Administration of the stress protein gp96 prolongs rat cardiac allograft survival, modifies rejection-associated inflammatory events, and induces a state of peripheral T-cell hyporesponsiveness

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.

Extracellular cell stress (heat shock) proteins—immune responses and disease: an overview

“…In contrast, no protective effect is observed when high doses (2x10 µg intradermally) of tumour-derived gp96 are administered to mice (125). Furthermore, appropriate doses of gp96 purified from normal liver can suppress the onset of diabetes in non-obese diabetic mice and myelin basic protein-or proteolipid protein-induced autoimmune encephalomyelitis (EAE) in SJL mice (127), as well as prolonging the survival of murine skin allografts (128) and rat cardiac allografts (129). The mechanisms that underlie these effects were originally proposed to involve the induction, activation and/or recruitment of as yet unidentified immunoregulatory T cell populations (127,128).…”

Heat-Shock Proteins in Autoimmunity

“…How the same proteins can mediate opposite outcomes is a dilemma for both basic researchers and physician investigators. This dual role of HSPs has been revealed in a wide variety of disorders, including autoimmune diseases and tumors, as well as in immune responses associated with organ transplantation [7, 8, 10, 13, 15, 17, 18]. It is becoming clear that the pro- versus anti-inflammatory activities of HSPs are contextual and affected by multiple factors including the concentration of HSP, the timing of exposure to HSP, and the overall physiopathological milieu at the target site.…”

Toll-like receptor signaling in transplantation

“…However, HSP gp96 can also inhibit immune responses, as treatment with HSP gp96 resulted in improved survival of mouse skin allografts bearing either minor or major mismatches [81]. In a model of rat cardiac allograft, administration of high doses of HSP gp96 purified from donor but not recipient strain livers also resulted in prolongation of graft survival that was associated with T cell hyporesponsivenes to polyclonal stimuli [82]. Finally, although transgenic expression of membrane-bound HSP gp96 resulted in hyper-responsiveness to LPS and a TLR4-dependent lupus-like syndrome, it was also shown to increase the suppressive function of Tregs in a TLR4-dependent manner, providing a putative mechanism for the regulatory properties of damage-associated TLR ligands [83].…”