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396 results on '"Roncarolo, M"'

1. Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes

Author

Haller, Michael J, Schatz, Desmond A, Skyler, Jay S, Krischer, Jeffrey P, Bundy, Brian N, Miller, Jessica L, Atkinson, Mark A, Becker, Dorothy J, Baidal, David, DiMeglio, Linda A, Gitelman, Stephen E, Goland, Robin, Gottlieb, Peter A, Herold, Kevan C, Marks, Jennifer B, Moran, Antoinette, Rodriguez, Henry, Russell, William, Wilson, Darrell M, Greenbaum, Carla J, Greenbaum, C, Atkinson, M, Baidal, D, Battaglia, M, Becker, D, Bingley, P, Bosi, E, Buckner, J, Clements, M, Colman, P, DiMeglio, L, Evans-Molina, C, Gitelman, S, Goland, R, Gottlieb, P, Herold, K, Knip, M, Krischer, J, Lernmark, A, Moore, W, Moran, A, Muir, A, Palmer, J, Peakman, M, Philipson, L, Raskin, P, Redondo, M, Rodriguez, H, Russell, W, Spain, L, Schatz, DA, Sosenko, J, Wherrett, D, Wilson, D, Winter, W, Ziegler, A, Anderson, M, Antinozzi, P, Benoist, C, Blum, J, Bourcier, K, Chase, P, Clare-Salzler, M, Clynes, R, Cowie, C, Eisenbarth, G, Fathman, CG, Grave, G, Harrison, L, Hering, B, Insel, R, Jordan, S, Kaufman, F, Kay, T, Kenyon, N, Klines, R, Lachin, J, Leschek, E, Mahon, J, Marks, JB, Monzavi, R, Nanto-Salonen, K, Nepom, G, Orban, T, Parkman, R, Pescovitz, M, Peyman, J, Pugliese, A, Ridge, J, Roep, B, Roncarolo, M, Savage, P, Simell, O, Sherwin, R, Siegelman, M, Skyler, JS, Steck, A, Thomas, J, Trucco, M, and Wagner, J

Subjects
Pediatric, Diabetes, Clinical Trials and Supportive Activities, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Metabolic and endocrine, Adolescent, Adult, Antilymphocyte Serum, C-Peptide, Child, Cytoprotection, Diabetes Mellitus, Type 1, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Glycated Hemoglobin, Granulocyte Colony-Stimulating Factor, Humans, Insulin-Secreting Cells, Male, Pilot Projects, Polyethylene Glycols, Recombinant Proteins, Young Adult, Type 1 Diabetes TrialNet ATG-GCSF Study Group
Abstract

ObjectiveA pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that 1) low-dose ATG/GCSF or 2) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration

Published
2018

2. Hematopoietic Stem/Progenitor Cells and Engineering: T-ALLO10 INFUSION AFTER AβDEPLETED-HSCT IN CHILDREN AND YOUNG ADULTS WITH HEMATOLOGIC MALIGNANCIES: IMPROVED IMMUNE RECONSTITUTION IN THE ABSENCE OF SEVERE GVHD

Author

Bertaina, A., primary, Bacchetta, R., additional, Shyr, D.C., additional, Saini, G., additional, Lee, J., additional, Kristovich, K., additional, Agarwal, R., additional, Klein, O., additional, Melsop, K., additional, Tate, K., additional, Barbarito, G., additional, Oppizzi, L., additional, Chen, P., additional, Cepika, A., additional, and Roncarolo, M., additional

Published
2023
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4. Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors

Author

Peccatori, J, Forcina, A, Clerici, D, Crocchiolo, R, Vago, L, Stanghellini, M T L, Noviello, M, Messina, C, Crotta, A, Assanelli, A, Marktel, S, Olek, S, Mastaglio, S, Giglio, F, Crucitti, L, Lorusso, A, Guggiari, E, Lunghi, F, Carrabba, M, Tassara, M, Battaglia, M, Ferraro, A, Carbone, M R, Oliveira, G, Roncarolo, M G, Rossini, S, Bernardi, M, Corti, C, Marcatti, M, Patriarca, F, Zecca, M, Locatelli, F, Bordignon, C, Fleischhauer, K, Bondanza, A, Bonini, C, and Ciceri, F

Published
2015
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5. Gene Editing/Gene Therapies: BENCH TO BEDSIDE: ENGINEERED AUTOLOGOUS CD4LVFOXP3 TREG-LIKE CELL PRODUCT FOR PHASE 1 STUDY IN PATIENTS WITH IPEX SYNDROME

Author

Nathan, A., primary, Sato, Y., additional, Tate, K., additional, wani, P., additional, Terry, C., additional, Fazeli, F., additional, Bouge, A., additional, Goodwin, E., additional, Wright, J., additional, Bertaina, A., additional, Klein, O., additional, Agarwal, R., additional, Roncarolo, M., additional, and Bacchetta, R., additional

Published
2022
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12. Sequential hematopoietic stem cell and kidney transplantation in schimke immuno-osseous dysplasia: towards a model for establishing functional immune tolerance for solid organ transplantation

Author

Bertaina, A., primary, Grimm, P., additional, Kristovich, K., additional, Barbarito, G., additional, Lippner, E., additional, Fathallah-Shaykh, S., additional, Al-Uzri, A., additional, van der Elst, K., additional, Agarwal, R., additional, Selpicka, P., additional, Shah, A., additional, Weinberg, K., additional, Parkman, R., additional, Roncarolo, M., additional, Gallo, A., additional, Conception, W., additional, and Lewis, D., additional

Published
2021
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17. Genotypes and haplotypes in the 3′ untranslated region of the HLA-G gene and their association with clinical outcome of hematopoietic stem cell transplantation for beta-thalassemia

Author

Sizzano, F., Testi, M., Zito, L., Crocchiolo, R., Troiano, M., Mazzi, B., Turchiano, G., Torchio, M., Pultrone, C., Gregori, S., Chiesa, R., Gaziev, J., Sodani, P., Marktel, S., Amoroso, A., Roncarolo, M. G., Lucarelli, G., Ciceri, F., Andreani, M., and Fleischhauer, K.

