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6. The x-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM

Author

Sayos, J., Wu, C., Morra, M., Wang, N., Zhang, x., Allen, D., van Schaik, S., Notarangelo, L., Geha, R., Roncarolo, M.G., Oettgen, H., De Vries, J.E., Aversa, G., and Terhorst, C.

Subjects
Epstein-Barr virus diseases -- Research, Lymphocytes -- Observations, Antigen receptors, T cell -- Observations, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Signalling lymphocyte-activation molecule (SLAM) is a glycosylated type-I transmembrane protein present on the surface of B and T cells. It is shown that a T-cell specific SLAM associated protein (SAP), containing an SH2 domain and a short tail, blocks recruitment of the SH2-domain containing signal transduction molecule SHP-2 to a SLAM cytoplasmic region docking site. Absence of the SAP inhibitor in XLP patients has an effect on T/B cell interactions, resulting in inability to control B-cell proliferation caused by Epstein-Barr viruses.

Published
1998

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

Author

Barzaghi, F., Hernandez, L.C.A., 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., Heredia, C.D. de, 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., Padilla, E.J.R., 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., Kawak, K., Haddad, E., Seidel, M.G., Duckers, G., Pai, S.Y., Dvorak, C.C., Ehl, S., Locatelli, F., Goldman, F., Gennery, A.R., Cowan, M.J., Roncarolo, M.G., Bacchetta, R., PIDTC, IEWP, European Soc Blood Marrow, Barzaghi, Federica, Hernandez, Laura Cristina Amaya, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J., Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R., Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M., Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frederic, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H., Kobayashi, Ichiro, Alonso, Laura, De Heredia, Cristina Diaz, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G., Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Padilla, Erick J. Richmond, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G., Kalwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C., Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J., Roncarolo, Maria-Grazia, Bacchetta, Rosa, Amaya Hernandez, Laura Cristina, Murguia-Favela, Lui, Shearer, William Thoma, Rieux-Laucat, Frédéric, Diaz De Heredia, Cristina, Richmond Padilla, Erick J., and Kałwak, Krzysztof

Subjects
0301 basic medicine, Male, Allergy, medicine.medical_treatment, Medizin, Disease, Hematopoietic stem cell transplantation, SIROLIMUS, Regenerative Medicine, primary immune deficiency, Medicine and Health Sciences, IPEX, Immunology and Allergy, 2.1 Biological and endogenous factors, Enteropathy, Aetiology, POLYENDOCRINOPATHY, Child, Pediatric, CÉLULAS-TRONCO, immunosuppression, Hematopoietic Stem Cell Transplantation, Genetic Diseases, X-Linked, Immunosuppression, Forkhead Transcription Factors, X-LINKED SYNDROME, Allografts, Survival Rate, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immune System Diseases, Genetic Diseases, Child, Preschool, hematopoietic stem cell transplantation, Female, hematopoietic stem, neonatal diabetes, FOXP3, Primary Immune Deficiency, Treg cells, enteropathy, genetic autoimmunity, rapamycin, Type 1, Diarrhea, Adult, medicine.medical_specialty, Adolescent, Immunology, Neonatal onset, Article, Disease-Free Survival, 03 medical and health sciences, Neonatal diabete, Clinical Research, Internal medicine, IMMUNODYSREGULATION, medicine, Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation, Diabetes Mellitus, Genetics, Humans, REGULATORY T-CELLS, cell transplantation, Preschool, Retrospective Studies, Immunosuppression Therapy, Transplantation, IMMUNE DYSREGULATION, business.industry, MUTATIONS, Infant, Retrospective cohort study, STEM-CELL TRANSPLANTATION, IPEX syndrome, X-Linked, medicine.disease, Stem Cell Research, BONE-MARROW-TRANSPLANTATION, Treg cell, FOXP3 MUTATIONS, Diabetes Mellitus, Type 1, 030104 developmental biology, ENGRAFTMENT, Mutation, business, Follow-Up Studies
Abstract

Background Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndromeis 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., GRAPHICAL ABSTRACT

