Blockade of LIGHT/HVEM and B7/CD28 signaling facilitates long-term islet graft survival with development of allospecific tolerance.
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 beta receptor-Ig (LTbetaR-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.


METHODS
Streptozotocin-induced chemical diabetic BALB/C mice underwent transplantation with allogeneic C57BL/6 islets and were treated with LTbetaR-Ig, CTLA4-Ig or a combination of both in the early peritransplant period.


RESULTS
Administration of CTLA4-Ig or LTbeta 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 1x10(6) CD4+ 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.
Fan
Kexing
K
International Joint Cancer Institute, The Second Military Medical University, Shanghai, PR China.
Wang
Hao
H
Wei
Huafeng
H
Zhou
Qian
Q
Kou
Geng
G
Hou
Sheng
S
Qian
Weizhu
W
Dai
Jianxin
J
Li
Bohua
B
Zhang
Yanyun
Y
Zhu
Tongyu
T
Guo
Yajun
Y
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen / Q000187:drug effects; D018106:CD28 Antigens / Q000187:drug effects*; D006085:Graft Survival; D018796:Immunoconjugates / Q000008:administration & dosage; D007136:Immunoglobulins / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000037:antagonists & inhibitors*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D018106:CD28 Antigens; D018796:Immunoconjugates; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D053240:Receptors, Tumor Necrosis Factor, Member 14; D000069594:Abatacept