No abstract

Although low doses of tumor-derived stress protein gp96 elicit protective immunity to the tumor from which it is isolated, protection is lost at high doses because of the induction of immunoregulatory CD4 ϩ T cells. This study evaluated the influence of gp96 on resting rat bone marrow-derived dendritic cells (BMDCs) and purified CD3 ϩ T cells. In contrast to previous reports, gp96 had no effect on adhesion and costimulatory molecule expression by BMDCs, nor did it influence interleukin (IL)-10 and IL-12 secretion or their allostimulatory capacity. Gp96 did not bind to BMDCs but dose-dependently bound to CD4 ϩ and CD8 ϩ T cells. At low concentrations (1 and 25 g/mL), gp96 acted as a costimulator of CD3 ϩ T cells, inducing proliferation and the secretion of interferon (IFN)-␥ and IL-10. Gp96 also increased the proliferation of CD28-costimulated CD3 ϩ T cells and their secretion of IFN-␥, IL-4, and IL-10. Gp96 had no effect at higher concentrations (50 and 100 g/mL), despite the occurrence of cell surface binding at these concentrations. These findings indicate that gp96 can act as a costimulatory molecule for CD3 ϩ T cells, and an observed increase in the IL-10:IFN-␥ secretion ratio induced by gp96 suggests that it might, at appropriate concentrations, promote a regulatory T-helper 2 (Th2)-like phenotype.

No abstract

High-dose gp96 has been shown to inhibit experimental autoimmune disease by a mechanism that appears to involve immunoregulatory CD4 ϩ T cells. This study tested the hypothesis that high-dose gp96 administration modifies allograft rejection and associated inflammatory events. Wistar cardiac allografts were transplanted into Lewis recipient rats and graft function was monitored daily by palpation. Intradermal administration of gp96 purified from Wistar rat livers (100 g) at the time of transplantation and 3 days later significantly prolonged allograft survival (14 vs 8 days in phosphate-buffered saline [PBS]-treated recipients; P ϭ 0.009). Rejected allografts from gp96-treated animals were significantly less enlarged than allografts from their PBS-treated counterparts (2.8 vs 4.3 g; P Ͻ 0.004). Gp96 was also effective when administered on days 1 and 8 (13 vs 7 days), but not if it was derived from recipient (Lewis) liver tissue or administered on days 0, 3, and 6. In parallel studies, CD3 ϩ T cells from gp96-treated untransplanted animals secreted less interleukin (IL)-4, IL-10, and interferon (IFN)-␥ after in vitro polyclonal stimulation than CD3 ϩ T cells from PBS-treated animals. Gp96 administration might therefore influence the induction of immunity to coencountered antigenic challenges and inflammatory events by inducing what appears to be a state of peripheral T-cell hyporesponsiveness.