Published
2018

8. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization

Author

Fuchs, A., Gliwinski, M., Grageda, N., Spiering, R., Abbas, A.K., Appel, S., Bacchetta, R., Battaglia, M., Berglund, D., Blazar, B., Bluestone, J.A., Bornhauser, M., Brinke, A. Ten, Brusko, T.M., Cools, N., Cuturi, M.C., Geissler, E., Giannoukakis, N., Golab, K., Hafler, D.A., Ham, S.M. van, Hester, J., Hippen, K., Ianni, M. Di, Ilic, N., Isaacs, J., Issa, F., Iwaszkiewicz-Grzes, D., Jaeckel, E., Joosten, I., Klatzmann, D., Koenen, H., Kooten, C. van, Korsgren, O., Kretschmer, K., Levings, M., Marek-Trzonkowska, N.M., Martinez-Llordella, M., Miljkovic, D., Mills, K.H., Miranda, J.P., Piccirillo, C.A., Putnam, A.L., Ritter, T., Roncarolo, M.G., Sakaguchi, S., Sanchez-Ramon, S., Sawitzki, B., Sofronic-Milosavljevic, L., Sykes, M., Tang, Q., Vives-Pi, M., Waldmann, H., Witkowski, P., Wood, K.J., Gregori, S., Hilkens, C.M., Lombardi, G., Lord, P., Martinez-Caceres, E.M., Trzonkowski, P., Fuchs, A., Gliwinski, M., Grageda, N., Spiering, R., Abbas, A.K., Appel, S., Bacchetta, R., Battaglia, M., Berglund, D., Blazar, B., Bluestone, J.A., Bornhauser, M., Brinke, A. Ten, Brusko, T.M., Cools, N., Cuturi, M.C., Geissler, E., Giannoukakis, N., Golab, K., Hafler, D.A., Ham, S.M. van, Hester, J., Hippen, K., Ianni, M. Di, Ilic, N., Isaacs, J., Issa, F., Iwaszkiewicz-Grzes, D., Jaeckel, E., Joosten, I., Klatzmann, D., Koenen, H., Kooten, C. van, Korsgren, O., Kretschmer, K., Levings, M., Marek-Trzonkowska, N.M., Martinez-Llordella, M., Miljkovic, D., Mills, K.H., Miranda, J.P., Piccirillo, C.A., Putnam, A.L., Ritter, T., Roncarolo, M.G., Sakaguchi, S., Sanchez-Ramon, S., Sawitzki, B., Sofronic-Milosavljevic, L., Sykes, M., Tang, Q., Vives-Pi, M., Waldmann, H., Witkowski, P., Wood, K.J., Gregori, S., Hilkens, C.M., Lombardi, G., Lord, P., Martinez-Caceres, E.M., and Trzonkowski, P.

Abstract

Contains fulltext : 191000.pdf (publisher's version ) (Open Access), Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

Published
2017

9. Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome

Author

Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese M.P, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello M.C, Bosticardo M, Evangelio C. , Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow D.J, Galy A, Miniero R, Finocchi A, Metin A, Banerjee P, Orange J, Galimberti S, Valsecchi M.G, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo M.G, and Naldini L.

Published
2013

10. Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

Author

Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale Sabrina, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo W.B, Nalini A. L. Mehta N.A.L, Cicalese M.P, Casiraghi M, Boelens J.B, Del Carro U, Dow D.J, Schmidt M, Assanelli, A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo M.G, Aiuti A, Sessa M, and Naldini L.

Published
2013

11. TREATMENT OF CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY (CIDP) WITH HIGH DOSE IMMUNOSUPPRESSIVE TREATMENT USING CYCLOPHOSPHAMIDE WITH AUTOLOGOUS HAEMOPOIETIC STEM CELL RESCUE

Author

Ciceri, F., Magnani, G., Zappone, E., Servida, P., Corradini, P., Bregni, M., Comi, G., Roncarolo, M.G., and Bordignon, C.

