Intestinal Immune Conditioning With Helminths Employs Host T Helper 2 (Th2) Pathway To Induce Mixed Chimerism And Regulate Graft-Versus-Host Disease

Mixed hematopoietic chimerism is proven to lead to immune tolerance after bone marrow transplant (BMT) and can reduce graft-vs-host disease (GVHD)-related mortality. It can be achieved with chemotherapeutic agents or strategies that block activation of donor or depletion of host T cells. Immune conditioning with helminthic commensals regulate the host immune system and promotes a transient mixed chimerism. Conditioning with helminths induces IL4 production via host Th2 pathway and regulates GVHD while preserving graft-versus-tumor effect.  IL4 signals through IL4 receptor (IL4R) and STAT6.  We hypothesize that induction of host Th2 pathway is critical for achieving mixed chimerism by intestinal immune conditioning Methods We evaluated the role of host Th2 signaling in the establishment of mixed chimerism in an MHC I/II major mismatch (H2b→H2d) model of BMT using total body irradiation (TBI). Three weeks after infection with mouse nematode h. polygyrus-bakeri ( Hpb ), GVHD was induced via delivery of T cell-depleted bone marrow (TCD-BM) and splenic T cells from uninfected WT C57BL/6 (MHC:H2b) donors into lethally-irradiated WT BALB/c, IL4 -/-, IL4Rα-/- and STAT6-/- recipients (MHC: H2d). Percentage of donor vs recipient T cells, GVHD-mediated inflammation in the colon and lung, and survival of mice were assessed Results In 3 models of disruption of the Th2 pathway, we demonstrated that host Th2 signaling is essential for establishing mixed chimerism.  Helminth infection promotes mixed chimerism in WT BALB/c BMT recipients; recipient T cells constitute 3-5% of peripheral population at 6 days post-BMT in infected mice, and Hpb -infected BMT recipients (p:NS) ( Fig 1 ). Helminths regulate GVHD-related inflammation in lungs and the colon of WT BALB/c recipients (p Fig 2 ). Helminth infection did not promote survival of Th2-/- BMT recipients; all mice died of lethal GVHD, in contrast to WT BALB/c BMT recipients (P Hpb infection, but absolute expression of CTLA4 was decreased Conclusions Immune conditioning with helminths promotes mixed chimerism after TBI and regulates lethal GVHD following BMT. The host Th2 pathway is critical for achieving this mixed chimerism and regulation of GVHD, and induction of CTLA4 is partially dependent on Th2 signaling.