Induction of xenogeneic islet transplantation tolerance by simultaneously blocking CD28-B7 and OX40-OX40L co-stimulatory pathways.
It has been demonstrated that prolonged graft survival can be achieved through inhibiting the activation of T cells, and addition of soluble CTLA4Ig and OX40Ig proteins to mixed lymphocyte reactions can effectively inhibit T cell proliferation. To explore the potential of this type of treatment in xenotransplantation, we infected streptozotocin-induced diabetic BalB/c mice (H-2d) (200 mg/kg, IV) with 5 x 10(8) pfu AdCTLA4Ig-IRES-OX40Ig on day 1 before islets transplantation through the tail vein. The results showed that this treatment prolonged the islet xenografts survival significantly. The reaction to exogenous glucose stimulation was normal and the cytokine secretion of the type Th1 cells was inhibited. The AdCTLA4Ig-IRES-OX40Ig-mediated treatment effectively induced the T cells into anergy and the Th1/Th2 cells into deviation. These results strongly supported the therapeutic potential of blockade of costimulation by AdCTLA4Ig-IRES-OX40Ig genes transfer in inducing the organ transplantation tolerance.
Wang
Guangming
G
Department of Immunology, Peking University Health Science Center, Beijing 100083, China.
Feng
Yougang
Y
Hao
Jie
J
Li
Ailing
A
Gao
Xiang
X
Xie
Shusheng
S
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000628:therapy; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D018796:Immunoconjugates / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053278:OX40 Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology
D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D053278:OX40 Ligand; C406562:OX40Ig; D053262:Receptors, OX40; C505718:Tnfrsf4 protein, rat; D000069594:Abatacept