Subjects
Care and treatment, Demyelinating diseases -- Care and treatment, Hematopoietic stem cell transplantation, Hematopoietic stem cells -- Transplantation
Abstract

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is considered to be an autoimmune disorder. Current treatment regimens leave 4-30% of patients with CIDP with moderate or severe disability. Conventional dose immunosuppressive [...]

Published
2001

12. The Quality of Life of Children and Adolescents with X-Linked Agammaglobulinemia

Author

Soresina A., Nacinovich R., Bomba M., Cassani M., Molinaro A., Sciotto A., Martino S., Cardinale F., De Mattia D., Putti C., Dellepiane R.M., Felici L., Parrinello G., Neri F., Plebani A., Pierani P., DeMattia D., Martire B., Armenio L., Dammacco F., Ranieri G., Masi M., Miniaci A., Pession A., Rondelli R., Notarangelo L. D., Cao, Cossu F., Del Giacco S., Manconi P., Evangelista I., Magro S., Morgione S., STRISCIUGLIO, PIETRO, Anastasio E., Schillirò G., Paganelli R., Sticca M., Sperlì D., Carpino L., Bernini G., Azzari C., Maggi E., Romagnani S., Matucci A., Vultaggio A., Castagnola E., Gattorno M., Presta G., Civino A., Gambaretto G., Fasoli S., Salpietro C., Pietrogrande M.C., DellePiane R.M., Panisi C., Cambiaghi G., Pietrogrande M., Roncarolo M.G., Aiuti A., Masera G., Biondi A., Sala A., PIGNATA, CLAUDIO, Poggi V., Menna G., Di Nardo R., D'Apuzzo A., Pelliccia A., Correra A., Marone G., SPADARO, GIUSEPPE, Carli M., Zanesco L., Basso G., Putti M.C., Semenzato G., Agostini C., Amato G.M., Aricò M., Trizzino A., Izzi G., Bertolini P., Locatelli F., Zecca M., Rondini G., Marseglia G.L., Maccario R., Bossi G., Favre C., Consolini R., Vecchi V., Sacchini P., Rinaldi G., Ugazio A.G., Rossi P., Livadiotti S., Cancrini C., Finocchi A., Stabile A., Duse M., Iacobini M., Quinti I., Moschese V., Cecere F., Morgese G., Acquaviva A., De Zan G., Strafella S., Tamaro P., Rabusin M., Tovo P.A., Nespoli L., Marinoni M., Porcellini A., Cazzola G.A., Annarosa, Soresina, Renata, Nacinovich, Monica, Bomba, Morena, Cassani, Molinaro, Anna, Antonella, Sciotto, Silvana, Martino, Fabio, Cardinale, Domenico, Mattia, Caterina, Putti, Rosa Maria, Dellepiane, Leonardo, Felici, Giovanni, Parrinello, Francesca, Neri, Alessandro, Plebani, Soresina, A, Nacinovich, R, Bomba, M, Cassani, M, Molinaro, A, Sciotto, A, Martino, S, Cardinale, F, De Mattia, D, Putti, C, Dellepiane, R, Felici, L, Parrinello, G, Neri, F, Plebani, A, Soresina, A., Nacinovich, R., Bomba, M., Cassani, M., Molinaro, A., Sciotto, A., Martino, S., Cardinale, F., De Mattia, D., Putti, C., Dellepiane, R. M., Felici, L., Parrinello, G., Neri, F., Plebani, A., Pierani, P., Demattia, D., Martire, B., Armenio, L., Dammacco, F., Ranieri, G., Masi, M., Miniaci, A., Pession, A., Rondelli, R., Notarangelo, L. D., Cao, Cossu, F., Del Giacco, S., Manconi, P., Evangelista, I., Magro, S., Morgione, S., Strisciuglio, Pietro, Anastasio, E., Schillirò, G., Paganelli, R., Sticca, M., Sperlì, D., Carpino, L., Bernini, G., Azzari, C., Maggi, E., Romagnani, S., Matucci, A., Vultaggio, A., Castagnola, E., Gattorno, M., Presta, G., Civino, A., Gambaretto, G., Fasoli, S., Salpietro, C., Pietrogrande, M. C., Panisi, C., Cambiaghi, G., Pietrogrande, M., Roncarolo, M. G., Aiuti, A., Masera, G., Biondi, A., Sala, A., Pignata, Claudio, Poggi, V., Menna, G., Di Nardo, R., D'Apuzzo, A., Pelliccia, A., Correra, A., Marone, G., Spadaro, Giuseppe, Carli, M., Zanesco, L., Basso, G., Putti, M. C., Semenzato, G., Agostini, C., Amato, G. M., Aricò, M., Trizzino, A., Izzi, G., Bertolini, P., Locatelli, F., Zecca, M., Rondini, G., Marseglia, G. L., Maccario, R., Bossi, G., Favre, C., Consolini, R., Vecchi, V., Sacchini, P., Rinaldi, G., Ugazio, A. G., Rossi, P., Livadiotti, S., Cancrini, C., Finocchi, A., Stabile, A., Duse, M., Iacobini, M., Quinti, I., Moschese, V., Cecere, F., Morgese, G., Acquaviva, A., De Zan, G., Strafella, S., Tamaro, P., Rabusin, M., Tovo, P. A., Nespoli, L., Marinoni, M., Porcellini, A., and Cazzola, G. A.

