MODULATION OF THE CD2 RECEPTOR AND NOT DISRUPTION OF THE CD2 CD48 INTERACTION IS THE PRINCIPAL ACTION OF CD2-MEDIATED IMMUNOSUPPRESSION IN THE RAT/

CD48, the murine homolog of human CD58, binds to CD2 in rats and mice. Whereas inhibition of CD2 signaling leads to profound immunosuppressi on, no information is available on CD48-targeted therapy in the rat, W e could show that anti-CD2 treatment (OX34) efficiently inhibited TCR- driven as well as CD2-mediated proliferation, whereas blocking of liga nd binding (OX45) remained completely uneffective. Inhibition of allog eneic MLR by OX45 turned out to be due to induction of unspecific supp ressive mechanisms. In vivo OX45 failed to prolong rat heart allograft survival in contrast to that seen with OX34. Grafts were rejected des pite persistent and complete downmodulation of CD48 on lymphocytes wit hout any cell depleting effect, rendering receptor/ligand interactions physically impossible. Combined application of CD2 and CD48 mAb did n ot enhance immunosuppression induced by CD2 mAb alone. Provided that t here is no alternative CD2 ligand in the rat, we conclude that CD2 dir ected immunotherapy is mediated by suppressive events induced by modul ation of the CD2 receptor (''negative signaling'') rather than by mere disruption of the CD2-CD48 interaction. (C) 1997 Academic Press.