Maria Grazia Roncarolo
e-mail: roncarolo.mariagrazia AT hsr.it
website: www.sanraffaele.org
affiliation: Università Vita-Salute San Raffaele
research area(s): Experimental Medicine, Immunity And Infection
Course:
Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
University/Istitution: Università Vita-Salute San Raffaele
EDUCATION:
1982, MD, School of Medicine, University of Turin, Italy
1986, Natl.Board, Pediatrics, School of Medicine, University of Milan, Italy
1990, Natl.Board, Clinical Immunology,School of Medicine,University of Milan,Italy
SCIENTIFIC CAREER:
1983-1984 Research Fellow, Division of Transplantation and Clinical Immunology, Hospital E. Herriot, Lyon, France.
1984 Research Associate, Laboratory for Immunological Research, UNICET (Schering-Plough), Dardilly, France.
1985-7/86 Intern, Department of Pediatrics, Division of Immunology , School of Medicine, University of Turin, Italy.
8/86-1/88 Associate Senior Scientist (Chargée de Recherches), Laboratory for Immunological Research, UNICET (Schering-Plough), Dardilly, France.
Assistant Professor (Assistant Etranger), School of Medicine, University Claude Bernard, Lyon, France.
2/88-2/89 Assistant pediatrician (Medecin Resident Etranger des Hospices Civils de Lyon), Division of Transplantation and Clinical Immunology , Hospital E. Herriot, Lyon, France.
3/89-3/92 Staff Scientist, Human Immunology Department, DNAX Research Institute for Molecular and Cellular Biology, Palo Alto, CA.
3/92- 12/96 Senior Staff Scientist, Human Immunology Department, DNAX Research Institute for Molecular and Cellular Biology, Palo Alto.
11/94-11/01 Professor in Pediatrics, Department of Pediatrics, School of Medicine, University of Turin, Turin, Italy.
11/01-02/07 Associate Professor in Pediatrics, School of Medicine and Surgery,
Vita-Salute San Raffaele University, Milan, Italy.
03/07-present Full Professor in Pediatrics, School of Medicine and Surgery,
Vita-Salute San Raffaele University, Milan, Italy.
2/98-12/98 Director of Cellular Therapy Laboratory Telethon Institute for Gene Therapy (TIGET), Scientific Institute H.S. Raffaele Milan, Italy.
12/98-05/00 Co-Director of San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) - Milan, Italy.
06/00-09/08 Director of San Raffaele Telethon Institute for Gene Therapy
(HSR-TIGET) - Milan, Italy.
07/03-present Chief of Clinic, Pediatric Immunology and Hematology and Clinical Research Unit (CRU-P), San Raffaele Hospital and San Raffaele Scientific Institute - Milan, Italy.
03/08-present Scientific Director of San Raffaele Scientific Institute - Milan, Italy.
HONORS:
1983 Recipient of a research fellowship from the "Comitato G. Ghirotti" of Turin for research in genetic diseases.
1984 Recipient of a research fellowship from the University of Turin for research in primary immunodeficiencies.
1986 Recipient of an award distributed by the "Club degli amici dell'Immunologia"of Italy for clinical immunological research.
1998 Recipient of the price "Clessidra d'Oro", distributed by the A.D.O. of Italy for transplantation research.
2000 Recipient of the honor of Ufficiale dell'Ordine "Al Merito della Repubblica Italiana" for scientific merits.
2005 Election to Member of the Academia Europaea of Sciences.
MEMBERSHIPS:
American Association of Immunologists
American Society of Gene and Cell Therapy
American Society of Hematology
Clinical Immunology Society
European Society for Immunodeficiencies
European Society for Gene and Cell Therapy
Italian Society of Pediatrics
Italian Society of Pediatric Allergy and Immunology
PROFESSIONAL ACTIVITIES:
Member of the Board for the Italian School of Immunology "Ruggero Ceppellini" of Naples (1997-present).
Member of the Scientific Committee of the European School of Hematology (ESH) (01/2004-present).
Member of the Membership Committee of the American Society of Gene and Cell Therapy (ASGCT) (2005-present).
Member of the ESGCT Regulatory and Ethics Committee (12/2006-present).
