CYCLOPHOSPHAMIDE, BUT NOT CTLA4IG, PROLONGS SURVIVAL OF FETAL PIG ISLET GRAFTS IN ANTI-T CELL MONOCLONAL ANTIBODY-TREATED NOD MICE

Fetal pig islets, xenografted after organ culture into non-immunosuppr essed prediabetic NOD mice, are rejected within 10 days. Immunosuppres sion with anti-T cell (anti-CD4 and anti-CD3) monoclonal antibodies al one is highly effective in delaying graft rejection in this discordant model, but rejection eventually occurs, usually within 80 days, despi te marked depletion of T cells. In an attempt to prevent rejection, we used cyclophosphamide (CP), a powerful anti-B cell agent, or CTLA4Ig, an inhibitor of T-cell co-stimulation [via B7-1 (CD80) and B7-2 (CD86 )], either given in combination with anti-CD4 (GK1.5) or anti-CD3 (KT3 ) MAb to the recipient mice. The addition of cyclophosphamide in a dos e that significantly depleted B cells in peripheral blood was highly e ffective in preventing rejection, with xenografts surviving for at lea st 112 days, when the experiment was terminated. CTLA4Ig, administered alone, did not prevent delayed rejection (rejection occurred in <60 d ays) and, in contrast to CP, did not prevent delayed rejection when us ed in combination with GK1.5 and KT3 treatment. Thus, immunosuppressiv e agents found to be highly effective in other strains, e.g., CTLA4Ig and anti-T cell MAbs, had a lesser effect in NOD mice but the addition of an anti-B cell drug, CP, was useful. This finding may be applicabl e to patients with IDDM.