Published
2012
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23. CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells

Author

Goodwin, M., primary, Lee, E., additional, Lakshmanan, U., additional, Shipp, S., additional, Froessl, L., additional, Barzaghi, F., additional, Passerini, L., additional, Narula, M., additional, Sheikali, A., additional, Lee, C. M., additional, Bao, G., additional, Bauer, C. S., additional, Miller, H. K., additional, Garcia-Lloret, M., additional, Butte, M. J., additional, Bertaina, A., additional, Shah, A., additional, Pavel-Dinu, M., additional, Hendel, A., additional, Porteus, M., additional, Roncarolo, M. G., additional, and Bacchetta, R., additional

Published
2020
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26. Identical and Nonidentical Twins: Risk and Factors Involved in Development of Islet Autoimmunity and Type 1 Diabetes

Author

Triolo, T.M., Fouts, A., Pyle, L., Yu, L., Gottlieb, P.A., Steck, A.K., Greenbaum, C.J., Atkinson, M., Baidal, D., Battaglia, M., Becker, D., Bingley, P., Bosi, E., Buckner, J., Clements, M., Colman, P., DiMeglio, L., Gitelman, S., Goland, R., Gottlieb, P., Herold, K., Knip, M., Krischer, J., Lernmark, A., Moore, W., Moran, A., Muir, A., Palmer, J., Peakman, M., Philipson, L., Raskin, P., Redondo, M., Rodriguez, H., Russell, W., Spain, L., Schatz, D.A., Sosenko, J., Wentworth, J., Wherrett, D., Wilson, D., Winter, W., Ziegler, A., Anderson, M., Antinozzi, P., Benoist, C., Blum, J., Bourcier, K., Chase, P., Clare-Salzler, M., Clynes, R., Eisenbarth, G., Fathman, C.G., Grave, G., Hering, B., Insel, R., Kaufman, F., Kay, T., Leschek, E., Mahon, J., Marks, J.B., Nanto-Salonen, K., Nepom, G., Orban, T., Parkman, R., Pescovitz, M., Peyman, J., Pugliese, A., Roep, B., Roncarolo, M., Savage, P., Simell, O., Sherwin, R., Siegelman, M., Skyler, J.S., Steck, A., Thomas, J., Trucco, M., Wagner, J., Krischer, J.P., Rafkin, L., Cowie, C., Foulkes, M., Krause-Steinrauf, H., Lachin, J.M., Malozowski, S., Ridge, J., Zafonte, S.J., Sosenko, J.M., Kenyon, N.S., Santiago, I., Bundy, B., Abbondondolo, M., Adams, T., Amado, D., Asif, I., Boonstra, M., Burroughs, C., Cuthbertson, D., Deemer, M., Eberhard, C., Fiske, S., Ford, J., Garmeson, J., Guillette, H., Geyer, S., Hays, B., Henderson, C., Henry, M., Heyman, K., Hsiao, B., Karges, C., Keaton, N., Kinderman, A., Law, P., Leinbach, A., Liu, S., Lloyd, J., Malloy, J., Maddox, K., Martin, J., Miller, J., Milliot, E., Moore, M., Muller, S., Nguyen, T., O'Donnell, R., Roberts, A., Sadler, K., Stavros, T., Tamura, R., Wood, K., Xu, P., Young, K., Alies, P., Badias, F., Baker, A., Bassi, M., Beam, C., Boulware, D., Bounmananh, L., Bream, S., Freeman, D., Gough, J., Ginem, J., Granger, M., Kieffer, M.H.M., Lane, P., Linton, C., Nallamshetty, L., Oduah, V., Parrimon, Y., Paulus, K., Pilger, J., Ramiro, J., Ritzie, A.L., Sharma, A., Shor, A., Song, X., Terry, A., Weinberger, J., Wootten, M., Harding, P., McDonough, S., Mcgee, P.F., Hess, K.O., Phoebus, D., Quinlan, S., Raiden, E., Batts, E., Buddy, C., Kirpatrick, K., Ramey, M., Shultz, A., Webb, C., Romesco, M., Fradkin, J., Aas, S., Blumberg, E., Beck, G., Brillon, D., Gubitosi-Klug, R., Laffel, L., Vigersky, R., Wallace, D., Braun, J., B. lo, Mitchell, H., Naji, A., Nerup, J., Orchard, T., Steffes, M., Tsiatis, A., Veatch, R., Zinman, B., Loechelt, B., Baden, L., Green, M., Weinberg, A., Marcovina, S., Palmer, J.P., Babu, S., Eisenbarth, G.S., Marks, J., Matheson, D., Gomez, D., McDonald, A., Pena, S., Pietropaolo, M., Shippy, K., Brown, T., Dove, A., Hammond, M., Hefty, D., Klein, J., Kuhns, K., Letlau, M., Lord, S., McCulloch-Olson, M., Miller, L., Odegard, J., Sachter, E., St Marie, M., Stickney, K., VanBuecken, D., Vellek, B., Webber, C., Allen, L., Bollyk, J., Hilderman, N., Ismail, H., Lamola, S., Sanda, S., Vendettuoli, H., Tridgell, D., Monzavi, R., Bock, M., Fisher, L., Halvorson, M., Jeandron, D., Kim, M., Wood, J., Geffner, M., Salazar, C., Cook, S., Freeby, M., Gallagher, M.P., Gandica, R., Greenberg, E., Kurland, A., Pollak, S., Wolk, A., Chan, M., Koplimae, L., Levine, E., Smith, K., Trast, J., Evans-Molina, C., Hufferd, R., Jagielo, B., Kruse, C., Patrick, V., Rigby, M., Spall, M., Swinney, K., Terrell, J., Christner, L., Ford, L., Lynch, S., Menendez, M., Merrill, P., and Pesc

