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 prevents acute graft-versus-host disease (GVHD)-induced mortality in a full major histocompatibility complex-plus multiple minor antigen-mismatched A/J-->B10 bone marrow transplantation (BMT) model, Because most patients have access to a haploidentical, one haplotype-mismatched donor, we have now investigated the protective effect of IL-12 against GVHD and GVHD-associated immune dysfunction in a haploidentical CBD2F1 (H2(kxd)) --> 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. Treatment 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 showed specific tolerance to both host and donor histocompatibility antigens, 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 bearing T cell receptors with V beta that recognize endogenous superantigens was observed among CD4(+)CD8(-) thymocytes, indicating a lack of GVHD-associated thymic selection abnormalities in IL-18-protected allogeneic BMT recipients, Conclusions, IL-12 provides permanent protection against an otherwise severe, rapidly lethal GVHD, with no clinical manifestations of chronic GVHD, immunosuppression or autoimmune features, in a full major histocompatibilty complex haplotype-mismatched murine BMT model.