Member of the External Scientific Advisory Board (ESAB) of the Tumorzentrum L. Heilmeyer, Comprehensive Cancer Center Freiburg (CCCF) (2007-present).
Member of the Organizing and Scientific Committees of the 36th Federation of European Biochemical Societies (FEBS) (03/2008-present).
Member of the EBMT Immunology Working Party (05/2008-present).
Charter Member of the Eureka Institute for Translational Medicine (05/2008-present).
Member of the American Society of Hematology (ASH) Committee in Immunology and Host Defense (2009-present).
Member of the Scientific Program Committee of the 15th International Congress of Immunology (ICI) (May 2009-present).
Member of the Organizing Committee of the Federation of Clinical Immunology Societies (FOCIS) 2011 Meeting (March 2010-present).
Member of the Scientific Committee for the 2nd International Conference on Immune Tolerance (July 2010-present).
Member of the Scientific Committee of the European Congress of Immunology (September 2010-present).
Member of the 2011 Nominating Committee of the American Society of Gene and Cell Therapy (ASGCT) (as from October 2010).
Member of the Scientific Advisory Board of the Global Health Institute (GHI) Lausanne (April 2011-present).
1982, MD, School of Medicine, University of Turin, Italy
1986, Natl.Board, Pediatrics, School of Medicine, University of Milan, Italy
1990, Natl.Board, Clinical Immunology,School of Medicine,University of Milan,Italy
SCIENTIFIC CAREER:
1983-1984 Research Fellow, Division of Transplantation and Clinical Immunology, Hospital E. Herriot, Lyon, France.
1984 Research Associate, Laboratory for Immunological Research, UNICET (Schering-Plough), Dardilly, France.
1985-7/86 Intern, Department of Pediatrics, Division of Immunology , School of Medicine, University of Turin, Italy.
8/86-1/88 Associate Senior Scientist (Chargée de Recherches), Laboratory for Immunological Research, UNICET (Schering-Plough), Dardilly, France.
Assistant Professor (Assistant Etranger), School of Medicine, University Claude Bernard, Lyon, France.
2/88-2/89 Assistant pediatrician (Medecin Resident Etranger des Hospices Civils de Lyon), Division of Transplantation and Clinical Immunology , Hospital E. Herriot, Lyon, France.
3/89-3/92 Staff Scientist, Human Immunology Department, DNAX Research Institute for Molecular and Cellular Biology, Palo Alto, CA.
3/92- 12/96 Senior Staff Scientist, Human Immunology Department, DNAX Research Institute for Molecular and Cellular Biology, Palo Alto.
11/94-11/01 Professor in Pediatrics, Department of Pediatrics, School of Medicine, University of Turin, Turin, Italy.
11/01-02/07 Associate Professor in Pediatrics, School of Medicine and Surgery,
Vita-Salute San Raffaele University, Milan, Italy.
03/07-present Full Professor in Pediatrics, School of Medicine and Surgery,
Vita-Salute San Raffaele University, Milan, Italy.
2/98-12/98 Director of Cellular Therapy Laboratory Telethon Institute for Gene Therapy (TIGET), Scientific Institute H.S. Raffaele Milan, Italy.
12/98-05/00 Co-Director of San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) - Milan, Italy.
06/00-09/08 Director of San Raffaele Telethon Institute for Gene Therapy
(HSR-TIGET) - Milan, Italy.
07/03-present Chief of Clinic, Pediatric Immunology and Hematology and Clinical Research Unit (CRU-P), San Raffaele Hospital and San Raffaele Scientific Institute - Milan, Italy.
03/08-present Scientific Director of San Raffaele Scientific Institute - Milan, Italy.
HONORS:
1983 Recipient of a research fellowship from the "Comitato G. Ghirotti" of Turin for research in genetic diseases.
1984 Recipient of a research fellowship from the University of Turin for research in primary immunodeficiencies.
1986 Recipient of an award distributed by the "Club degli amici dell'Immunologia"of Italy for clinical immunological research.
1998 Recipient of the price "Clessidra d'Oro", distributed by the A.D.O. of Italy for transplantation research.
2000 Recipient of the honor of Ufficiale dell'Ordine "Al Merito della Repubblica Italiana" for scientific merits.
2005 Election to Member of the Academia Europaea of Sciences.
MEMBERSHIPS:
American Association of Immunologists
American Society of Gene and Cell Therapy
American Society of Hematology
Clinical Immunology Society
European Society for Immunodeficiencies
European Society for Gene and Cell Therapy
Italian Society of Pediatrics
Italian Society of Pediatric Allergy and Immunology
PROFESSIONAL ACTIVITIES:
Member of the Board for the Italian School of Immunology "Ruggero Ceppellini" of Naples (1997-present).
Member of the Scientific Committee of the European School of Hematology (ESH) (01/2004-present).
Member of the Membership Committee of the American Society of Gene and Cell Therapy (ASGCT) (2005-present).
Member of the ESGCT Regulatory and Ethics Committee (12/2006-present).
Member of the External Scientific Advisory Board (ESAB) of the Tumorzentrum L. Heilmeyer, Comprehensive Cancer Center Freiburg (CCCF) (2007-present).
Member of the Organizing and Scientific Committees of the 36th Federation of European Biochemical Societies (FEBS) (03/2008-present).
Member of the EBMT Immunology Working Party (05/2008-present).
Charter Member of the Eureka Institute for Translational Medicine (05/2008-present).
Member of the American Society of Hematology (ASH) Committee in Immunology and Host Defense (2009-present).
Member of the Scientific Program Committee of the 15th International Congress of Immunology (ICI) (May 2009-present).
Member of the Organizing Committee of the Federation of Clinical Immunology Societies (FOCIS) 2011 Meeting (March 2010-present).
Member of the Scientific Committee for the 2nd International Conference on Immune Tolerance (July 2010-present).
Member of the Scientific Committee of the European Congress of Immunology (September 2010-present).
Member of the 2011 Nominating Committee of the American Society of Gene and Cell Therapy (ASGCT) (as from October 2010).
Member of the Scientific Advisory Board of the Global Health Institute (GHI) Lausanne (April 2011-present).
Prof. Roncarolo has a long-lasting interest in the mechanisms that induce and maintain tolerance in bone marrow and organ transplantation, autoimmune diseases and gene therapy. Her group was leader in the demonstration and biological characterization of the first subset of inducible regulatory T cells named T regulatory type 1 cells. In addition, she was instrumental in the characterization of human natural regulatory T cells and in methods for in vivo or ex vivo Treg expansion. She is now actively investigating novel drugs (biological and small molecular weight compounds) that drive the differentiation and expansions of tolerogenic DC and/or antigen specific Tregs. Prof. Roncarolo pioneered the successful gene therapy clinical trial for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency (Aiuti et al. NEJM 2009,360:447). She is also performing the first in men trial with ex-vivo generated donor-derived Tr1 cells to prevent the occurrence of severe graft versus host disease in leukemia patients undergoing haploidentical hematopoietic stem cell transplantation (clinical trial HSR-ALT-TEN ongoing in our Institute).
CURRENT RESEARCH INTERESTS:
Immunetolerance: Mechanisms underlying T-cell tolerance, induction of T-cell anergy and regulatory T cells
Immunomodulation: mAbs, proteins and small molecules which can modulate T-cell activation
Primary immunodeficiencies: Characterization of molecular and immunological
defects
Gene therapy: Gene transduction of hematopoietic cells for gene therapy in
primary immunodeficiencies and metabolic diseases
Hematopoiesis: Mechanisms underlying growth and differentiation of
hematopoietic stem cells
Transplantation: Immune reconstitution and T-cell tolerance after
allogenic stem cell transplantation
Cytokines: Role in regulation of immune and inflammatory responses
CURRENT RESEARCH INTERESTS:
Immunetolerance: Mechanisms underlying T-cell tolerance, induction of T-cell anergy and regulatory T cells
Immunomodulation: mAbs, proteins and small molecules which can modulate T-cell activation
Primary immunodeficiencies: Characterization of molecular and immunological
defects
Gene therapy: Gene transduction of hematopoietic cells for gene therapy in
primary immunodeficiencies and metabolic diseases
Hematopoiesis: Mechanisms underlying growth and differentiation of
hematopoietic stem cells
Transplantation: Immune reconstitution and T-cell tolerance after
allogenic stem cell transplantation
Cytokines: Role in regulation of immune and inflammatory responses
A. Valle, T. Jofra, A. Stabilini, M. Atkinson, M.G. Roncarolo and M. Battaglia. (2009). Rapamycin prevents and breaks the anti-CD3-induced tolerance in NOD mice. Diabetes. 58: 875-881.