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Concordance, Twins, Autoimmunity, 030209 endocrinology & metabolism, Type 2 diabetes, Environment, medicine.disease_cause, Islets of Langerhans, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Seroepidemiologic Studies, Diabetes mellitus, Internal medicine, Diseases in Twins, Twins, Dizygotic, Internal Medicine, medicine, Genetic predisposition, Humans, Insulin, Mass Screening, Genetic Predisposition to Disease, 030212 general & internal medicine, Child, Mass screening, Autoantibodies, Advanced and Specialized Nursing, Type 1 diabetes, Glutamate Decarboxylase, business.industry, Siblings, Autoantibody, Twins, Monozygotic, Predicting Diabetes Using Genetic Risk Scores, medicine.disease, Diabetes Mellitus, Type 1, Endocrinology, Child, Preschool, Disease Progression, Female, business
Abstract

OBJECTIVE There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody–positive, 13% for single autoantibody–positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody–positive, 12% for single autoantibody–positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody–positive identical twins and multiple autoantibody–positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.

Published
2019

32. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study

Author

Ferrua, F, Cicalese, M, Galimberti, S, Giannelli, S, Dionisio, F, Barzaghi, F, Migliavacca, M, Bernardo, M, Calbi, V, Assanelli, A, Facchini, M, Fossati, C, Albertazzi, E, Scaramuzza, S, Brigida, I, Scala, S, Basso-Ricci, L, Pajno, R, Casiraghi, M, Canarutto, D, Salerio, F, Albert, M, Bartoli, A, Wolf, H, Fiori, R, Silvani, P, Gattillo, S, Villa, A, Biasco, L, Dott, C, Culme-Seymour, E, van Rossem, K, Atkinson, G, Valsecchi, M, Roncarolo, M, Ciceri, F, Naldini, L, Aiuti, A, Cicalese, MP, Bernardo, ME, Assanelli, AA, Albert, MH, Wolf, HM, Fiori, Rossan, Culme-Seymour, EJ, Valsecchi, MG, Roncarolo, MG, Ferrua, F, Cicalese, M, Galimberti, S, Giannelli, S, Dionisio, F, Barzaghi, F, Migliavacca, M, Bernardo, M, Calbi, V, Assanelli, A, Facchini, M, Fossati, C, Albertazzi, E, Scaramuzza, S, Brigida, I, Scala, S, Basso-Ricci, L, Pajno, R, Casiraghi, M, Canarutto, D, Salerio, F, Albert, M, Bartoli, A, Wolf, H, Fiori, R, Silvani, P, Gattillo, S, Villa, A, Biasco, L, Dott, C, Culme-Seymour, E, van Rossem, K, Atkinson, G, Valsecchi, M, Roncarolo, M, Ciceri, F, Naldini, L, Aiuti, A, Cicalese, MP, Bernardo, ME, Assanelli, AA, Albert, MH, Wolf, HM, Fiori, Rossan, Culme-Seymour, EJ, Valsecchi, MG, and Roncarolo, MG

Abstract

Background: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC)gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. Methods: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP)expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462)and EudraCT (number 2009-017346-32). Findings: Between April 20, 2010, and Feb 26, 201

Published
2019

34. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variants RNAs

Author

Hannum, C., Culpepper, J., Campbell, D., McClanahan, T., Zurawski, S., Bazan, J.F., Kastelein, R., Hudak, S., Wagner, J., Mattson, J., Luh, J., Duda, G., Martina, N., Peterson, D., Menon, S., Shanafelt, A., Muench, M., Kelner, G., Namikawa, R., Rennick, D., Roncarolo, M.-G., Zoltnik, A., Rosnet, O., Dubreuil, P., and Birnbaum, D.

Subjects
Ligands (Biochemistry) -- Analysis, Macrophage colony stimulating factor -- Physiological aspects, Interleukins -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Isolation and sequencing studies on soluble FLT3/FLK2 ligands obtained from mouse thymic stromal cells reveal that the purified ligand increases the mouse stem cells and human progenitor cell population to growth factors including interleukins 3 and 6. The response to granulocyte-macrophage colony-stimulating factor and fetal thymocyte activity are enhanced.

Published
1994

38. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Author

Barzaghi, F., Amaya Hernandez, L. C., Neven, B., Ricci, S., Kucuk, Z. Y., Bleesing, J. J., Nademi, Z., Slatter, M. A., Ulloa, E. R., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, J. F., Baris, S., Ozen, A., Karakoc-Aydiner, E., Kiykim, A., Schulz, A., Steinmann, S., Notarangelo, L. D., Gambineri, E., Lionetti, P., Shearer, W. T., Forbes, L. R., Martinez, C., Moshous, D., Blanche, S., Fisher, A., Ruemmele, F. M., Tissandier, C., Ouachee-Chardin, M., Rieux-Laucat, F., Cavazzana, M., Qasim, W., Lucarelli, B., Albert, M. H., Kobayashi, I., Alonso, L., Diaz De Heredia, C., Kanegane, H., Lawitschka, A., Seo, J. J., Gonzalez-Vicent, M., Diaz, M. A., Goyal, R. K., Sauer, M. G., Yesilipek, A., Kim, M., Yilmaz-Demirdag, Y., Bhatia, M., Khlevner, J., Richmond Padilla, E. J., Martino, S., Montin, D., Neth, O., Molinos-Quintana, A., Valverde-Fernandez, J., Broides, A., Pinsk, V., Ballauf, A., Haerynck, F., Bordon, V., Dhooge, C., Garcia-Lloret, M. L., Bredius, R. G., Kalwak, K., Haddad, E., Seidel, M. G., Duckers, G., Pai, S. -Y., Dvorak, C. C., Ehl, S., Locatelli, Franco, Goldman, F., Gennery, A. R., Cowan, M. J., Roncarolo, M. -G., Bacchetta, R., Locatelli F. (ORCID:0000-0002-7976-3654), Barzaghi, F., Amaya Hernandez, L. C., Neven, B., Ricci, S., Kucuk, Z. Y., Bleesing, J. J., Nademi, Z., Slatter, M. A., Ulloa, E. R., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, J. F., Baris, S., Ozen, A., Karakoc-Aydiner, E., Kiykim, A., Schulz, A., Steinmann, S., Notarangelo, L. D., Gambineri, E., Lionetti, P., Shearer, W. T., Forbes, L. R., Martinez, C., Moshous, D., Blanche, S., Fisher, A., Ruemmele, F. M., Tissandier, C., Ouachee-Chardin, M., Rieux-Laucat, F., Cavazzana, M., Qasim, W., Lucarelli, B., Albert, M. H., Kobayashi, I., Alonso, L., Diaz De Heredia, C., Kanegane, H., Lawitschka, A., Seo, J. J., Gonzalez-Vicent, M., Diaz, M. A., Goyal, R. K., Sauer, M. G., Yesilipek, A., Kim, M., Yilmaz-Demirdag, Y., Bhatia, M., Khlevner, J., Richmond Padilla, E. J., Martino, S., Montin, D., Neth, O., Molinos-Quintana, A., Valverde-Fernandez, J., Broides, A., Pinsk, V., Ballauf, A., Haerynck, F., Bordon, V., Dhooge, C., Garcia-Lloret, M. L., Bredius, R. G., Kalwak, K., Haddad, E., Seidel, M. G., Duckers, G., Pai, S. -Y., Dvorak, C. C., Ehl, S., Locatelli, Franco, Goldman, F., Gennery, A. R., Cowan, M. J., Roncarolo, M. -G., Bacchetta, R., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P =.035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Published
2018

39. Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes A Randomized Clinical Trial

Author

Greenbaum, C., Atkinson, M., Baidal, D., Battaglia, M., Bingley, P., Bosi, E., Buckner, J., Clements, M., Colman, P., DiMeglio, L., Evans-Molina, C., Gitelman, S., Goland, R., Gottlieb, P., Herold, K., Knip, M., Krischer, J., Lernmark, A., Moore, W., Moran, A., Muir, A., Palmer, J., Peakman, M., Philipson, L., Raskin, P., Redondo, M., Rodriguez, H., Russell, W., Spain, L., Schatz, D.A., Sosenko, J., Wherrett, D., Wilson, D., Winter, W., Ziegler, A., Anderson, M., Antinozzi, P., Benoist, C., Blum, J., Bourcier, K., Chase, P., Clare-Salzler, M., Clynes, R., Cowie, C., Eisenbarth, G., Fathman, C.G., Grave, G., Harrison, L., Hering, B., Insel, R., Jordan, S., Kaufman, F., Kay, T., Kenyon, N., Klines, R., Lachin, J., Leschek, E., Mahon, J., Marks, J.B., Monzavi, R., Nanto-Salonen, K., Nepom, G., Orban, T., Parkman, R., Pescovitz, M., Peyman, J., Pugliese, A., Ridge, J., Roep, B., Roncarolo, M., Savage, P., Simell, O., Sherwin, R., Siegelman, M., Skyler, J.S., Thomas, J., Trucco, M., Wagner, J., Greenbaum, C.J., Krischer, J.P., Rafkin, L., Foulkes, M., Krause-Steinrauf, H., Lachin, J.M., Malozowski, S., Zafonte, S.J., Kenyon, N.S., Santiago, I., Bundy, B., Abbondondolo, M., Adams, T., Asif, D.A.I., Boonstra, M., Boulware, D., Burroughs, C., Cuthbertson, D., Eberhard, C., Fiske, S., Ford, J., Garmeson, J., Guillette, H., Geyer, S., Hays, B., Henderson, C., Henry, M., Heyman, K., Hsiao, B., Karges, C., Kinderman, A., Lane, L., Leinbach, A., Liu, S., Lloyd, J., Malloy, J., Maddox, K., Martin, J., Miller, J., Moore, M., Muller, S., Nguyen, T., O'Donnell, R., Parker, M., Pereyra, M.J., Reed, N., Roberts, A., Sadler, K., Stavros, T., Tamura, R., Wood, K., Xu, P., Young, K., Alies, P., Badias, F., Baker, A., Bassi, M., Beam, C., Bounmananh, L., Bream, S., Deemer, M., Freeman, D., Gough, J., Ginem, J., Granger, M., Holloway, M., Kieffer, M., Lane, P., Law, P., Linton, C., Nallamshetty, L., Oduah, V., Parrimon, Y., Paulus, K., Pilger, J., Ramiro, J., Ritzie, A.Q.L., Sharma, A., Shor, A., Song, X.H., Terry, A., Weinberger, J., Wootten, M., Harding, M.F.P., McDonough, S., Mcgee, P.F., Hess, K.O., Phoebus, D., Quinlan, S., Raiden, E., Fradkin, J., Beck, G., Blumberg, E., Gubitosi-Klug, R., Laffel, L., Veatch, R., Wallace, D., Braun, J., Brillon, D., B. lo, Mitchell, H., Naji, A., Nerup, J., Orchard, T., Steffes, M., Tsiatis, A., Zinman, B., Loechelt, B., Baden, L., Green, M., Weinberg, A., Marcovina, S., Palmer, J.P., Yu, L.P., Shultz, A., Batts, E., Fitzpatrick, K., Ramey, M., Guerra, R., Webb, C., Caffey, F., Carr, L., Ergun-Longmire, B., Fenton, C., Giebner, D., Johnson, J., Maglionico, D., Marinelli, M., Martin, K., Minnozzi, E., Riley, W., Wilson, M., Gougeon, C., Ho, J., Huang, C., Pacaud, D., Virtanen, H., Craig, C., Ghatak, A., Henderson, T., Leyland, H., Padmore, K., Paul, P., Brickman, W., Halsey-Lyda, M., Petrie, P., Rizzo, D., Steuer, R., Suchyta, K., Torchen, L., Zimmerman, D., Bode, B., Dial, M., Gazaway, K., Hosey, R., Alkanani, A., Barker, J., Barr, M., Blau, A., Burdick, P., Burke, B., Chase, H., Drye, M., Escobar, E., Fitzgerald-Miller, L., Fouts, A., Gage, V., Gall, E., Goettle, H., Harris, S., Ketchum, K., King, M., Klingensmith, G., Lehr, D., Lehr, J., Lewis, L., Logsden-Sackett, N., Lykens, J., Maahs, D., Michels, A., Pelletier, S., Rihanek, M., Rodriguez, P., Schauwecker, A., Simmons, K., Smith, J., Steck, A., Tran, B., Tran, T., Wadwa, P., Wagner, R., Wright, H., Betancourt, J., Bui, V., DeSalvo, D., Gomez, D., Jake, K., Lynds, J., McCartney, T., McDonald, A., Pena, S., Pietropaolo, M., Greenbaum, C., Atkinson, M., Baidal, D., Battaglia, M., Becker, D., Bingley, P., Bosi, E., Buckner, J., Clements, M., Colman, P., Dimeglio, L., Evans-Molina, C., Gitelman, S., Goland, R., Gottlieb, P., Herold, K., Knip, M., Krischer, J., Lernmark, A., Moore, W., Moran, A., Muir, A., Palmer, J., Peakman, M., Philipson, L., Raskin, P., Redondo, M., Rodriguez, H., Russell, W., Spain, L., Schatz, D. A., Sosenko, J., Wherrett, D., Wilson, D., Winter, W., and Ziegler, A.

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Administration, Oral, 030209 endocrinology & metabolism, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Interquartile range, law, Internal medicine, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, Insulin, Family, Treatment Failure, Child, Original Investigation, Autoantibodies, Type 1 diabetes, Glucose tolerance test, medicine.diagnostic_test, business.industry, General Medicine, ta3121, Glucose Tolerance Test, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 1, Child, Preschool, Cohort, Female, business, Follow-Up Studies
Abstract

Importance Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect. Objective To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes. Design, Setting, and Participants Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016. Interventions Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186). Main Outcome and Measures The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported. Results Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0-1.2;P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82;P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95% CI, 0-2.11;P = .53) and for the entire cohort of 560 participants was 0.83 (95% CI, 0-1.07;P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred. Conclusions and Relevance Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention. Trial Registration clinicaltrials.gov Identifier:NCT00419562

Published
2017

41. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells

Author

Gagliani, N, Magnani, C, Huber, S, Gianolini, M, Pala, M, Licona Limon, P, Guo, B, Herbert, D, Bulfone, A, Trentini, F, Di Serio, C, Bacchetta, R, Andreani, M, Brockmann, L, Gregori, S, Flavell, R, Roncarolo, M, Roncarolo, M., MAGNANI, CHIARA FRANCESCA, Gagliani, N, Magnani, C, Huber, S, Gianolini, M, Pala, M, Licona Limon, P, Guo, B, Herbert, D, Bulfone, A, Trentini, F, Di Serio, C, Bacchetta, R, Andreani, M, Brockmann, L, Gregori, S, Flavell, R, Roncarolo, M, Roncarolo, M., and MAGNANI, CHIARA FRANCESCA

Abstract

CD4+ type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases. © 2013 Nature America, Inc. All rights reserved

Published
2013

43. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway

Author

Gregori, S, Tomasoni, D, Pacciani, V, Scirpoli, M, Battaglia, M, Magnani, C, Hauben, E, Roncarolo, M, Roncarolo, M., MAGNANI, CHIARA FRANCESCA, Gregori, S, Tomasoni, D, Pacciani, V, Scirpoli, M, Battaglia, M, Magnani, C, Hauben, E, Roncarolo, M, Roncarolo, M., and MAGNANI, CHIARA FRANCESCA

Abstract

Type 1 T regulatory (Tr1) cells suppress immune responses in vivo and in vitro and play a key role in maintaining tolerance to self- and non-self-antigens. Interleukin-10 (IL-10) is the crucial driving factor for Tr1 cell differentiation, but the molecular mechanisms underlying this induction remain unknown. We identified and characterized a subset of IL-10-producing human dendritic cells (DCs), termed DC-10, which are present in vivo and can be induced in vitro in the presence of IL-10. DC-10 are CD14+, CD16 +, CD11c+, CD11b+, HLA-DR+, CD83+, CD1a-, CD1c-, express the Ig-like transcripts (ILTs) ILT2, ILT3, ILT4, and HLA-G antigen, display high levels of CD40 and CD86, and up-regulate CD80 after differentiation in vitro. DC-10 isolated from peripheral blood or generated in vitro are potent inducers of antigen-specific IL-10-producing Tr1 cells. Induction of Tr1 cells by DC-10 is IL-10-dependent and requires the ILT4/HLA-G signaling pathway. Our data indicate that DC-10 represents a novel subset of tolerogenic DCs, which secrete high levels of IL-10, express ILT4 and HLA-G, and have the specific function to induce Tr1 cells. © 2010 by The American Society of Hematology

Published
2010

44. Role of human leukocyte antigen-G in the induction of adaptive type 1 regulatory T cells

Author

Gregori, S, Magnani, C, Roncarolo, M, Roncarolo, M., MAGNANI, CHIARA FRANCESCA, Gregori, S, Magnani, C, Roncarolo, M, Roncarolo, M., and MAGNANI, CHIARA FRANCESCA

Abstract

Adaptive type 1 regulatory T (Tr1) cells are suppressor cells characterized by the production of interleukin (IL)-10 in the absence of IL-4. IL-10 is essential not only for suppression of effector cells by Tr1 cells, but also for their differentiation in vitro and in vivo. However, little is known on the molecular mechanisms underneath the IL-10-mediated induction of Tr1 cells. Human Leukocyte Antigen (HLA)-G, a non-classical HLA class I molecule, has both direct inhibitory effects on natural killer cells, dendritic cells (DC), and T cells and long-term tolerogenic indirect effects by inducing regulatory T (Tr) cells. In the present review, we discuss current findings on Tr-cell induction by the different isoforms of HLA-G, focusing on the relationship among HLA-G, its ligands, and IL-10. We recently described a subset of human DC, termed DC-10, that express high levels of HLA-G and ILT4, secrete high amounts of IL-10, and induce allospecific Tr1 cells in vitro via an IL-10-dependent ILT4/HLA-G pathway. IL-10, HLA-G, and ILT4 may also be involved in Tr1-cell induction in vivo. Overall, these data demonstrate that cross-regulation between IL-10 and HLA-G may be instrumental for Tr1-cell induction and tolerance. © 2009 American Society for Histocompatibility and Immunogenetics