Subjects
Male, Pediatrics, medicine.medical_specialty, x-linked agammaglobulinemia, Activities of daily living, Adolescent, X-linked agammaglobulinemia, Health Status, Immunology, pedsql 4.0 generic core scale, Quality of life, children, Agammaglobulinemia, Surveys and Questionnaires, Activities of Daily Living, health-related quality of life, parents, medicine, Humans, Immunology and Allergy, PedsQL 4.0 Generic Core Scale, Child, Settore MED/38 - Pediatria Generale e Specialistica, Health related quality of life, quality of live, business.industry, Immunoglobulins, Intravenous, Genetic Diseases, X-Linked, medicine.disease, Socioeconomic Factors, Child, Preschool, Mutation, Quality of Life, Female, X-linked agammaglobulinemia - children - parents - health-related quality of life - PedsQL 4.0 Generic Core Scale, business
Abstract

Introduction: The health-related quality of life in X-linked agammaglobulinemia was investigated in 25 children and adolescents patients through the Italian version of Pediatric Quality of Life Inventory 4.0 Generic Core Scale for patients aged less then 18 years, comparing child perception to that of the parents and the physician's evaluation. The data were compared with the ones of 80 healthy controls and the literature data of a group of patients with rheumatic diseases. Discussion: The agammaglobulinemia subjects perceived a lower global quality of life than the healthy subjects, but significantly higher than the rheumatic diseases controls. The clinical relevance of health-related quality of life assessment in X-linked agammaglobulinemia pediatric patients is discussed. © 2008 Springer Science+Business Media, LLC.

Published
2009

14. B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients

Author

Brigida, I. (Immacolata), Sauer, A.V. (Aisha), Ferrua, F. (Francesca), Giannelli, S. (Stefania), Scaramuzza, S. (Samantha), Pistoia, V. (Valentina), Castiello, M.C. (Maria Carmina), Barendregt, B.H. (Barbara), Cicalese, M.P. (Maria Pia), Casiraghi, F. (Federica), Brombin, C. (Chiara), Puck, J. (Jennifer), Muller, K. (Karin), Notarangelo, L.D. (Luigi Daniele), Montin, D. (Davide), Montfrans, J.M. (Joris) van, Roncarolo, M.G. (Maria Grazia), Traggiai, E. (Elisabetta), Dongen, J.J.M. (Jacques) van, Burg, M. (Mirjam) van der, Aiuti, A. (Alessandro), Brigida, I. (Immacolata), Sauer, A.V. (Aisha), Ferrua, F. (Francesca), Giannelli, S. (Stefania), Scaramuzza, S. (Samantha), Pistoia, V. (Valentina), Castiello, M.C. (Maria Carmina), Barendregt, B.H. (Barbara), Cicalese, M.P. (Maria Pia), Casiraghi, F. (Federica), Brombin, C. (Chiara), Puck, J. (Jennifer), Muller, K. (Karin), Notarangelo, L.D. (Luigi Daniele), Montin, D. (Davide), Montfrans, J.M. (Joris) van, Roncarolo, M.G. (Maria Grazia), Traggiai, E. (Elisabetta), Dongen, J.J.M. (Jacques) van, Burg, M. (Mirjam) van der, and Aiuti, A. (Alessandro)

Abstract

Background Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor. Objective We sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function. Methods Flow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation. Results Despite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT. Conclusions ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.