M. Battaglia and M.G. Roncarolo. (2009). The fate of human Treg cells. Immunity 30: 763-765.
G. Serafini, M. Andreani, M. Testi, M. Battarra, A. Bontadini, K. Fleischhauer, S. Marktel, G. Lucarelli, M.G. Roncarolo, and R. Bacchetta. (2009). Type 1 regulatory T cells are associated with persistent split erythroid/lymphoid chimerism after allogeneic hematopoietic stem cell transplantation for thalassemia. Haematologica. 94: 1415-1426.
A.Annoni, B.D. Brown, A. Cantore, L. Sergi Sergi, L. Naldini and M.G. Roncarolo. (2009). In vivo delivery of a microRNA regulated transgene induces antigen-specific regulatory T cells and promotes immulogical tolerance. Blood. 114: 5152-5161.
S. Di Nunzio, M. Cecconi, L. Passerini, A.N. McMurchy, U. Baron, I. Turbachova, S. Vignola, S. Valencic, A. Tommasini, A. Junker, G. Cazzola, S. Olek , M.K. Levings, L. Perroni, M.G. Roncarolo, and R. Bacchetta. (2009). Wild-type FOXP3 is selectively active in CD4+CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood 114: 4138-4141.
N. Gagliani, A. Ferraro, M.G. Roncarolo, and M. Battaglia. (2009). Autoimmune diabetic patients undergoing allogeneic islet transplantation: are we ready for a regulatory T-cell therapy? Immunol Lett 127: 1-7.
N. Gagliani, T. Jofra, A. Stabilini, A. Valle, M. Atkinson, M.G. Roncarolo, and M. Battaglia. (2010). Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplantation. Diabetes 59:433-439.
V. Pacciani, S. Gregori, L. Chini, S. Corrente, M. Chianca, V. Moschese, P. Rossi, M.G. Roncarolo, and F. Angelini. (2010). Induction of adergi allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites. J Allergy Clin Immunol. 125:727-736.
S. Gregori, D. Tomasoni,, V. Pacciani, M. Scirpoli, M. Battaglia, C.F. Magnani, E. Hauben, and M.G.Roncarolo. (2010). Differentiation of type 1 T regulatory (Tr1) cells by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood.116: 935-944.
C. Cancrini, F. Ferrua, A. Scarselli, I. Brigida, M.L. Romiti, G. Barera, A. Finocchi, M.G. Roncarolo, M. Caniglia, and A. Aiuti. (2010). Role of reduced intensity conditioning in T-cell and B-cell immune reconstitution after HLA-identical bone marrow transplantation in ADA-SCID. Haematologica. 95: 1778-1782.
R.Bacchetta, S. Gregori, G. Serafini, C. Sartirana, U.Schultz, E.Zino, S. Tomiuk, U.Jan"en, M. Ponzoni C.T. Paties, K.Fleischhauer, and M.G. Roncarolo (2010). Molecular and functional characterization of alloantigen-specific anergic T-cells suitable for cell therapy. Haematologica. 95: 2134-2143.
S. Gregori, M.G. Roncarolo, and R. Bacchetta (2010). Methods for in vitro generation of human type 1 regulatory T cells. Methods Mol Biol. 677:31-46.
M. Rossetti, S. Gregori, and M.G. Roncarolo (2010). Granulocyte-colony stimulating factor drives the in vitro differentiation of human dendritic cells that induce anergy in naïve T cells. Eur J Immunol. 40: 3097-3106.
S. Huber, N. Gagliani, E. Esplugues, W. O"Connor Jr., F.J. Huber, A. Chaudhry, M. Kamanaka, Y. Kobayashi, C.J. Booth, A.Y. Rudensky, M. Battaglia, M.G. Roncarolo, and R.A. Flavell. (2011). Th17 cells express IL-10Ra and are controlled by Foxp3- and Foxp3+ regulatory CD4+ T cells in an IL-10 dependent manner. Immunity 34: 554-565.
