IL4KO MICE FAIL TO DEVELOP LONG-TERM ALLOGRAFT SURVIVAL

Abstract

671 Introduction: This study examines the role of IL4 in long-term cardiac allograft survival initiated by short-term treatment with gallium nitrate (GN) or the anti-CD4 mAb, GK1.5. Methods: DBA/2 cardiac allografts were implanted heterotopically into IL4-intact or IL4-KO C57BL/6 (B6) recipients which were then treated peri-transplant with GK1.5, or for 28 days with GN. Graft survival was monitored by transabdominal palpation. Immune function in these allograft recipients was assessed at >60 days post transplant by testing for donor-reactive alloantibody, and donor-reactive DTH responses. Results: DBA/2 heterotopic cardiac allografts are not rejected by IL4-intact C57BL/6 (B6) recipients if the animals are rendered functionally tolerant by transient treatment with GN or with GK1.5. Most(78%) IL4-intact cardiac allograft recipients produce donor-reactive IgG alloantibody. None of these animals exhibits donor-reactive DTH responses. The lack of donor-reactive DTH responses is due to active down regulation, evidenced by the linked unresponsiveness DTH assay. In this assay, splenocytes from long term allograft recipients interfere with DTH responses to an unrelated antigen, tetanus toxoid (TT), but only if both the donor antigen and the TT are locally provided. Unlike IL4-intact mice, IL4-KO B6 recipients reject DBA/2 cardiac allografts after the immunosuppressive effect of GN or GK1.5 dissipates. IL4-KO mice also exhibit donor-reactive DTH when challenged via the allo-MHC-restricted pathway, and are unable to down-regulate TT DTH responses in the linked unresponsiveness DTH assay. Like the IL4-intact recipients, IL4-KO graft recipients produce donor-reactive IgG alloantibody. Conclusions: Immunosuppression with GN or GK1.5 induces an alternative pattern of allosensitization which allows donor-reactive Ab production but not acute rejection or alloreactive DTH. The latter is due to the generation of a DTH regulator. Our data indicate that IL4 is required for the induction and/or maintenance of this alternative allosensitization process.