B Lymphocyte-induced Maturation Protein 1 (Blimp-1) Enhances Alloskin Graft Take via T-cell Immunomodulation

• Main Authors: Wei Hong Khoo, 古瑋紅
• Other Authors: F. C. Wei
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/w8yr6z

碩士 === 長庚大學 === 生物醫學研究所 === 104 === Safe, reliable strategies for the induction of full immunologic tolerance remains an elusive goal in transplant immunology and clinical transplantation. Skin is known to be the most immunogenic component of a composite tissue, hence in allotransplantation, it is the primary target of T cell-mediated rejection. Studies in the literature have demonstrated great difficulty in obtaining allograft acceptance in skin transplantation between fully mismatched MHC animals. B lymphocyte-induced maturation protein 1 (Blimp-1) was first discovered as a transcription factor that regulates the terminal differentiation of B cells into plasma cells. It is also expressed in multiple cell lineages and in particular, T cells. Blimp-1-deficient mice develop spontaneous inflammatory colitis mediated by the infiltration of activated T cells, with more effector T cells than wild type mice. This suggests that Blimp-1 may play a critical immunomodulatory role in the development of inflammatory or regulatory T cells (Treg). However, the role of Blimp-1 in T cell-mediated allograft tolerance has never been explored. In this study, transgenic (Tg) C57BL/6 mice with Blimp-1 overexpression in T cells were used to explore their potential roles in T cells following skin allograft transplantation. Without any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. A lesser degree of allograft lymphocytic infiltration in Tg(+) mice and dampened donor-stimulated alloimmune response were observed. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and type 1 regulatory T cells was significantly decreased in lymphoid organs and allograft, as well as cytolytic proteins. T-cell-intrinsic alloprotective effects of transgenic Blimp-1 T cells were confirmed when they were adoptively transferred to wild-type mice with ongoing allograft rejection. The evidence presented conclusively proves that overexpression of Blimp-1 in T cells is key in the orchestration of an anti-inflammatory cell-cytokine composition, both systemically, peri-graft and locally, which in turn results in the promotion of high allogeneic graft survival through the creation of an ‘allograft protective microenvironment’.