Prolonged survival of class II transactivator-deficient cardiac allografts.
BACKGROUND: Major histocompatibility complex (MHC) antigenic complexes trigger allogeneic T-cell responses and allograft rejection. MHC class II and related antigen processing genes, such as invariant chain (Ii) and H2-DM accessory molecules, are controlled by the master transcriptional regulator, class II transactivator (CIITA). CIITA also up-regulates MHC class I gene expression in vitro. Thus, disruption of a single factor, namely CIITA, represents an ideal strategy for reducing transplant rejection. METHODS: We studied the immunological advantages of transplanting CIITA deficient hearts into mismatched recipients in comparison to wild-type (B6) allografts or MHC class II-deficient (Abeta ) hearts. RESULTS: Elimination of CIITA greatly enhanced graft survival (median survival time [MST] 36 days) over the survival of wild-type (MST 9 days) and even over Abeta (MST 20 days) cardiac grafts. This was accompanied by greatly reduced mixed lymphocyte reactivity and in vivo antigen priming capacity. Analyses for CD4, CD8, and other inflammatory cells, plus cytotoxic T-cell activity and MHC class I specific alloantibody production, did not reveal significant differences in CIITA allograft tissues. Some cytokines that may support immunosuppression, such as transforming growth factor (TGF)-beta, were increased in mice receiving either Abeta or CIITA cardiac grafts. CONCLUSIONS: We conclude that disruption of CIITA function plays a beneficial role in preventing normal allogeneic T-cell responses. Even though inflammatory cells are present in CIITA allografts, the dramatic prolongation in allograft survival of CIITA hearts as compared with wild-type grafts provides a foundation for designing molecular therapies to interfere with MHC class II function and thereby reduce transplantation rejection.
June Brickey, W; Felix, NJ; Griffiths, R; Zhang, J; Wang, B; Piskurich, JF; Itoh-Lindstrom, Y; Coffman, TM; Ting, JP-Y
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