INDUCTION OF TOLERANCE WITH NONDEPLETING ANTI-CD4 MONOCLONAL-ANTIBODIES IS ASSOCIATED WITH DOWN-REGULATION OF TH2 CYTOKINES

Background. Induction of tolerance with anti-CD4 has mainly focused on monoclonal antibodies (mAbs) that deplete CD4(+) T cells. In this stu dy, the mechanisms by which nondepleting anti-CD4 mAbs induce toleranc e in the Dark Agouti to PVG rat heart graft model were examined, Metho ds. Five anti-CD4 mAbs were tested, Immuno-histology and cytokine mRNA profiles were analyzed within grafts. Effects of combining anti-CD4 t herapy with alloantibody (alloAb), interleukin (IL)-4, and anti-IL-4 m Ab were also examined, Results. All mAbs tested induced indefinite gra ft survival (>150 days), with blocking of alloAb production. Exogenous alloAb did not restore rejection. Similar T cell. receptor alpha beta (+), CD8(+), IL-2 receptor(+) T cell, macrophage, and natural killer c ell infiltration and comparable MHC II and intercellular adhesion mole cule-1 levels were seen in rejecting and tolerant grafts, mRNA for IL- 2, interferon-gamma, lymphotoxin, tumor necrosis factor-alpha, transfo rming growth factor-beta, cytolysin, and granzyme-A/B was comparable, although inducible nitric oxide synthase was slightly reduced in toler ant grafts. IL-4 and IL-5 were significantly reduced in tolerant graft s, although IL-6, IL-10, and IL-13 levels were similar; this was consi stent with partial T helper (Th)2 response inhibition, which was also manifested by inhibited alloAb. The combination of alloAb, IL-4, or an ti IL-4 mAb with anti-CD4 did not prevent tolerance induction. Conclus ions. This study demonstrated that anti-CD4 mAb therapy did not inhibi t activation and infiltration of Th1 and CD8(+) effector T cells. pref erential induction of Th2 responses, especially IL-4, was not essentia l for the induction of tolerance, Our studies also found no evidence t o support induction of anergy or transforming growth factor-beta as me chanisms of tolerance induction. These results question whether IL-4 i s required for induction of transplantation tolerance.