Published
2009

46. Clinical features and follow-up in patients with 22q11.2 deletion syndrome

Author

Cancrini, C, Puliafito, P, Digilio, M, Soresina, A, Martino, S, Rondelli, R, Consolini, R, Ruga, E, Cardinale, F, Finocchi, A, Romiti, Ml, Martire, B, Bacchetta, R, Albano, V, Carotti, A, Specchia, F, Montin, D, Cirillo, E, Cocchi, G, Trizzino, A, Bossi, G, Milanesi, O, Azzari, C, Corsello, G, Pignata, C, Aiuti, A, Pietrogrande, M, Marino, B, Ugazio, A, Plebani, A, Rossi, P, Pierani, P, Gabrielli, A, Danieli, M, De Mattia, D, Sisto, C, Dammacco, F, Ranieri, G, Pession, A, Ricci, G, Minelli, P, Lougaris, V, Badolato, R, Cattaneo, R, Airò, P, Mura, R, Cossu, F, Del Giacco, S, Manconi, P, Consarino, C, Dello Russo, A, Miniero, R, Anastasio, E, Marino, S, Russo, G, Paganelli, R, Sperlì, D, Carpino, L, Aricò, M, Gambineri, E, Lippi, F, Canessa, C, Maggi, E, Romagnani, S, Matucci, A, Vultaggio, A, Gattorno, M, Castagnola, E, Nigro, G, Presta, G, Civino, A, Buzi, F, Gambaretto, G, Fasoli, S, Salpietro, C, Gallizzi, R, Dellepiane, R, Panisi, C, Fabio, G, Carrabba, M, Roncarolo, M, Biondi, A, Vallinoto, C, Poggi, V, Menna, G, Di Nardo, R, Sottile, R, Marone, G, Spadaro, G, Carli, M, Basso, G, Putti, C, Semenzato, G, Agostini, C, D'Angelo, P, Izzi, G, Bertolini, P, Zecca, M, Marseglia, G, Maccario, R, Felici, L, Favre, C, Vecchi, V, Sacchini, P, Rinaldi, G, Livadiotti, S, Simonetti, A, Stabile, A, Duse, M, Iacobini, M, Quinti, I, Fiorilli, M, Moschese, V, Cecere, F, D'Ambrosio, A, De Zan, G, Strafella, S, Tamaro, P, Rabusin, M, Tommasini, A, Tovo, P, De Carli, M, De Carli, S, Nespoli, L, Marinoni, M, Porcellini, A, Lunardi, C, Patuzzo, G, Boner, A, Degani, D, Cancrini, C, Puliafito, P, Digilio, Mc, Soresina, A, Martino, S, Rondelli, R, Consolini, R, Ruga, Em, Cardinale, F, Finocchi, A, Romiti, Ml, Martire, B, Bacchetta, R, Albano, V, Carotti, A, Specchia, F, Montin, D, Cirillo, E, Cocchi, G, Trizzino, A, Bossi, G, Milanesi, O, Azzari, C, Corsello, G, Pignata, C, Aiuti, Alessandro, Pietrogrande, Mc, Marino, B, Ugazio, Ag, Plebani, A, Rossi, P., Cancrini, Caterina, Puliafito, Pamela, Digilio, Maria Cristina, Soresina, Annarosa, Martino, Silvana, Rondelli, Roberto, Consolini, Rita, Ruga, Ezia Maria, Cardinale, Fabio, Finocchi, Andrea, Romiti, Maria Luisa, Martire, Baldassarre, Bacchetta, Rosa, Albano, Veronica, Carotti, Adriano, Specchia, Fernando, Montin, Davide, Cirillo, Emilia, Cocchi, Guido, Trizzino, Antonino, Bossi, Grazia, Milanesi, Ornella, Azzari, Chiara, Corsello, Giovanni, Pignata, Claudio, Pietrogrande, Maria Cristina, Marino, Bruno, Ugazio, Alberto Giovanni, Plebani, Alessandro, Rossi, Paolo, Aiuti, A, Rossi, P, Pierani, P, Gabrielli, A, Danieli, Mg, De Mattia, D, Sisto, C, Dammacco, F, Ranieri, G, Pession, A, Ricci, G, Minelli, P, Lougaris, V, Badolato, R, Cattaneo, R, Airò, P, Mura, Rm, Cossu, F, Del Giacco, S, Manconi, Pe, Consarino, C, Dello Russo, Am, Miniero, R, Anastasio, E, Marino, S, Russo, G, Paganelli, R, Sperlì, D, Carpino, L, Aricò, M, Gambineri, E, Lippi, F, Canessa, C, Maggi, E, Romagnani, S, Matucci, A, Vultaggio, A, Gattorno, M, Castagnola, E, Nigro, G, Presta, G, Civino, A, Buzi, F, Gambaretto, G, Fasoli, S, Salpietro, C, Gallizzi, R, Dellepiane, Rm, Panisi, C, Fabio, G, Carrabba, M, Pietrogrande, M, Roncarolo, Mg, Biondi, A, Vallinoto, C, Poggi, V, Menna, G, Di Nardo, R, Sottile, R, Marone, G, Spadaro, G, Carli, M, Basso, G, Putti, C, Semenzato, G, Agostini, C, D'Angelo, P, Izzi, G, Bertolini, P, Zecca, M, Marseglia, G, Maccario, R, Felici, L, Favre, C, Vecchi, V, Sacchini, P, Rinaldi, G, Livadiotti, S, Simonetti, A, Stabile, A, Duse, M, Iacobini, M, Quinti, I, Fiorilli, M, Moschese, V, Cecere, F, D'Ambrosio, A, De Zan, G, Strafella, S, Tamaro, Paolo, Rabusin, M, Tommasini, A, Tovo, P, De Carli, M, De Carli, S, Nespoli, L, Marinoni, M, Porcellini, A, Lunardi, C, Patuzzo, G, Boner, A, Degani, D., Cancrini, C., Pulisfito, P., Digilio, M. C., Soresina, A., Martino, S., Rondelli, R., Consolini, R., Ruga, E. M., C. a. r. d. i. n. a. l. e., F., Finocchi, A., Romiti, M. L., Martire, B., Bacchetta, R., Albano, V., Carotti, A., Specchia, F., Montin, D., Cocchi, G., Trizzino, A., Bossi, G., Milanesi, O., Azzari, C., Corsello, G., Aiuti, A., Pietrogrande, M. C., Marino, B., Ugazio, A. G., Plebani, A., Digilio, MC, Ruga, EM, Romiti, ML, trizzino, A, Aiuti, Pietrogrande, MC, and Ugazio, AG

