and/or anti-gp41 monoclonal antibody (2F5), or HIV-negative transdominants genes (Tat, Rev)., Methods: Human monocytoid cell line (U937) was transfected with IFN alpha, beta or gamma genes. 3T3 murine fibroblastic cell line was transfected with sCD4-IgG or 2F5, or both genes, and a human T4 cell line (CEM) was grafted to SCID mice. Negative transdominant genes (Tat, Rev or both) were also transduced in CEM T cell line. Animals were then challenged with HIV-1, Viral load was followed., Results: IFN alpha or beta were potent anti-HIV, reducing viral load in vivo and inhibiting reverse transcriptase activity in human-removed cells from animals. sCD4-IgG immunoadhesin and gp41 monoclonal antibody resulted in a dramatic reduction of HIV-1 cellular and plasmatic viral load in humanized SCID mice. The simultaneous introduction of negative Tat and Rev genes resulted in a synergistic inhibition of HIV-1 replication in vivo., Conclusions: Despite the marked reduction of HIV-1 propagation by IFN genes or by negative Tat and Rev transdominants, the gene therapy using soluble CD4 immunoadhesin or anti-gp41 was a more efficient preventive treatment against HIV infection.

Published
2003

48. Interstitial expression of alpha-SMA: an early marker of chronic renal allograft dysfunction.

Author

Badid C, Desmouliere A, Babici D, Hadj-Aissa A, McGregor B, Lefrancois N, Touraine JL, and Laville M

Subjects
Adolescent, Adult, Biomarkers analysis, Chronic Disease, Disease Progression, Female, Fibroblasts pathology, Fibrosis, Glomerular Filtration Rate, Humans, Kidney pathology, Kidney Diseases pathology, Kidney Glomerulus metabolism, Male, Middle Aged, Muscle, Smooth pathology, Actins metabolism, Kidney physiopathology, Kidney Diseases etiology, Kidney Diseases physiopathology, Kidney Transplantation adverse effects, Muscle, Smooth metabolism
Abstract

Background: Renal myofibroblast infiltration has been shown to be strongly associated with renal function decline in several chronic renal diseases. The purpose of the present study was to investigate whether early detection of myofibroblast infiltration using alpha-smooth-muscle actin (alpha-SMA) expression in time-zero biopsies predicts renal allograft dysfunction., Methods: We studied renal tissue from 38 renal transplant patients from whom biopsies had been taken after vascular anastomosis during transplantation to ascertain whether myofibroblasts infiltration predicts renal graft survival. Immunohistochemistry was performed on time-zero biopsies to determine alpha-SMA expression, and this was compared to annual glomerular filtration rate (GFR) variation and other parameters including cold ischaemic time (CIT), donor and recipient age, number of acute rejections, and delayed graft function (DGF). GFR was measured by inulin clearance during of 3 years of follow-up after the transplantation. Progressors were defined as patients with an annual GFR decline >5 ml/min/year., Results: We found a significant correlation between interstitial alpha-SMA expression in time-zero biopsies and GFR evolution during the post-transplantation course (r=0.60, P<0.001). Although progressors had greater interstitial alpha-SMA expression than non progressors (7.9+/-0.7 vs 4.3+/-0.4%), they showed only a tendency towards higher glomerular alpha-SMA expression. In addition, progressors had more interstitial fibrosis in time-zero biopsies than non-progressors. There was no relationship between alpha-SMA expression and CIT, donor and recipient ages, number of acute rejections, and occurrence of DGF., Conclusion: This study suggests that alpha-SMA evaluation in time-zero biopsies, especially the combination of alpha-SMA expression and interstitial fibrosis, can strongly predict chronic renal allograft dysfunctions.

Published
2002
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49. Clinical features of acute retroviral syndrome differ by route of infection but not by gender and age.

Author

Vanhems P, Routy JP, Hirschel B, Baratin D, Vora S, Maenza J, Carr A, Trépo C, Touraine JL, Gillibert RP, Collier AC, Cooper DA, Vizzard J, Sékaly RP, Fabry J, and Perrin L

Subjects
Acute Disease, Adolescent, Adult, Age Factors, Female, HIV Infections diagnosis, HIV Infections transmission, Humans, Male, Sex Factors, Sexual Behavior, Substance Abuse, Intravenous complications, Syndrome, HIV Infections etiology
Abstract

The rate of HIV disease progression is associated with the severity of the acute retroviral syndrome (ARS). We explored the clinical features of ARS by gender, age and route of infection among 378 individuals with documented ARS enrolled in 5 prospective cohort studies with similar enrollment criteria. No major differences were detected by gender or by age. Several symptoms were reported less frequently in the injecting drug users as compared with infection acquired through sexual contacts (either heterosexual or homosexual). This was observed in particular for fever (50% vs. 77%, p=.001), skin rash (21% vs. 51%, p=.001), pharyngitis (18% vs. 43%, p=.004), and myalgia (29% vs. 52%, p=.01). Genital ulcerations were present only in cases of sexual exposure to HIV. Injecting drug users had or reported symptoms associated with the ARS less frequently than persons acquiring HIV via sexual transmission.

Published
2002
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50. Hepatocyte growth factor (HGF) as a rapid diagnostic marker and its potential in the prevention of acute renal rejection.

Author

Yoshimura R, Watanabe Y, Kasai S, Wada S, Ohyama A, Hase T, Nakatani T, Chargui J, Touraine JL, and Nakamura T

Subjects
Acute Disease, Animals, Biomarkers analysis, Graft Rejection pathology, Immunosuppressive Agents therapeutic use, Kidney Transplantation pathology, Male, Rats, Rats, Inbred Lew, Rats, Wistar, Transplantation, Homologous immunology, Transplantation, Isogeneic immunology, Graft Rejection prevention & control, Hepatocyte Growth Factor analysis, Hepatocyte Growth Factor therapeutic use, Kidney Transplantation immunology
Abstract

Several investigators have reported that hepatocyte growth factor (HGF) may be related to the protection or reconstruction of the kidney during acute renal rejection. To address this question, we examined the relationship between HGF and acute rejection in the following two studies with rat renal transplantation models. In study 1, the relationship between serum HGF levels and acute renal rejection in iso-, allo- and allograft with cyclosporine (CsA)-treated models was examined. In study 2, the focus was whether or not the injection of recombinant HGF can prevent acute renal rejection. Our results demonstrated that HGF levels were rapidly increased during acute rejection and that recombinant HGF effectively protected the kidney from acute rejection. These results suggest that HGF may be induced as a counter-response to the renal injury and that it can be used as a reliable indicator for the diagnosis of acute rejection. We suggest that recombinant HGF suppresses the onset of the pathological changes of acute rejection.

Published
2002
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