Combination therapy with Brequinar sodium and cyclosporine synergistically prolongs hamster-to-rat cardia xenograft survival.
The accelerated rejection of hamster cardiac xenografts by Lewis rat recipients is due primarily to a humoral immune response. Traditional immunosuppressive agents, including cyclosporine, FK 506, and rapamycin, have not been effective in prolonging the rejection of xenografts in this model. We have recently examined the ability of the combination of cyclosporine and a new immunosuppressive agent, Brequinar sodium, to prevent the rejection of hamster xenografts. Prolongation of xenograft survival by treatment with Brequinar sodium alone (3 mg/kg/day) was minimally effective, with a median survival of 5.5 days. Conversely, a combination of Brequinar sodium (3 mg/kg/day) and cyclosporine (10 mg/kg/day), was associated with a significant prolongation of median graft survival (> 100 days). A quantitative analysis of the dose-effect relationship of Brequinar sodium and cyclosporine demonstrated a potent synergistic interaction for this combination therapy (combination index < 1). A sharp increase occurred in the binding of immunoglobulin M antibodies at day 4 after transplantation in the serum of untreated and cyclosporine-treated Lewis recipients of cardiac xenografts, whereas a clear decrease occurred in anti-hamster immunoglobulin M antibody production during this period of time in the animals treated by combined immunosuppression. Inhibition of anti-donor immunoglobulin M antibody production, as evaluated by the direct enzyme-linked immunosorbent assay and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide measurements, extended for more than 100 days after transplantation in the combination therapy group.(ABSTRACT TRUNCATED AT 250 WORDS)
Cosenza
C A
CA
Department of Surgery, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, Calif.
Cramer
D V
DV
Tuso
P J
PJ
Chapman
F A
FA
Wang
H K
HK
Makowka
L
L
D000005:Abdomen; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D006224:Cricetinae; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D004338:Drug Combinations; D004357:Drug Synergism; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008214:Lymphocytes / Q000276:immunology; D008647:Mesocricetus; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000276:immunology / Q000473:pathology; D016042:Transplantation, Heterotopic / Q000276:immunology / Q000473:pathology; D011798:Quinaldines
D000906:Antibodies; D001713:Biphenyl Compounds; D016572:Cyclosporine; D004338:Drug Combinations; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; C046943:brequinar; D011798:Quinaldines