Subjects
Male, Pediatrics, 22q11.2 deletion, Delayed Diagnosis, Time Factors, Chromosomes, Human, Pair 22, Developmental Disabilities, digeorge syndrome, Sex Factor, Severity of Illness Index, Retrospective Studie, DiGeorge syndrome, Early Diagnosi, Age Factor, Prospective Studies, Neonatal hypocalcemia, Prospective cohort study, Child, medicine.diagnostic_test, Delayed Diagnosi, Primary immune disorders, Age Factors, del 22q, MIM, Abnormalities, Multiple, Adolescent, Adult, Child, Preschool, DiGeorge Syndrome, Early Diagnosis, Female, Follow-Up Studies, Genetic Testing, Humans, Infant, Infant, Newborn, Monitoring, Physiologic, Retrospective Studies, Risk Assessment, Sex Factors, Young Adult, Disease Progression, Cohort, Abnormalities, Multiple, Pediatrics, Perinatology and Child Health, Human, medicine.medical_specialty, Time Factor, Monitoring, Developmental Disabilitie, Italian Association of Pediatric Haematology and Oncology, Context (language use), Chromosomes, Follow-Up Studie, Severity of illness, medicine, 22q11DS, 22q11.2 deletion syndrome, AIEOP, Mendelian Inheritance in Man, Preschool, Physiologic, Genetic testing, Settore MED/38 - Pediatria Generale e Specialistica, business.industry, Retrospective cohort study, medicine.disease, Newborn, Prospective Studie, Pair 22, business
Abstract

Objective To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. Study design A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. Results The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations ( P = .015) and speech disorders ( P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. Conclusions Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.

Published
2014

47. Termporal, quantitative and functional characteristics of single-KIR positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation

Author

VAGO L, FORNO B, SORMANI M. P, CROCCHIOLO R, ZINO E, DI TERLIZZI S, LUPO STANGHELLINI M. T, MAZZI B, PERNA S. K, BONDANZA A, MIDDLETON D, PALINI A, BERNARDI M, BACCHETTA R, PECCATORI J, ROSSINI S, RONCAROLO M. G, BORDIGNON , CLAUDIO, BONINI C, CICERI, FABIO, AND K. FLEISCHHAUER, Vago, L, Forno, B, SORMANI M., P, Crocchiolo, R, Zino, E, DI TERLIZZI, S, LUPO STANGHELLINI M., T, Mazzi, B, PERNA S., K, Bondanza, A, Middleton, D, Palini, A, Bernardi, M, Bacchetta, R, Peccatori, J, Rossini, S, RONCAROLO M., G, Bordignon, Claudio, Bonini, C, Ciceri, Fabio, and AND K., Fleischhauer

Published
2008

48. B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome

Author

Castiello, M.C. (Maria Carmina), Scaramuzza, S. (Samantha), Pala, G. (Gianni), Ferrua, F. (Francesca), Uva, P. (Paolo), Brigida, I. (Immacolata), Sereni, L. (Lucia), Burg, M. (Mirjam) van der, Ottaviano, G. (Giorgio), Albert, M. (Michael), Grazia Roncarolo, M. (Maria), Naldini, L. (Luigi), Aiuti, A. (Alessandro), Villa, A. (Anna), Bosticardo, M. (Marita), Castiello, M.C. (Maria Carmina), Scaramuzza, S. (Samantha), Pala, G. (Gianni), Ferrua, F. (Francesca), Uva, P. (Paolo), Brigida, I. (Immacolata), Sereni, L. (Lucia), Burg, M. (Mirjam) van der, Ottaviano, G. (Giorgio), Albert, M. (Michael), Grazia Roncarolo, M. (Maria), Naldini, L. (Luigi), Aiuti, A. (Alessandro), Villa, A. (Anna), and Bosticardo, M. (Marita)

Abstract

Background Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene-corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach. Objective Because B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration. Methods We evaluated B-cell counts, B-cell subset distribution, B cell-activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott-Aldrich syndrome protein. Results After lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19+CD21-CD35- and CD21low B

Published
2015
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49. Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors

Author

Peccatori, J., Forcina, A., Clerici, D., Crocchiolo, R., Vago, L., Stanghellini, M. T. L., Noviello, M., Messina, C., Crotta, A., Assanelli, A., Marktel, S., Olek, S., Mastaglio, S., Giglio, F., Crucitti, L., Lorusso, A., Guggiari, E., Lunghi, F., Carrabba, M., Tassara, M., Battaglia, M., Ferraro, A., Carbone, M. R., Oliveira, G., Roncarolo, M. G., Rossini, S., Bernardi, M., Corti, C., Marcatti, M., Patriarca, F., Zecca, M., Locatelli, Franco, Bordignon, C., Fleischhauer, K., Bondanza, A., Bonini, C., Ciceri, F., Locatelli F. (ORCID:0000-0002-7976-3654), Peccatori, J., Forcina, A., Clerici, D., Crocchiolo, R., Vago, L., Stanghellini, M. T. L., Noviello, M., Messina, C., Crotta, A., Assanelli, A., Marktel, S., Olek, S., Mastaglio, S., Giglio, F., Crucitti, L., Lorusso, A., Guggiari, E., Lunghi, F., Carrabba, M., Tassara, M., Battaglia, M., Ferraro, A., Carbone, M. R., Oliveira, G., Roncarolo, M. G., Rossini, S., Bernardi, M., Corti, C., Marcatti, M., Patriarca, F., Zecca, M., Locatelli, Franco, Bordignon, C., Fleischhauer, K., Bondanza, A., Bonini, C., Ciceri, F., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

