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.
High-dose gp96 has been shown to inhibit experimental autoimmune disease by a mechanism that appears to involve immunoregulatory CD4+ 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 microg) 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 = 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 < 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+ T cells from gp96-treated untransplanted animals secreted less interleukin (IL)-4, IL-10, and interferon (IFN)-gamma after in vitro polyclonal stimulation than CD3+ 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.
Slack
Laura K
LK
Immunobiology Research Unit, School of Medicine and Biomedical Sciences (University of Sheffield), L Floor, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK.
Muthana
Munitta
M
Hopkinson
Kay
K
Suvarna
S Kim
SK
Espigares
Elena
E
Mirza
Shabana
S
Fairburn
Barbara
B
Pockley
A Graham
AG
D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000379:methods*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
D017252:CD3 Complex; D016207:Cytokines; D008562:Membrane Glycoproteins; C053387:endoplasmin