Aline Yen Ling Wang1, Charles Yuen Yung Loh2, Shyi-Jou Chen3, Huang-Kai Kao4, Cheng-Hung Lin5, Sheng-Hao Chuang6, Chin-Ming Lee7, Huey-Kang Sytwu8, Fu-Chan Wei9. 1. Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan. Electronic address: aline2355@yahoo.com.tw. 2. Division of Surgery and Interventional Science, University College London, London, United Kingdom; St Andrew's Center for Burns and Plastic Surgery, Chelmsford, United Kingdom. 3. Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan. 4. Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. 5. Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 6. Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 7. Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan. 8. Department of Microbiology and Immunology, Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. 9. Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Abstract
BACKGROUND: B lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is expressed in multiple cell lineages and in particular, T cells. However, the role of Blimp-1 in T cell-mediated allograft tolerance is still unknown. METHODS: This study is the first to investigate transplanted skin allograft survival using transgenic (Tg) mice with T cell overexpression of Blimp-1. RESULTS: Without any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. Allograft lymphocytic infiltration was decreased in Tg(+) mice and a dampened donor-stimulated alloimmune response was seen. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and IL-10-producing T cells, as well as cytolytic proteins, were significantly decreased in lymphoid organs and allograft. Blimp-1 transgenic T cells displayed an increased Treg differentiation capability and enhanced suppression of T cell proliferation. Overexpression of Blimp-1 in T cells promoted the formation of an anti-inflammatory cell-cytokine composition, both systemically and locally via transcription factor modulation such as T-bet downregulation and FoxP3 upregulation. DISCUSSION: As such, allograft survival was made possible due to Th1 suppression and Treg amplification with the creation of an 'allograft protective microenvironment'.
BACKGROUND:B lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is expressed in multiple cell lineages and in particular, T cells. However, the role of Blimp-1 in T cell-mediated allograft tolerance is still unknown. METHODS: This study is the first to investigate transplanted skin allograft survival using transgenic (Tg) mice with T cell overexpression of Blimp-1. RESULTS: Without any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. Allograft lymphocytic infiltration was decreased in Tg(+) mice and a dampened donor-stimulated alloimmune response was seen. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and IL-10-producing T cells, as well as cytolytic proteins, were significantly decreased in lymphoid organs and allograft. Blimp-1 transgenic T cells displayed an increased Treg differentiation capability and enhanced suppression of T cell proliferation. Overexpression of Blimp-1 in T cells promoted the formation of an anti-inflammatory cell-cytokine composition, both systemically and locally via transcription factor modulation such as T-bet downregulation and FoxP3 upregulation. DISCUSSION: As such, allograft survival was made possible due to Th1 suppression and Treg amplification with the creation of an 'allograft protective microenvironment'.