CTLA-4Ig in Combination with Anti-CD40L Prolongs Xenograft Survival and Inhibits Anti-Gal Ab Production in GT-Ko Mice

Abstract

The generation of GT-Ko mice has provided unique opportunities to study allograft and xenograft rejection in the context of anti-a1,3-Gal antibody (anti-Gal Ab) responses. In this study we used the allotransplantation model of C3H hearts into galactosyltransferase-deficient (GT-Ko) mice and the xenotransplantation model of baby Lewis rat hearts into GT-Ko mice to investigate the ability of CTLA-4Ig in combination with anti-CD40L mAb to control graft rejection and anti-Gal Ab production. Murine CTLA-4Ig or anti-CD40L monotherapy prolonged allograft survival, and the combination of these reagents was most immunosuppressive. However short-term treatment with murine cytotoxic T lymphocyte associated antigen-4 (muCTLA-4Ig) and/or CD40 ligand (CD154) monoclonal antibodies (anti-CD40L mAbs) was unable to induce indefinite allograft survival. CTLA-4-immunoglobulin fusion protein (CTLA-4Ig) or anti-CD40L monotherapy only marginally prolonged xenograft survival; the combination of human CTLA-4Ig and anti-CD40L significantly prolonged xenograft survival (74 days), while the combination of murine CTLA-4Ig and anti-CD40L resulted in graft survival of Ͼ120 days. CTLA-4Ig or anti-CD40L monotherapy or the combination of these agents inhibited the production of alloAbs, including anti-Gal Abs. CTLA-4Ig or anti-CD40L monotherapy partially controlled xenoAb and anti-Gal Ab production, while the combination was more effective. These observations corroborate our previous observations that humoral, including anti-Gal Ab, responses and rejection following allograft or concordant xenograft transplantation in GT-Ko mice are T-cell dependent and can be controlled by costimulation blockade.

Premature labor: a state of platelet activation?

“…These mice display a selective deficiency in humoral immunity with lower basal serum immunoglobulin isotype concentrations and undetectable IgE [81]. Moreover, these mice fail to mount a secondary antigen-specific response to immunization with a thymus-specific antigen, suggesting that CD40L is required for T cell-dependent antibody response [21,105,121,136].…”

Acute Xenograft Rejection Mediated by Antibodies Produced Independently of TH1/TH2 Cytokine Profiles

“…The kinetics were delayed and the titers of the antigraft IgG response was significantly reduced in C57BL/6 compared with BALB/c recipients. We have previously reported that the mouse antirat IgM response is T-cell dependent and is inhibited by nondepleting anti-CD4 mAbs or costimulation blockade with CTLA4-Ig and anti-154 (22,25). However neither the rate nor magnitude of the antigraft IgM response was affected by the absence of IFN-g or IL-4.…”

Effects of combined treatment with PD‑L1 Ig and CD40L mAb on immune tolerance in the CBA/J x DBA/2 mouse model

“…Therefore, the cd40-cd40l signaling pathway plays a role in the formation of antibodies in the body and blocking this pathway can reduce the production of pathogenic autoantibodies or unrelated antibodies, which might be a novel approach for the clinical treatment of related autoimmune diseases. Furthermore, it has been reported that combined treatment of anti-cd40l mabs and cTla-4 ig in a mouse skin and heart transplantation model, as well as in a non-human primate kidney transplantation model, could significantly prolong the survival time of the graft (20,35,36). However, the effects of combined treatment with Pd-l1 ig and anti-cd40l mabs on spontaneous abortion are not completely understood, and the underlying mechanisms remain unclear.…”