Cyclosporine dosage can be reduced when used in combination with an anti-intercellular adhesion molecule-1 monoclonal antibody in rats undergoing heterotopic heart transplantation.
BACKGROUND
Intercellular adhesion molecule-1 (ICAM-1) is believed to play a role in acute rejection of allografted tissues. This molecule is involved in the interaction of T cells with antigen-presenting cells expressed on the vascular endothelium of transplanted organs and is involved in the adhesion of inflammatory cells to this endothelium and their subsequent migration into the underlying tissues.


METHODS
Rat abdominal heterotopic heart transplantation was used to study the role of ICAM-1 in the rejection process. American Cancer Institute rats were used as donors; Lewis rats were used as recipients. Graft survival was monitored daily via donor heart palpation. Nine groups (n = 6/group) were studied: untreated controls; olive oil; cyclosporine at 1.5, 2.75, and 5.0 mg/kg, respectively; R3.1, a control monoclonal antibody; 1A29, a rat anti-ICAM-1 monoclonal antibody, 3 mg/kg administered intraperitoneally; a combination of 1A29 (3 mg/kg) and cyclosporine (1.5 mg/kg); and a combination of 1A29 (3 mg/kg) and cyclosporine (2.75 mg/kg).


RESULTS
Mean rejection time was 8.8 +/- 0.6 days for the untreated allografted controls and 9.7 +/- 1.1 days for the olive oil controls. Cyclosporine (1.5, 2.75, and 5.0 mg/kg) showed mean rejection times of 8.5 +/- 0.3, 20.5 +/- 1.9, and 28.8 +/- 3.6 days, respectively. The 1A29 treatment showed a mean rejection time of 9.3 +/- 0.7 days. Combination therapy of 1A29 and cyclosporine at 1.5 or 2.75 mg/kg demonstrated mean rejection times of 17.7 +/- 3.3 and 29.2 +/- 6.7 days, respectively. Thus 1A29 alone does not prolong cardiac allograft survival; however, combination therapy with either a subthreshold or a moderate dose of cyclosporine significantly extends the time to rejection of heterotopically transplanted rat hearts.


CONCLUSIONS
Although monotherapy with an ICAM-1 antagonist alone may not be beneficial in preventing acute rejection episodes after organ transplantation, combination therapy of an anti-ICAM-1 monoclonal antibody may allow for a reduction in the dose of cyclosporine necessary for immune suppression. Such a reduction could lead to a lowering of the incidence of nephrotoxicity and other side effects associated with long-term cyclosporine administration.
Harrison
P C
PC
Department of Immunological Diseases, Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut 06877-0368, USA.
Mainolfi
E
E
Madwed
J B
JB
D000005:Abdomen; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D016572:Cyclosporine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000276:immunology; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine