Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease. Regulatory role of donor CD8+ T cells.
Acute and chronic graft-versus-host disease (GVHD) in the parent-into-F1 model are mediated by predominantly cellular or humoral immune responses, respectively, and are strikingly different entities by 2 wk of disease. Both forms of GVHD, however, evolve from a common starting point, i.e., donor CD4+ T cell recognition of host alloantigen and IL-2 production. Our study examines the first 2 wk of GVHD to delineate the events that critically influence GVHD development. Surprisingly, both forms of GVHD are initially characterized by increased Th2 cytokine (IL-4 and IL-10) production and B cell activation which persists into wk 2. The earliest distinguishing features of acute GVHD were detectable at days 5 through 7 of disease and consisted of 1) expansion of donor CD8+ T cells, and 2) increased IFN-gamma production by donor CD4+ and CD8+ T cells. Interestingly, IFN-gamma production by donor CD4+ T cells was not seen if donor CD8+ T cells were not engrafted in comparable numbers. Chronic GVHD in the DBA-into-BDF1 model was found to be caused by a relative defect in the ability of DBA CD8+ T cells to induce acute GVHD and to produce IFN-gamma. These studies demonstrate that both acute and chronic GVHD begin as a Th2 cytokine-mediated, B cell stimulatory response. The transition to acute GVHD is critically dependent on the engraftment of donor CD8+ T cells, which terminate B cell hyperactivity by 1) eliminating activated B cells and 2) promoting IFN-gamma secretion by donor CD4+ T cells.
Rus
V
V
Research Service, Baltimore VA Medical Center, MD 21201, USA.
Svetic
A
A
Nguyen
P
P
Gause
W C
WC
Via
C S
CS
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D018417:Th1 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*
D016207:Cytokines; D011506:Proteins; D012333:RNA, Messenger; D007371:Interferon-gamma