Feng-Cheng Chou1, Heng-Yi Chen2, Hsin-Hui Chen3, Gu-Jiun Lin4, Shih-Hua Lin5, Huey-Kang Sytwu6,7. 1. Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan. 2. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. 3. Department of Medicine, National Defense Medical Center, Taipei, Taiwan. 4. Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan. 5. Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. 6. Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, 161, Section 6, MinChuan East Road, Neihu, Taipei 114, Taiwan. sytwu@ndmctsgh.edu.tw. 7. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. sytwu@ndmctsgh.edu.tw.
Abstract
AIMS/HYPOTHESIS: The relative contribution of T helper (Th)1 and Th17 cells in graft rejection is inconclusive, on the basis of evidence provided by different T cell-related cytokine-deficient animal models and graft types. METHODS: We used novel antigen-presenting-cell-specific Il-12p35 (also known as Il12a)-knockout (KO), IL-23p19-knockdown (KD) and IL-27p28-KD strategies to investigate T cell differentiation in islet graft rejection. RESULTS: In vitro dendritic cell-T cell coculture experiments revealed that dendritic cells from Il-12p35-KO and IL-23p19-KD mice showed reduced ability to stimulate IFN-γ and IL-17 production in T cells, respectively. To further explore the T cell responses in islet graft rejection, we transplanted islets into streptozotocin-induced diabetic NOD/severe combined immunodeficiency (SCID) recipient mice with IL-12-, IL-23-, or IL-27-deficient backgrounds and then challenged them with NOD.BDC2.5 T cells. The survival of islet grafts was significantly prolonged in Il-12p35-KO and IL-23p19-KD recipients compared with the control recipients. T cell infiltrations and Th1 cell populations were also decreased in the grafts, correlating with prolonged graft survival. CONCLUSIONS/ INTERPRETATION: Our results suggest that IL-12 and IL-23 promote and/or maintain Th1 cell-mediated islet graft rejection. Thus, blockade of IL-12 and IL-23 might act as therapeutic strategies for reducing rejection responses.
AIMS/HYPOTHESIS: The relative contribution of T helper (Th)1 and Th17 cells in graft rejection is inconclusive, on the basis of evidence provided by different T cell-related cytokine-deficient animal models and graft types. METHODS: We used novel antigen-presenting-cell-specific Il-12p35 (also known as Il12a)-knockout (KO), IL-23p19-knockdown (KD) and IL-27p28-KD strategies to investigate T cell differentiation in islet graft rejection. RESULTS: In vitro dendritic cell-T cell coculture experiments revealed that dendritic cells from Il-12p35-KO and IL-23p19-KD mice showed reduced ability to stimulate IFN-γ and IL-17 production in T cells, respectively. To further explore the T cell responses in islet graft rejection, we transplanted islets into streptozotocin-induced diabetic NOD/severe combined immunodeficiency (SCID) recipient mice with IL-12-, IL-23-, or IL-27-deficient backgrounds and then challenged them with NOD.BDC2.5 T cells. The survival of islet grafts was significantly prolonged in Il-12p35-KO and IL-23p19-KD recipients compared with the control recipients. T cell infiltrations and Th1 cell populations were also decreased in the grafts, correlating with prolonged graft survival. CONCLUSIONS/ INTERPRETATION: Our results suggest that IL-12 and IL-23 promote and/or maintain Th1 cell-mediated islet graft rejection. Thus, blockade of IL-12 and IL-23 might act as therapeutic strategies for reducing rejection responses.
Authors: Ivan D Mascanfroni; Ada Yeste; Silvio M Vieira; Evan J Burns; Bonny Patel; Ido Sloma; Yan Wu; Lior Mayo; Rotem Ben-Hamo; Sol Efroni; Vijay K Kuchroo; Simon C Robson; Francisco J Quintana Journal: Nat Immunol Date: 2013-09-01 Impact factor: 25.606
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