LONG-TERM SURVIVAL OF RAT TO MOUSE CARDIAC XENOGRAFTS WITH PROLONGED BLOCKADE OF CD28-B7 INTERACTION COMBINED WITH PERITRANSPLANT T-CELL DEPLETION

Background. The hCTLA4Ig/mCTLA4Ig fusion protein of the extracellular domain of human/mouse CTLA4 and the Fe portion of the human/mouse immu noglobulin G1 block the CD28/B7 costimulatory T-cell activation pathwa y. We evaluated the effect of prolonged B7-CD28 blockade T-cell deplet ion, or both on rat to mouse cardiac xenografts. Methods. C57BL/6 (H-2 (b)) mice receiving infant Wistar Furth (RT1(u)) rat cardiac xenograft s were treated with anti-CD4 (GK1.5) and anti-CD8 (2.43) monoclonal an tibodies (mAb; 0.2 mg intravenous each) on days -2 and 0, hCTLA4Ig or mCTLA4Ig every other day from day 0 until day 14 and then twice a week until day 50 or day 100, or both. Changes in cellular reactivity were assayed by mixed lymphocyte culture and cell-mediated cytotoxicity an d the development of cytotoxic antibodies was serially measured after transplantation. Results. Either human CTLA4Ig or murine CTLA4Ig alone led to significant prolongation of rat to mouse cardiac xenografts (m edian survival time [MST], 22 or 26 days, respectively [p = 0.008], ve rsus control). hCTLA4Ig given for 50 days in combination with two dose s of anti-CD4/CD8 monoclonal antibodies further prolonged graft surviv al (MST, 61 days; p versus control <0.0001). In this combination, when hCTLA4Ig was continued until day 100, the graft survival was further prolonged (MST, 119 days). mCTLA4Ig for 100 days plus anti-CD4/CD8 sim ilarly prolonged rat xenograft survival (MST, 94 days). However, all c ardiac xenografts eventually failed, primarily from humoral rejection. Cytotoxic antibody titers rose rapidly only in animals rejecting a gr aft, and suppressed cell-mediated immunity had completely recovered in rejecting recipients. Conclusions, Blockage of the CD28-B7 costimulat ory interaction can inhibit both humoral and cell-mediated immune resp onses and result in the prolonged acceptance of rat to mouse cardiac x enografts. Longer administration of CTLA4Ig and anti-CD4/CD8 monoclona l antibodies further prolongs but does not achieve indefinite survival of rat cardiac xenografts.