Cyclophosphamide, but not CTLA4Ig, prolongs survival of fetal pig islet grafts in anti-T cell monoclonal antibody-treated NOD mice

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Fetal pig islets, xenografted after organ culture into nonimmunosuppressed prediabetic NOD mice, are rejected within 10 days. Immunosuppression with anti-T cell (anti-CD4 and anti-CD3) monoclonal antibodies alone is highly effective in delaying graft rejection in this discordant model, but rejection eventually occurs, usually within 80 days, despite 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 dose that significantly depleted B cells in peripheral blood was highly effective in preventing rejection, with xenografts surviving for at least 112 days, when the experiment was terminated. CTLA4Ig, administered alone, did not prevent delayed rejection (rejection occurred in <60 days) and, in contrast to CP, did not prevent delayed rejection when used in combination with GK1.5 and KT3 treatment. Thus, immunosuppressive 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 applicable to patients with IDDM.

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