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  • Title: Long-term survival of rat to mouse cardiac xenografts with prolonged blockade of CD28-B7 interaction combined with peritransplant T-cell depletion.
    Author: Rehman A, Tu Y, Arima T, Linsley PS, Flye MW.
    Journal: Surgery; 1996 Aug; 120(2):205-12. PubMed ID: 8751584.
    Abstract:
    BACKGROUND: The hCTLA4Ig/mCTLA4Ig fusion protein of the extracellular domain of human/mouse CTLA4 and the Fc portion of the human/mouse immunoglobulin G1 block the CD28/B7 costimulatory T-cell activation pathway. We evaluated the effect of prolonged B7-CD28 blockade, T-cell depletion, or both on rat to mouse cardiac xenografts. METHODS: C57BL/6 (H-2b) mice receiving infant Wistar Furth (RT1u) rat cardiac xenografts were treated with anti-CD4 (GK1.5) and anti-CD8 (2.43) monoclonal antibodies (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 and 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 (median survival time [MST], 22 or 26 days, respectively [p = 0.008], versus control). hCTLA4Ig given for 50 days in combination with two doses of anti-CD4/CD8 monoclonal antibodies further prolonged graft survival (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 similarly prolonged rat xenograft survival (MST, 94 days). However, all cardiac xenografts eventually failed, primarily from humoral rejection. Cytotoxic antibody titers rose rapidly only in animals rejecting a graft, and suppressed cell-mediated immunity had completely recovered in rejecting recipients. CONCLUSIONS: Blockage of the CD28-B7 costimulatory interaction can inhibit both humoral and cell-mediated immune responses and result in the prolonged acceptance of rat to mouse cardiac xenografts. Longer administration of CTLA4Ig and anti-CD4/CD8 monoclonal antibodies further prolongs but does not achieve indefinite survival of rat cardiac xenografts.
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