C.F. Magnani, G. Alberigo, R. Bacchetta, G. Serafini, M. Andreani, M.G. Roncarolo, and S. Gregori. (2011). Killing of myeloid APC via HLA Class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol.
J. Mátrai, A. Cantore, C.C. Bartholomae, A. Annoni, W.Wang, A. Acosta-Sanchez, E. Samara-Kuko, L. De Waele, L. Ma, P. Genovese, M. Damo, A. Arens, K. Goudy, T.C. Nichols, C.von Kalle, M.K. L Chuah, M.G. Roncarolo, M. Schmidt, T. Vandendriessche, and Naldini L. (2011). Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces antigen-specific tolerance in mice with low genotoxic risk. Hepatology, 53:1696-1707.
L. Passerini, S. Di Nunzio, S. Gregori, E. Gambineri, M. Cecconi, M.G. Seidel, G. Cazzola, L. Perroni, A. Tommasini, S. Vignola, L. Guidi, M.G. Roncarolo, and R. Bacchetta. (2011). Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. Eur J Immunol. 41:1120-1131.
M.G Roncarolo, S. Gregori, B. Lucarelli, F. Ciceri, R. Bacchetta (2011). Clinical tolerance in allogeneic hematopoietic stem cell transplantation. Immunological Reviews, 241:145-163.
E. Tresoldi, I. Dell'albani, A. Stabilini, T. Jofra, A. Valle, N. Gagliani, A. Bondanza, M.G. Roncarolo, and M. Battaglia. (2011). Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells. Haematologica. Prepublished online May 12, 2011.
M. Battaglia and M.G. Roncarolo. (2009). The fate of human Treg cells. Immunity 30: 763-765.
G. Serafini, M. Andreani, M. Testi, M. Battarra, A. Bontadini, K. Fleischhauer, S. Marktel, G. Lucarelli, M.G. Roncarolo, and R. Bacchetta. (2009). Type 1 regulatory T cells are associated with persistent split erythroid/lymphoid chimerism after allogeneic hematopoietic stem cell transplantation for thalassemia. Haematologica. 94: 1415-1426.
A.Annoni, B.D. Brown, A. Cantore, L. Sergi Sergi, L. Naldini and M.G. Roncarolo. (2009). In vivo delivery of a microRNA regulated transgene induces antigen-specific regulatory T cells and promotes immulogical tolerance. Blood. 114: 5152-5161.
S. Di Nunzio, M. Cecconi, L. Passerini, A.N. McMurchy, U. Baron, I. Turbachova, S. Vignola, S. Valencic, A. Tommasini, A. Junker, G. Cazzola, S. Olek , M.K. Levings, L. Perroni, M.G. Roncarolo, and R. Bacchetta. (2009). Wild-type FOXP3 is selectively active in CD4+CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood 114: 4138-4141.
N. Gagliani, A. Ferraro, M.G. Roncarolo, and M. Battaglia. (2009). Autoimmune diabetic patients undergoing allogeneic islet transplantation: are we ready for a regulatory T-cell therapy? Immunol Lett 127: 1-7.
N. Gagliani, T. Jofra, A. Stabilini, A. Valle, M. Atkinson, M.G. Roncarolo, and M. Battaglia. (2010). Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplantation. Diabetes 59:433-439.
V. Pacciani, S. Gregori, L. Chini, S. Corrente, M. Chianca, V. Moschese, P. Rossi, M.G. Roncarolo, and F. Angelini. (2010). Induction of adergi allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites. J Allergy Clin Immunol. 125:727-736.
S. Gregori, D. Tomasoni,, V. Pacciani, M. Scirpoli, M. Battaglia, C.F. Magnani, E. Hauben, and M.G.Roncarolo. (2010). Differentiation of type 1 T regulatory (Tr1) cells by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood.116: 935-944.
C. Cancrini, F. Ferrua, A. Scarselli, I. Brigida, M.L. Romiti, G. Barera, A. Finocchi, M.G. Roncarolo, M. Caniglia, and A. Aiuti. (2010). Role of reduced intensity conditioning in T-cell and B-cell immune reconstitution after HLA-identical bone marrow transplantation in ADA-SCID. Haematologica. 95: 1778-1782.