Published
2014
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15. In-Vivo Expansion of T Regulatory Cells by Rapamycin in a Calcineurin-Inhibitor Free GVHD Prophylaxis in Unmanipulated Haploidentical Stem Cell Transplantation (SCT)

Author

Peccatori, J., primary, Clerici, D., additional, Forcina, A., additional, Bondanza, A., additional, Messina, C., additional, Giglio, F., additional, Mastaglio, S., additional, Crotta, A., additional, Lupo Stanghellini, M.T., additional, Marcatti, M., additional, Crocchiolo, R., additional, Assanelli, A., additional, Bernardi, M., additional, Corti, C., additional, Noviello, M., additional, Olek, S., additional, Ferraro, A., additional, Battagglia, M., additional, Roncarolo, M.G., additional, Locatelli, F., additional, Bonini, C., additional, and Ciceri, F., additional

Published
2011
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18. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression

Author

Waal Malefijt, R. de, Haanen, J., Spits, H., Roncarolo, M.G., Velde, A.A. te, Figdor, C.G., Johnson, K., Kastelein, R., Yssel, H., Vries, J.E. de, Waal Malefijt, R. de, Haanen, J., Spits, H., Roncarolo, M.G., Velde, A.A. te, Figdor, C.G., Johnson, K., Kastelein, R., Yssel, H., and Vries, J.E. de

Abstract

Contains fulltext : 27187.PDF (publisher's version ) (Open Access)

Published
1991

26. Thymic hormones II

Author

Tovo, P.A., primary, Del Piano, A., additional, Palomba, E., additional, Roncarolo, M.G., additional, Salomone, C., additional, and Aiuti, F., additional

Published
1985
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29. Treatment with rapamycin can restore regulatory T-cell function in IPEX patients

Author

Pier Alberto Testoni, Rosalia Curto, Federica Barzaghi, Olaf Neth, Maria Grazia Roncarolo, Alessandro Aiuti, Francesca Tucci, Claudia Sartirana, Laura Passerini, Rosa Bacchetta, Vito Lampasona, Graziano Barera, Daniele Zama, Maria Pia Cicalese, Elena Bazzigaluppi, Manfred Hoenig, Ansgar Schulz, Alberto Mariani, Sven Olek, Luca Albarello, Ivana Rabbone, Emanuele Bosi, Markus G. Seidel, Passerini, L., Barzaghi, F., Curto, R., Sartirana, C., Barera, G., Tucci, F., Albarello, L., Mariani, A., Testoni, P. A., Bazzigaluppi, E., Bosi, E., Lampasona, V., Neth, O., Zama, D., Hoenig, M., Schulz, A., Seidel, M. G., Rabbone, I., Olek, S., Roncarolo, M. G., Cicalese, M. P., Aiuti, A., Bacchetta, R., Passerini L., Barzaghi F., Curto R., Sartirana C., Barera G., Tucci F., Albarello L., Mariani A., Testoni P.A., Bazzigaluppi E., Bosi E., Lampasona V., Neth O., Zama D., Hoenig M., Schulz A., Seidel M.G., Rabbone I., Olek S., Roncarolo M.G., Cicalese M.P., Aiuti A., and Bacchetta R.

