Blockade of LIGHT/HVEM and B7/CD28 Signaling Facilitates Long-Term Islet Graft Survival With Development of Allospecific Tolerance

Kexing Fan, Hao Wang, Huafeng Wei, Qian Zhou, Geng Kou, Sheng Hou, Weizhu Qian, Jianxin Dai, Bohua Li, Yanyun Zhang, Tongyu Zhu, Yajun Guo
2007 Transplantation  
Background. Previous studies have shown that blockade of LIGHT, a T-cell costimulatory molecule belonging to the tumor necrosis factor (TNF) superfamily, by soluble lymphotoxin ␤ receptor-Ig (LT␤R-Ig) inhibited the development of graft-versus-host disease. The cardiac allografts were significantly prolonged in LIGHT deficient mice. No data are yet available regarding the role of the LIGHT/HVEM pathway in more stringent fully allogeneic models such as skin and islet transplantation models.
more » ... ation models. Methods. Streptozotocin-induced chemical diabetic BALB/C mice underwent transplantation with allogeneic C57BL/6 islets and were treated with LT␤R-Ig, CTLA4-Ig or a combination of both in the early peritransplant period. Results. Administration of CTLA4-Ig or LT␤ R-Ig alone only increased graft survival to 55 days and 27 days respectively, whereas simultaneous blockade of both pathways significantly prolonged the islet allograft survival for more than 100 days. Long-term survivors were retransplanted with donor-specific (C57BL/6) islets and the grafted islets remained functional for more than 100 days. All of islet allografts were protected against rejection when the mixtures of 1ϫ10 6 CD4 ϩ T cells from tolerant mice and islet allografts were cotransplanted under the renal capsule of the naïve BALB/c recipients. Conclusions. These data indicate that: 1) a synergistic effect for prolonged graft survival can be obtained by simultaneously blocking LIGHT and CD28 signaling in the stringent model of islet allotransplantation; 2) development of donor-specific immunological tolerance is associated with the presence of regulatory T-cell activity; and 3) local cotransplantation of the allografts with the regulatory T cells can effectively prevent allograft rejection and induce donor-specific tolerance in lymphocytes-sufficient recipients.
doi:10.1097/01.tp.0000280545.14489.df pmid:17893608 fatcat:3xngiqlw7ffyxdpzofacwohjiu