title: Th2 cell therapy of established acute graft-versus-host disease requires IL-4 and IL-10 and is abrogated by IL-2 or host-type antigen-presenting cells.
abstract: Delayed donor Th2 cell infusion permits a graft-versus-tumor (GVT) effect to occur with subsequent amelioration of established graft-versus-host disease (GVHD). Relative to GVHD controls (B6-into-BALB/c model), recipients of delayed Th2 cells (day 14 post-BMT) had increased survival (3/3 experiments [exp]; each exp P < .0001) and reduced GVHD by histology analysis 5 days post-Th2 infusion without increased tumor burden (3 of 3 exp; each exp P < or = .02). Th2 cell-mediated amelioration of GVHD was associated with greatly reduced allospecific IFN-gamma secretion, in vivo augmentation of allospecific IL-4 and IL-10 secretion, and reduction in donor CD8(+) T cell number post-BMT (3 of 3 exp; each comparison, P < or = .003). To better understand the molecular mechanism of this GVHD therapy, Th2 cells were generated from wild-type (WT), IL-4 deficient (KO), or IL-10 KO donors: remarkably, recipients of IL-4 or IL-10 KO Th2 cells had no survival advantage, no improvement in GVHD by histology, no reduction in CD8(+) T cell expansion post-BMT, and no in vivo shift toward type II cytokines. We reasoned that IL-2 and alloantigen availability may be limiting factors for Th2 cell therapy, and as such, evaluated whether coadministration of IL-2 or coinfusion of host-type antigen-presenting cells (APC) might intensify the anti-GVHD effect. However, contrary to these hypotheses, concomitant IL-2 therapy or APC administration fully abrogated the Th2 cell-mediated survival advantage and histology-defined GVHD reduction, reduced Th2 cell expansion in vivo while promoting CD8(+) T cell expansion from cells originating from the initial allograft, and impaired type II polarization in vivo. In conclusion, Th2 cell therapy can rapidly ameliorate severe GVHD via IL-4 and IL-10 mediated mechanisms, and potentially, via IL-2 consumption and APC modulation mechanisms.
authors: Center for Cancer Research, National Institutes of Health, Experimental Transplantation and Immunology Branch; Bethesda, Maryland.
authors: Jason E
authors: JE
authors: Foley
authors: Center for Cancer Research, National Institutes of Health, Experimental Transplantation and Immunology Branch; Bethesda, Maryland.
authors: Jacopo
authors: J
authors: Mariotti
authors: Center for Cancer Research, National Institutes of Health, Experimental Transplantation and Immunology Branch; Bethesda, Maryland.
authors: Kaitlyn
authors: K
authors: Ryan
authors: National Center for Research Resources, National Institutes of Health, Bethesda, Maryland.
authors: Michael
authors: M
authors: Eckhaus
authors: Center for Cancer Research, National Institutes of Health, Experimental Transplantation and Immunology Branch; Bethesda, Maryland. Electronic address: dhfowler@helix.nih.gov.
authors: Daniel H
authors: DH
authors: Fowler
mesh_terms: D000208:Acute Disease; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: D007376:Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma