Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplant
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Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplant. / Gagliani, Nicola; Jofra, Tatiana; Stabilini, Angela; Valle, Andrea; Atkinson, Mark; Roncarolo, Maria-Grazia; Battaglia, Manuela.
in: DIABETES, Jahrgang 59, Nr. 2, 02.2010, S. 433-9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplant
AU - Gagliani, Nicola
AU - Jofra, Tatiana
AU - Stabilini, Angela
AU - Valle, Andrea
AU - Atkinson, Mark
AU - Roncarolo, Maria-Grazia
AU - Battaglia, Manuela
PY - 2010/2
Y1 - 2010/2
N2 - OBJECTIVE: In type 1 diabetes, allogeneic pancreatic islet transplant restores insulin production, but life-threatening immunosuppression is required to avoid graft rejection. Induction of antigen (Ag)-specific tolerance by cell therapy with regulatory T-cells (Tregs) represents an attractive alternative approach but its therapeutic efficacy in islet transplant remains to be determined. Among the different subsets of CD4(+) Tregs, the T inducible regulatory type 1 (Tr1) cells can be generated from naive T-cells in the presence of interleukin-10 (IL-10) and represent one promising therapeutic choice. This study was designed to define the efficacy of Tr1-cell therapy in preclinical models of islet transplant.RESEARCH DESIGN AND METHODS: Non-Ag-specific polyclonal Tr1 cells and donor Ag-specific Tr1 cells were transferred, in the absence of any pharmacological treatment, in two distinct mouse models of islet transplant. The two models differed in their therapeutic stringency, based on the mean rejection time of untreated mice that underwent a transplant.RESULTS: Transfer of polyclonal Tr1 cells engendered graft tolerance only in the nonstringent mouse model. Conversely, cell therapy with Ag-specific Tr1 cells induced an IL-10-dependent tolerance in the stringent mouse model of islet transplant. The therapeutic advantage of Ag-specific Tr1 cells over polyclonal Tr1 cells was due to their donor Ag specificity.CONCLUSIONS: These results demonstrate that Tr1-cell therapy leads to tolerance in settings of islet transplant and that its therapeutic efficacy is highly dependent on the antigen specificity of these cells.
AB - OBJECTIVE: In type 1 diabetes, allogeneic pancreatic islet transplant restores insulin production, but life-threatening immunosuppression is required to avoid graft rejection. Induction of antigen (Ag)-specific tolerance by cell therapy with regulatory T-cells (Tregs) represents an attractive alternative approach but its therapeutic efficacy in islet transplant remains to be determined. Among the different subsets of CD4(+) Tregs, the T inducible regulatory type 1 (Tr1) cells can be generated from naive T-cells in the presence of interleukin-10 (IL-10) and represent one promising therapeutic choice. This study was designed to define the efficacy of Tr1-cell therapy in preclinical models of islet transplant.RESEARCH DESIGN AND METHODS: Non-Ag-specific polyclonal Tr1 cells and donor Ag-specific Tr1 cells were transferred, in the absence of any pharmacological treatment, in two distinct mouse models of islet transplant. The two models differed in their therapeutic stringency, based on the mean rejection time of untreated mice that underwent a transplant.RESULTS: Transfer of polyclonal Tr1 cells engendered graft tolerance only in the nonstringent mouse model. Conversely, cell therapy with Ag-specific Tr1 cells induced an IL-10-dependent tolerance in the stringent mouse model of islet transplant. The therapeutic advantage of Ag-specific Tr1 cells over polyclonal Tr1 cells was due to their donor Ag specificity.CONCLUSIONS: These results demonstrate that Tr1-cell therapy leads to tolerance in settings of islet transplant and that its therapeutic efficacy is highly dependent on the antigen specificity of these cells.
KW - Animals
KW - Blood Glucose
KW - CD4 Antigens
KW - CD4-Positive T-Lymphocytes
KW - Diabetes Mellitus, Experimental
KW - Disease Models, Animal
KW - Enzyme-Linked Immunosorbent Assay
KW - Female
KW - Graft Rejection
KW - Islets of Langerhans Transplantation
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C3H
KW - Mice, Inbred C57BL
KW - Rats
KW - T-Lymphocytes, Regulatory
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.2337/db09-1168
DO - 10.2337/db09-1168
M3 - SCORING: Journal article
C2 - 19934002
VL - 59
SP - 433
EP - 439
JO - DIABETES
JF - DIABETES
SN - 0012-1797
IS - 2
ER -