Published
2015

50. Transplantation in patients with SCID: mismatched related stem cells or unrelated cord blood?

Author

Fernandes, Jf, Rocha, V, Labopin, M, Neven, B, Moshous, D, Gennery, Ar, Friedrich, W, Porta, F, Diaz de Heredia, C, Wall, D, Bertrand, Y, Veys, P, Slatter, M, Schulz, A, Chan, Kw, Grimley, M, Ayas, M, Gungor, T, Ebell, W, Bonfim, C, Kalwak, K, Taupin, P, Blanche, S, Gaspar, Hb, Landais, P, Fischer, A, Gluckman, E, Cavazzana Calvo, M, Eurocord, Inborn Errors Working Party of European Group for Blood, Marrow Transplantation: Ahmed, A, Auiti, A, Biffi, A, Cant, A, Fasth, A, Gennery, A, Hassan, A, Lankester, A, O'Mera, A, Plabani, A, Rovelli, A, Salmon, A, Scarselli, A, Thrasher, A, Van Royen, A, Villa, A, Wawer, A, Wahadneh, A, Worth, A, Belohradsky, B, Wolska, B, Gaspar, B, Bonfirm, C, Booth, C, Klein, C, Messina, C, Peters, C, Steward, C, Lindemans, C, Schuetz, C, de Heredia Rubio CD, Bensoussan, D, Gleadow, D, Lilic, D, Gambineri, Eleonora, Smith, E, Aerts, F, Caracseghi, F, Roberts, G, Davies, G, Al Mousa, H, Jossanc, H, Ozsahim, H, Hirsch, I, Meyts, I, Tezcan, I, Mueller, I, Andresc, I, Boelens, J, Fernandes, J, Folloni, J, Keuhl, J, Reichenbach, J, Stary, J, Wachowiak, J, Xu Bayford, J, Cunha, Jm, Ehlert, J, Rao, K, Sykora, K, Andais, L, Brown, L, Dal Cortivo, L, Griffith, L, Notarangelo, L, Abinun, M, Albert, M, Bierings, M, Bouchet, M, Cavazzana, M, Hirschfield, M, Cowan, M, Hoenig, M, Loubser, M, Roncarolo, M, Sauer, M, Schneider, M, Verstegen, M, Schroeder, M, Essink, M, Yesilipek, M, Entz Werle, N, Mahlaoui, N, Schlautmann, N, Taylor, N, Vanroyen, N, Walffraat, N, Sanal, O, Amrolia, P, Bordigoni, P, De Coppi, P, Frange, P, Orchard, P, Sedlacek, P, Shaw, P, Stephensky, P, Bacchetta, R, Bredius, R, Formankova, R, Gale, R, Seger, R, Wynn, R, Corbacioglu, S, Ehl, S, Hacein Bey, S, Hambleton, S, Mohsen, S, Mueller, S, Pai, Sy, Espanol, T, Flood, T, Guengoer, T, Bordon, V, Ormoor, V, Pashano, V, Courteille, V, Czogala, W, Qasim, W, Camci, Y, and Nademi, Z.

Subjects
Male, medicine.medical_specialty, Transplantation Conditioning, medicine.medical_treatment, Immunology, Graft vs Host Disease, Kaplan-Meier Estimate, Cord Blood Stem Cell Transplantation, Hematopoietic stem cell transplantation, Biochemistry, Gastroenterology, SCID HSCT, Internal medicine, medicine, Humans, Proportional Hazards Models, Retrospective Studies, Preparative Regimen, Severe combined immunodeficiency, business.industry, Umbilical Cord Blood Transplantation, Incidence, Hematopoietic Stem Cell Transplantation, Infant, Newborn, Infant, Cell Biology, Hematology, medicine.disease, Surgery, Transplantation, Treatment Outcome, Child, Preschool, Histocompatibility, Cord blood, Female, Severe Combined Immunodeficiency, business
Abstract

Pediatric patients with SCID constitute medical emergencies. In the absence of an HLA-identical hematopoietic stem cell (HSC) donor, mismatched related-donor transplantation (MMRDT) or unrelated-donor umbilical cord blood transplantation (UCBT) are valuable treatment options. To help transplantation centers choose the best treatment option, we retrospectively compared outcomes after 175 MMRDTs and 74 UCBTs in patients with SCID or Omenn syndrome. Median follow-up time was 83 months and 58 months for UCBT and MMRDT, respectively. Most UCB recipients received a myeloablative conditioning regimen; most MMRDT recipients did not. UCB recipients presented a higher frequency of complete donor chimerism (P = .04) and faster total lymphocyte count recovery (P = .04) without any statistically significance with the preparative regimen they received. The MMRDT and UCBT groups did not differ in terms of T-cell engraftment, CD4+ and CD3+ cell recoveries, while Ig replacement therapy was discontinued sooner after UCBT (adjusted P = .02). There was a trend toward a greater incidence of grades II-IV acute GVHD (P = .06) and more chronic GVHD (P = .03) after UCBT. The estimated 5-year overall survival rates were 62% ± 4% after MMRDT and 57% ± 6% after UCBT. For children with SCID and no HLA-identical sibling donor, both UCBT and MMRDT represent available HSC sources for transplantation with quite similar outcomes.

Published
2012

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