Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model.
BACKGROUND
Chronic graft vascular disease (CGVD) in cardiac allografts has been defined as a slowly evolving vasculopathy unresponsive to conventional immunosuppression. We compared 4 rodent models of CGVD to evaluate the reproducibility of CGVD in heart allografts. Rapamycin (Rapa) and cyclosporine (CSA) were then used to treat CGVD.


RESULTS
Hearts were harvested and placed heterotopically into allogenic recipients. CGVD scores of PVG allografts from ACI recipients treated with CSA on days 1 through 10 were significantly elevated on day 90 (n=16) compared with other models (immunosuppression used): (1) Lewis to F344 recipients (CSA), (2) Brown Norway to Lewis (FK506), and (3) DA to Wistar-Firth (methylprednisolone, azathioprine, CSA). Although delayed (day 60 to 90) CSA treatment had no effect (n=6), delayed Rapa (3 mg. kg-1. d-1 IP) reversed CGVD in PVG grafts (0.22+/-0.19 on day 90, n=6). ACI isografts showed no evidence of CGVD (n=6) at day 90. Immunohistochemistry of PVG grafts revealed perivascular infiltrates consisting of CD4(+) T cells and limited numbers of macrophages persisting up to day 90. Flow cytometry demonstrated increased levels of anti-donor antibody at day 90, which was significantly inhibited by Rapa treatment.


CONCLUSIONS
PVG grafts developed a significant increase in CGVD without evidence of ongoing myocardial rejection. This CGVD appeared to be mediated by both cellular and humoral mechanisms, given CD4(+) perivascular infiltrates and increased levels of anti-donor antibody. The anti-CGVD effectiveness of Rapa during a period in which there was little myocardial cellular infiltrate supports a novel mechanism of effect such as smooth muscle or B-cell inhibition.
Stanford University School of Medicine, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford, CA, USA.
R S
RS
Poston
M
M
Billingham
E G
EG
Hoyt
J
J
Pollard
R
R
Shorthouse
R E
RE
Morris
R C
RC
Robbins
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000918:Antibody Specificity; D003327:Coronary Disease / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D016572:Cyclosporine / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005434:Flow Cytometry; D006084:Graft Rejection; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000276:immunology; D006648:Histocompatibility; D006649:Histocompatibility Antigens / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects; D007074:Immunoglobulin G / Q000097:blood; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D011912:Rats, Inbred ACI; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D015203:Reproducibility of Results; D020123:Sirolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology
D006649:Histocompatibility Antigens; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007518:Isoantibodies; C038353:histocompatibility antigens RT, rat; D009569:Nitric Oxide; D016572:Cyclosporine; D020123:Sirolimus