Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis.
CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.
Russell
M E
ME
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, MA 02115, USA. russell@cvlab.harvard.edu.
Hancock
W W
WW
Akalin
E
E
Wallace
A F
AF
Glysing-Jensen
T
T
Willett
T A
TA
Sayegh
M H
MH
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects*; D000943:Antigens, Differentiation / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000517:prevention & control; D018122:B7-1 Antigen / Q000187:drug effects; D001483:Base Sequence; D018106:CD28 Antigens / Q000187:drug effects; D060908:CTLA-4 Antigen; D003331:Coronary Vessels / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D051381:Rats; D011916:Rats, Inbred F344; D014184:Transplantation, Homologous; D015854:Up-Regulation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept