Administration of anti-CD4 monoclonal antibody with intrathymic injection of alloantigen results in rat cardiac allograft tolerance*

Abstract

We have previously reported the induction of donor-specific tolerance to cardiac allografts after intrathymic injection of alloantigen with simultaneous administration of antilymphocyte serum treatment to eliminate peripheral T cells. The present study determines whether prolongation of a fully major histocompatibility complex-mismatched cardiac allograft is achieved after a single administration of anti-CD4 monoclonal antibody (MoAb) combined with intrathymic injection of alloantigen. Male Buffalo rats were given Lewis splenocytes via the intrathymic or intravenous route in combination with a single administration of anti-CD4 monoclonal antibody (OX-38) or anti-CD8 MoAb (OX-8) or both. Heterotopic cardiac transplantation was performed 21 days after intrathymic alloantigen or MoAb pretreatment or both. Fluorescence-activated cell sorter analysis determined changes in lymphocyte compartment T-cell subsets, and in vitro studies examined recipient cellular reactivity. By 21 days after anti-CD4 MoAb treatment earlier nonspecific immunosuppression had resolved with 80% recovery of peripheral CD4+ T cells and restoration of recipient immunocompetence to allow normal rejection of a cardiac allograft. Combined treatment with intrathymic, but not intravenous, alloantigen plus anti-CD4 MoAb induced donor-specific tolerance to subsequent rat cardiac allografts. However, anti-CD8 MoAb combined with intrathymic alloantigen failed to induce tolerance despite a profound depletion of the CD8+ T-cell subset. Combined treatment of rats with intrathymic donor alloantigen and a single administration of anti-CD4, but not anti-CD8, MoAb significantly prolongs cardiac allograft survival across a fully major histocompatibility complex mismatched strain combination.