INTERLEUKIN-12 PREVENTS SEVERE ACUTE GRAFT-VERSUS-HOST DISEASE (GVHD)AND GVHD-ASSOCIATED IMMUNE DYSFUNCTION IN A FULLY MAJOR HISTOCOMPATIBILITY COMPLEX HAPLOTYPE-MISMATCHED MURINE BONE-MARROW TRANSPLANTATION MODEL

Background, We have recently reported that interleukin (IL)-12 prevent s acute graft-versus-host disease (GVHD)-induced mortality in a full m ajor histocompatibility complex-plus multiple minor antigen-mismatched A/J-->B10 bone marrow transplantation (BMT) model, Because most patie nts have access to a haploidentical, one haplotype-mismatched donor, w e have now investigated the protective effect of IL-12 against GVHD an d GVHD-associated immune dysfunction in a haploidentical CBD2F1 (H2(kx d)) --> B6D2F1 (H2(bxd)) strain combination, Methods. GVHD was induced by injecting CBD2F1 marrow and spleen cells into lethally irradiated B6D2F1 mice, Results, In untreated control mice, GVHD resulted in 87% mortality by day 8 after BRIT, with no survivors beyond day 17. Treatm ent with a single injection of IL-12 on the day of BMT led to 87% long -term survival, with no significant weight loss, diarrhea or GVHD skin changes, The majority of T cells recovering: in these mice showed the CD62L(+), CD4(low), CD45RB(high) naive phenotype, These T cells showe d specific tolerance to both host and donor histocompatibility antigen s, but normal anti-third party (H2(s)) alloresponses in vitro., B-cell proliferative responses to lipopolysaccharide were also normal in IL- 12-protected mice, Moreover, normal negative selection of thymocytes b earing T cell receptors with V beta that recognize endogenous superant igens was observed among CD4(+)CD8(-) thymocytes, indicating a lack of GVHD-associated thymic selection abnormalities in IL-18-protected all ogeneic BMT recipients, Conclusions, IL-12 provides permanent protecti on against an otherwise severe, rapidly lethal GVHD, with no clinical manifestations of chronic GVHD, immunosuppression or autoimmune featur es, in a full major histocompatibilty complex haplotype-mismatched mur ine BMT model.