Subject(s)
Graft vs Host Reaction , Immunosuppressive Agents/pharmacology , Lymph Nodes/immunology , Lymphocyte Transfusion , NF-kappa B/antagonists & inhibitors , T-Lymphocytes/immunology , Transcription Factor AP-1/antagonists & inhibitors , Transplantation, Homologous/immunology , Animals , Cyclosporine/pharmacology , Hyperplasia , Isoantigens/immunology , Lymph Nodes/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Organic Chemicals , Spleen , T-Lymphocytes/drug effects , Time FactorsSubject(s)
Biphenyl Compounds/pharmacology , Cyclosporine/pharmacology , Heart Transplantation/physiology , Immunosuppressive Agents/pharmacology , Isoxazoles/pharmacology , Lymphocyte Activation/drug effects , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/metabolism , Pyrimidines/biosynthesis , Animals , Animals, Newborn , Biphenyl Compounds/antagonists & inhibitors , Dihydroorotate Dehydrogenase , Heart Transplantation/immunology , Isoxazoles/antagonists & inhibitors , Leflunomide , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Orotic Acid/pharmacology , Rats , Transplantation, Homologous , Uridine/pharmacologyABSTRACT
Strategies targeting lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) and intercellular adhesion molecule-1 (ICAM-1) have previously been shown to produce long-term survival of solid organ allografts in animals only when both CD11a and ICAM-1 are targeted for a brief (6-7 days) time or when extended (14 weeks) treatment with anti-CD11a monoclonal antibody (mAb) is administered. We show that recipient pretreatment followed by a brief (13 days) treatment course with high-dose anti-CD11a mAb alone produces long-term survival of cardiac allografts in the rigorous, nonprimarily vascularized heart allograft model in mice. This treatment regimen induces specific unresponsiveness in our model. In recipients bearing long-term beating cardiac grafts after treatment with anti-CD11a mAb, there still exists a high frequency of potentially antigen-reactive T cells in isolated peripheral blood lymphocyte fractions. Therefore, clonal deletion does not appear to explain the induction of specific unresponsiveness by treatment with anti-CD11a mAb in this model. These findings support the further investigation of the use of high-dose anti-LFA-1 mAb monotherapy in the pre- and early postoperative period to promote solid organ allograft survival.