Subjects
Male, 0301 basic medicine, regulatory T cell, medicine.medical_treatment, Hematopoietic stem cell transplantation, Lymphocyte Activation, medicine.disease_cause, T-Lymphocytes, Regulatory, regulatory T cells, Autoimmunity, Immunosuppressive Agent, 0302 clinical medicine, Cell Movement, IPEX, Immunology and Allergy, Sirolimu, Child, Cells, Cultured, autoimmunity, FOXP3, Forkhead Transcription Factors, Genetic Diseases, X-Linked, hemic and immune systems, EBI3, Regulatory T cells, suppression, Minor Histocompatibility Antigen, medicine.anatomical_structure, Immune System Diseases, mTOR, Immunosuppressive Agents, Human, Diarrhea, Ebi3, Immune System Disease, Regulatory T cell, Immunology, chemical and pharmacologic phenomena, Minor Histocompatibility Antigens, 03 medical and health sciences, TIGIT, Glucocorticoid-Induced TNFR-Related Protein, Immune Tolerance, medicine, Humans, GITR, Sirolimus, rapamycin, business.industry, Interleukins, Forkhead Transcription Factor, Interleukin, IPEX syndrome, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, Gene Expression Regulation, CTLA-4, Mutation, Cancer research, business, 030215 immunology
Abstract

[Background] Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear., [Objective] We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations., [Methods] Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR., [Results] Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor–related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients’ Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor–related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells., [Conclusions] Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

Published
2020
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30. Induction of tolerance via T regulatory cells. A clinical reality or just a nice experiment in mice?

Author

Battaglia, M., Prakken, A.B.J., Roncarolo, M.G., and University Utrecht

Subjects
Geneeskunde, tolerance, rapamycin, T regulatory cells, Graft rejection, autoimmunity, IL-10, chemical and pharmacologic phenomena
Abstract

T regulatory (Treg) cells are a subset of lymphocytes specifically dedicated to maintain the correct balance between efficient immune responses towards harmful events (such as a viral infections) and tolerogenic responses towards self and non-harmless antigens (such as food antigens). This is a delicate process that needs to be finely tuned. It is clear that Treg cells can be infused in animals and induce tolerance thus leading to, for example, reversal of autoimmunity. However, how much data generated in animals can be successfully translated into humans remains one of the key questions. There are two distinct ways to perform Treg-cell–based therapy: (i) via infusion of ex vivo manipulated Treg cells or (ii) via the direct in vivo induction of Treg cells. Both methods have advantages and disadvantages. Aim of our work was to address some of the still open and key questions to be solved to make Treg-cell therapy in humans a reality. Some of the key issues related to the infusion of ex manipulated Treg cells that need to be addressed - and that were subjects of this thesis - are: (i) the definition of an efficient and safe protocol for the ex vivo manipulation of Treg cells; (ii) the demonstration that that the ex vivo treated Treg cells can promote tolerance in vivo; and (iii) the demonstration that the protocol is equally efficient and safe by using human cells obtained from both healthy donors and patients. We showed that a drug commonly used in the field of transplantation (named rapamycin) can efficiently expand functional Treg cells ex vivo and that these cells, when infused in transplanted mice, protect from graft rejection. In addition, the same protocol is efficacious for the ex vivo manipulation of Treg cells from both healthy donors and patients with autoimmune type 1 diabetes. Some of the important issues that need to be addressed in case of direct in vivo induction of Treg cells - and that were subjects of this thesis- are: (i) the definition of a therapy that allows control of aggressive and unwanted immune responses while permitting induction of functional Treg cells; (ii) the demonstration that such a Treg-cell–permissive therapy is efficient in inducing tolerance in more than one disease animal models; and (iii) the clinical relevance of the findings eventually reported in animals. We showed that two drugs already used in patients (namely, rapamycin and interleuchin-10 (IL-10)) can control unwanted aggressive immune responses and at the same time boost Treg cells that can control allograft rejection and autoimmunity. In addition, we observed that patients with autoimmunity and treated with rapamycin have more functional circulating Treg cells as compared to those isolated before therapy. Overall, we developed an efficient, safe and clinical translatable protocol for the expansion of functional Treg cells and we showed that induction of tolerance via Treg-cells directly in vivo is also feasible and efficient.

Published
2014

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