R.Bacchetta, S. Gregori, G. Serafini, C. Sartirana, U.Schultz, E.Zino, S. Tomiuk, U.Jan"en, M. Ponzoni C.T. Paties, K.Fleischhauer, and M.G. Roncarolo (2010). Molecular and functional characterization of alloantigen-specific anergic T-cells suitable for cell therapy. Haematologica. 95: 2134-2143.
S. Gregori, M.G. Roncarolo, and R. Bacchetta (2010). Methods for in vitro generation of human type 1 regulatory T cells. Methods Mol Biol. 677:31-46.
M. Rossetti, S. Gregori, and M.G. Roncarolo (2010). Granulocyte-colony stimulating factor drives the in vitro differentiation of human dendritic cells that induce anergy in naïve T cells. Eur J Immunol. 40: 3097-3106.
S. Huber, N. Gagliani, E. Esplugues, W. O"Connor Jr., F.J. Huber, A. Chaudhry, M. Kamanaka, Y. Kobayashi, C.J. Booth, A.Y. Rudensky, M. Battaglia, M.G. Roncarolo, and R.A. Flavell. (2011). Th17 cells express IL-10Ra and are controlled by Foxp3- and Foxp3+ regulatory CD4+ T cells in an IL-10 dependent manner. Immunity 34: 554-565.
C.F. Magnani, G. Alberigo, R. Bacchetta, G. Serafini, M. Andreani, M.G. Roncarolo, and S. Gregori. (2011). Killing of myeloid APC via HLA Class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol.
J. Mátrai, A. Cantore, C.C. Bartholomae, A. Annoni, W.Wang, A. Acosta-Sanchez, E. Samara-Kuko, L. De Waele, L. Ma, P. Genovese, M. Damo, A. Arens, K. Goudy, T.C. Nichols, C.von Kalle, M.K. L Chuah, M.G. Roncarolo, M. Schmidt, T. Vandendriessche, and Naldini L. (2011). Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces antigen-specific tolerance in mice with low genotoxic risk. Hepatology, 53:1696-1707.
L. Passerini, S. Di Nunzio, S. Gregori, E. Gambineri, M. Cecconi, M.G. Seidel, G. Cazzola, L. Perroni, A. Tommasini, S. Vignola, L. Guidi, M.G. Roncarolo, and R. Bacchetta. (2011). Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. Eur J Immunol. 41:1120-1131.
M.G Roncarolo, S. Gregori, B. Lucarelli, F. Ciceri, R. Bacchetta (2011). Clinical tolerance in allogeneic hematopoietic stem cell transplantation. Immunological Reviews, 241:145-163.
E. Tresoldi, I. Dell'albani, A. Stabilini, T. Jofra, A. Valle, N. Gagliani, A. Bondanza, M.G. Roncarolo, and M. Battaglia. (2011). Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells. Haematologica. Prepublished online May 12, 2011.
Project Title:
Project Title:
Dissecting the molecular mechanisms responsible for Tr1 cell phenotype and functions.
Regulatory T cells comprise several subsets of cells (both naturally occurring or induced) that share the ability to regulate immune responses. Induced type 1 Tr (Tr1) cells are characterized by the ability to secrete high levels of IL-10 in the absence of IL-4, and to suppress T cell responses through cytokine-dependent mechanisms and selective killing of target cells. Despite significant progress in understanding the biology of Tr1 cells, studies of in vivo-induced Tr1 cells have been hampered by the lack of specific surface markers. To identify Tr1 cell markers and cell signature we performed comparative gene expression profile of Tr1 and Th0 cell clones isolated from peripheral blood of normal donors. We found a variety of gene differentially expressed by Tr1 cells as compared as to Th0 cells, including surface proteins.
The aim of the present project is to define the best panel of markers to identify Tr1 cells in peripheral blood and tissues and to investigate the role of selected genes in Tr1 cell induction and functions. Based on the selected markers Tr1 cells will be isolated from tissues and functionally characterized in vitro. To define the role of identified genes in Tr1 cell induction we will overexpression candidate gene(s) in T cells using lentiviral vectors (LVs) In parallel, effects of knocking down these gene(s) will be investigated by interfering their expression in Tr1 cells with LVs encoding siRNA. Functional studies of the resulting T cells will be performed both in vitro and in vivo. Moreover, genes putative implicated the effector function of Tr1 cells will be investigated. These experiments will allow us to identify specific molecular markers that could be used to identify Tr1 cells in vivo and molecules involved in their induction, activation, and function, and to develop new targets to modulate T-cell mediated diseases.
References:
1. Roncarolo MG., Gregori S., Battaglia M., Bacchetta R., Fleischhauer K., Levings MK. IL-10 secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006 Aug;212:28-50.
2. Bacchetta R.*, Gregori S.*, Serafini G., Sartirana C., Schulz U., Zino E., Tomiuk S., Jansen U., Ponzoni M., Paties CT., Fleischhauer K., Roncarolo MG. Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy. *Equal contributors. Haematologica. 2010 Dec;95(12):2134-43. Epub 2010 Aug 16.
3. Magnani C.F., Alberigo G., Bacchetta R., Serafini G., Andreani M., Roncarolo M.G., and Gregori S. Type 1 Regulatory T Cells Lyse Myeloid Antigen Presenting Cells via a Granzyme B- and HLA Class I- Dependent Mechanism. Eur J Immunol. 2011 Apr 6. doi: 10.1002/eji.201041120. [Epub ahead of print]
The aim of the present project is to define the best panel of markers to identify Tr1 cells in peripheral blood and tissues and to investigate the role of selected genes in Tr1 cell induction and functions. Based on the selected markers Tr1 cells will be isolated from tissues and functionally characterized in vitro. To define the role of identified genes in Tr1 cell induction we will overexpression candidate gene(s) in T cells using lentiviral vectors (LVs) In parallel, effects of knocking down these gene(s) will be investigated by interfering their expression in Tr1 cells with LVs encoding siRNA. Functional studies of the resulting T cells will be performed both in vitro and in vivo. Moreover, genes putative implicated the effector function of Tr1 cells will be investigated. These experiments will allow us to identify specific molecular markers that could be used to identify Tr1 cells in vivo and molecules involved in their induction, activation, and function, and to develop new targets to modulate T-cell mediated diseases.
References:
1. Roncarolo MG., Gregori S., Battaglia M., Bacchetta R., Fleischhauer K., Levings MK. IL-10 secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006 Aug;212:28-50.
2. Bacchetta R.*, Gregori S.*, Serafini G., Sartirana C., Schulz U., Zino E., Tomiuk S., Jansen U., Ponzoni M., Paties CT., Fleischhauer K., Roncarolo MG. Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy. *Equal contributors. Haematologica. 2010 Dec;95(12):2134-43. Epub 2010 Aug 16.
3. Magnani C.F., Alberigo G., Bacchetta R., Serafini G., Andreani M., Roncarolo M.G., and Gregori S. Type 1 Regulatory T Cells Lyse Myeloid Antigen Presenting Cells via a Granzyme B- and HLA Class I- Dependent Mechanism. Eur J Immunol. 2011 Apr 6. doi: 10.1002/eji.201041120. [Epub ahead of print]
Project Title:
miRNA-regulated LV gene transfer for the induction of Ag-specific tolerance.
Effectively establishing immune tolerance to prevent or resolve autoimmunity,
allergy, or gene transfer clearance is critical for developing successful
immunotherapies. An attractive approach to induce tolerance is to harness the
immunomodulatory abilities intrinsic to organs. The liver has potent immunoregulatory
effects that can induce both antigen (Ag)-specific and non-specific
tolerogenic responses. In particular, our recent studies show that the liver can induce
Ag-specific, CD4+ regulatory T cells (Treg) capable of mediating long-term tolerance
to a foreign Ag. These important findings raise many new questions regarding the
induction of immune regulation in the liver and how it can be exploited toward a
therapeutic goal.
One way to induce sustained immune tolerance is to establish a pool of Treg that can
suppress pathogenic effector T cells in an Ag-specific manner. Recently, we found
that tolerance induction in the liver depends upon the context in which the Ag is
recognized. When an LV-encoded Ag is widely expressed in the liver, including
antigen presenting cells (APC), a potent immune response develops, and cells
expressing the transgene are cleared. However, when the Ag expression is restricted
to hepatocytes using microRNA142-regulated (miR142T) expression cassette that
de-targets APC, tolerance is achieved and transgene expression is maintained. Thus,
we show that liver tolerance is conditional in our model system. Whether detargeting
APC is the natural process by which the liver induces tolerance has yet to
be established; regardless, induction of Ag-specific tolerance in this manner creates
a unique approach with translatable possibilities.
