A NOVEL MURINE MODEL FOR THE ASSESSMENT OF HUMAN CD2-RELATED REAGENTSIN-VIVO

CD2 is a T cell surface glycoprotein that mediates both cell-cell adhe sion and transmembrane signal transduction. To construct a model for t he in vivo evaluation of human (h)CD2 function and hCD2-related reagen ts, hCD2 transgenic mice and murine (m)CD2 knockout mice were crossed, and the F-2 generation selected for mCD2(-) hCD2(+) animals by fluore scent flow cytometry, The mCD2(-)hCD2(+) mice are healthy and have a n ormal distribution of mCD3, mCD4, and mCD8 in thymus, spleen, and lymp h node. Therefore expression of the hCD2 transgene does not appear to disrupt normal T cell development, The functionality of hCD2 was demon strated by T lymphocyte proliferation upon stimulation by combined ant i-CD2 plus anti-CD2R (anti-T11(2) plus anti-T11(3)) mAbs. Anti-T11(2) plus anti-T11(3) anti-human CD2 mAbs also induced proliferation of mCD 2(+)hCD2(+)F(1) lymphocytes, but not mCD2(+)hCD2(-) wild-type murine l ymphocytes. Either an anti-murine or the human CD2 specific (anti-T11( 1)) mAbs inhibited proliferation in alloantigen, PHA, or anti-CD3 mAb stimulated cultures and inhibited only cells bearing the appropriate c ognate CD2. In vivo studies of immune function yielded results consist ent with these in vitro assays, Thus, anti-T11(1) mAb suppressed conta ct sensitivity in vivo in the transgenic/knockout mice. mCD2(-)hCD2(+) mice treated with anti-T11(1) or LFA-3 fusion proteins also showed si gnificant prolongation of cardiac allograft survival, This prolongatio n was associated both with depletion and down-modulation of CD2 on rem aining T cells, These data suggest that the transgenic/knockout mice p rovide a useful in vivo model for the assessment of hCD2-related reage nts and CD2 function, free from any potential interactions with mCD2 a nd mCD2 ligands.