Induction of xenogeneic islet transplantation tolerance by simultaneously blocking CD28-B7 and OX40-OX40L co-stimulatory pathways

Abstract

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.

Efficacy of pretreatment of allografts with methoxypolyethylene glycol-succinimidyl-propionic acid ester in combination with an anti-OX40L monoclonal antibody in relieving graft-versus-host disease in mice

“…T lymphocytes mediated by CD28/B7 [7]. Therefore, blocking the OX40/ OX40L co-stimulatory signaling pathway can inhibit the activation of T lymphocytes and induce immune tolerance [8]. The activation of donor T lymphocytes is a key step in GVHD development [9,10].…”