Aims of the project are the detailed characterization of the mechanism of Ag-specific
tolerance induction, and development of novel LV.142T gene-transfer platform
applications in which Ag-specific tolerance is desirable for correction of immune
disorders (autoimmunity, immune mediated neutralization of ERT).
Mátrai J, Cantore A, Bartholomae C, Annoni A, Wang W, Acosta-Sanchez A, Samara-
Kuko E De Waele L, Ma L, Genovese P, Damo M, Arens A, Goudy K, Nichols T, von
Kalle C, Chuah M, Roncarolo MG, Schmidt M, VandenDriessche T, Naldini L.
Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces
transgene-specific immune tolerance with low genotoxic risk. Hepatology (2011),
53:1696-707 .
Annoni A, Brown D.B., Cantore A., Sergi Sergi L, Naldini L, and Roncarolo MG. In
vivo delivery of a microRNA regulated transgene induces antigen-specific regulatory
T cells and promotes immunological tolerance. Blood (2009), 114:5152-6511.
Brown BD, Cantore A, Annoni A, Sergi Sergi L, Lombardo A, Della Valle P, D'Angelo
A, Naldini L. A microRNA-regulated lentiviral vector mediates stable correction of
hemophilia B mice. Blood (2007), 110:4144-52.
allergy, or gene transfer clearance is critical for developing successful
immunotherapies. An attractive approach to induce tolerance is to harness the
immunomodulatory abilities intrinsic to organs. The liver has potent immunoregulatory
effects that can induce both antigen (Ag)-specific and non-specific
tolerogenic responses. In particular, our recent studies show that the liver can induce
Ag-specific, CD4+ regulatory T cells (Treg) capable of mediating long-term tolerance
to a foreign Ag. These important findings raise many new questions regarding the
induction of immune regulation in the liver and how it can be exploited toward a
therapeutic goal.
One way to induce sustained immune tolerance is to establish a pool of Treg that can
suppress pathogenic effector T cells in an Ag-specific manner. Recently, we found
that tolerance induction in the liver depends upon the context in which the Ag is
recognized. When an LV-encoded Ag is widely expressed in the liver, including
antigen presenting cells (APC), a potent immune response develops, and cells
expressing the transgene are cleared. However, when the Ag expression is restricted
to hepatocytes using microRNA142-regulated (miR142T) expression cassette that
de-targets APC, tolerance is achieved and transgene expression is maintained. Thus,
we show that liver tolerance is conditional in our model system. Whether detargeting
APC is the natural process by which the liver induces tolerance has yet to
be established; regardless, induction of Ag-specific tolerance in this manner creates
a unique approach with translatable possibilities.
Aims of the project are the detailed characterization of the mechanism of Ag-specific
tolerance induction, and development of novel LV.142T gene-transfer platform
applications in which Ag-specific tolerance is desirable for correction of immune
disorders (autoimmunity, immune mediated neutralization of ERT).
Mátrai J, Cantore A, Bartholomae C, Annoni A, Wang W, Acosta-Sanchez A, Samara-
Kuko E De Waele L, Ma L, Genovese P, Damo M, Arens A, Goudy K, Nichols T, von
Kalle C, Chuah M, Roncarolo MG, Schmidt M, VandenDriessche T, Naldini L.
Hepatocyte-targeted expression by integrase-defective lentiviral vectors induces
transgene-specific immune tolerance with low genotoxic risk. Hepatology (2011),
53:1696-707 .
Annoni A, Brown D.B., Cantore A., Sergi Sergi L, Naldini L, and Roncarolo MG. In
vivo delivery of a microRNA regulated transgene induces antigen-specific regulatory
T cells and promotes immunological tolerance. Blood (2009), 114:5152-6511.
Brown BD, Cantore A, Annoni A, Sergi Sergi L, Lombardo A, Della Valle P, D'Angelo
A, Naldini L. A microRNA-regulated lentiviral vector mediates stable correction of
hemophilia B mice. Blood (2007), 110:4144-52.