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 11 and related antigen processing genes, such as invariant chain (Ii) and H2-DM accessory molecules, are controlled by the master transcriptional regulator, class 11 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 re, activity 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 11 function and thereby reduce transplantation rejection.