Anti-LFA-1 alpha reduces the dose of cyclosporin A needed to produce immunosuppression in heterotopic cardiac transplanted rats.
BACKGROUND
Monoclonal antibodies (MAb) against cell adhesion molecules prolong the time to acute rejection of transplanted organs in animals. Postulated mechanisms of action include blockade of trafficking of host leukocytes into or recognizing of effector/target cells within the allograft. We examined whether an anti-ICAM-1 (1A29), anti-LFA-1 alpha (WT.1), or anti-CD-18 (WT.3) could reduce the immunosuppressive dose of cyclosporin A (CsA) when used in combination.


METHODS
A rat heterotopic cardiac transplant model with ACI donors and Lewis recipients was used. MAb dose was 3 mg/kg, i.p. with treatment on Days -3 and -1 prior to transplant, followed by daily dosing for 10 days post-transplantation (Tx). Cyclosporin A doses were either 1.5 or 2.75 mg/kg, PO beginning the day of and for 10 days post-Tx.


RESULTS
Untreated allografted rats demonstrated a mean rejection time (MRT) +/- SEM of 8.8 +/- 0.6 days. Cyclosporin A at 1.5 and 2.75 mg/kg showed mean rejection times of 8.5 +/- 0.3 (NS) and 20.5 +/- 1.9 (p < 0.05) days, respectively. Monotherapy with 1A29 or WT.3 did not prolong MRT, whereas WT.1 increased MRT to 21.7 +/- 4.3 days (p < 0.05). MAb combination therapy did not extend MRT greater than that demonstrated by WT.1 alone. However, MAb and CsA combination therapy significantly increased MRT with WT.1 and CsA resulting in the greatest extension. WT.1 combination with CsA at 1.5 mg/kg and 2.75 mg/kg increased MRT to > 46.8 +/- 6.3 and > 44.2 +/- 9.4 days, respectively.


CONCLUSIONS
Anti-LFA-1 alpha and CsA combination therapy significantly extends the time to rejection of transplanted rat hearts. We conclude that combining an anti-LFA-1 alpha and CsA may be beneficial in prolonging allograft rejection times and in reducing the amount of CsA necessary for immune suppression, thereby minimizing its toxic effects.
Harrison
P C
PC
Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877-0368, USA.
Madwed
J B
JB
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D018821:CD18 Antigens / Q000276:immunology; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008297:Male; D011292:Premedication; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine