title: Type I-IFNs control GVHD and GVL responses after transplantation.
abstract: Although the effects of type II-IFN (IFN-γ) on GVHD and leukemia relapse are well studied, the effects of type I-interferon (type I-IFN, IFN-α/β) remain unclear. We investigated this using type I-IFN receptor-deficient mice and exogenous IFN-α administration in established models of GVHD and GVL. Type I-IFN signaling in host tissue prevented severe colon-targeted GVHD in CD4-dependent models of GVHD directed toward either major histocompatibility antigens or multiple minor histocompatibility antigens. This protection was the result of suppression of donor CD4(+) T-cell proliferation and differentiation. Studies in chimeric recipients demonstrated this was due to type I-IFN signaling in hematopoietic tissue. Consistent with this finding, administration of IFN-α during conditioning inhibited donor CD4(+) proliferation and differentiation. In contrast, CD8-dependent GVHD and GVL effects were enhanced when type I-IFN signaling was intact in the host or donor, respectively. This finding reflected the ability of type I-IFN to both sensitize host target tissue/leukemia to cell-mediated cytotoxicity and augment donor CTL function. These data confirm that type I-IFN plays an important role in defining the balance of GVHD and GVL responses and suggests that administration of the cytokine after BM transplantation could be studied prospectively in patients at high risk of relapse.
authors: Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
authors: Renee J
authors: RJ
authors: Robb
authors: Ellen
authors: E
authors: Kreijveld
authors: Rachel D
authors: RD
authors: Kuns
authors: Yana A
authors: YA
authors: Wilson
authors: Stuart D
authors: SD
authors: Olver
authors: Alistair L J
authors: AL
authors: Don
authors: Neil C
authors: NC
authors: Raffelt
authors: Nicole A
authors: NA
authors: De Weerd
authors: Katie E
authors: KE
authors: Lineburg
authors: Antiopi
authors: A
authors: Varelias
authors: Kate A
authors: KA
authors: Markey
authors: Motoko
authors: M
authors: Koyama
authors: Andrew D
authors: AD
authors: Clouston
authors: Paul J
authors: PJ
authors: Hertzog
authors: Kelli P A
authors: KP
authors: Macdonald
authors: Geoffrey R
authors: GR
authors: Hill
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology; D016899:Interferon-beta / Q000276:immunology; D007938:Leukemia / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency* / Q000276:immunology; D015398:Signal Transduction; D015996:Survival Rate; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D016898:Interferon-alpha; D015778:Minor Histocompatibility Antigens; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta