CD4+ T Cells Mediate Murine Syngeneic Graft-versus-Host Disease-Associated Colitis

Abstract

Syngeneic graft-vs-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow, and treatment with a 21-day course of the immunosuppressive agent cyclosporin A (CsA). Following cessation of CsA, this inducible disease is characterized by weight loss, diarrhea, and development of inflammation in the colon and liver. Although nonspecific effector cells and Th1 cytokines have been shown to participate in disease induction, the role of T cells has not been fully elucidated. Initial studies demonstrated significant increases in CD4+ T cells, but not other T cell populations in the colons of diseased animals relative to transplant control animals. To demonstrate a functional linkage between increases in colonic CD4+ T cells and disease induction, in vivo T cell depletion studies were performed. Beginning on the day of bone marrow transplantation, groups of control and CsA-treated animals were treated with mAb against either CD4 or CD8 for 21 days. Treatment with anti-CD4, but not anti-CD8, eliminated clinical symptoms and colon pathology. Interestingly, neither anti-CD4 nor anti-CD8 therapy affected the development of liver pathology associated with SGVHD. These findings demonstrated that CD4+ T cells initiate development of the intestinal inflammation associated with murine SGVHD.

Accumulation of CD4+T cells in the colon of CsA-treated mice following myeloablative conditioning and bone marrow transplantation

“…ϩ ␣␤TCR ϩ T cells isolated from SGVHD mice at 2-4 wk after CsA treatment (5-7 wk post-BMT) relative to control BMT animals, with no changes in the composition of CD8 ϩ ␣␤ ϩ or ␥␦ ϩ T cells (9). A twofold increase in CD4 ϩ T cells was also observed in the IEL isolated from CsA vs. control BMT mice at 21 days post-BMT at the end of CsA therapy.…”

“…In vivo depletion of CD4 ϩ T cells during, but not after, CsA therapy inhibited significantly the induction of SGVHD (9). Finally, SGVHD could be adoptively transferred with CD4 ϩ T cells from diseased animals into secondary recipients (4).…”

“…In the mouse, clinical symptoms of the disease appear 2-3 wk after cessation of CsA therapy, and diseaseassociated inflammation occurs primarily in the colon and liver (6,7). The development of murine SGVHD is a multistep process resulting from the cooperative interaction of various effector cell populations, including NK cells, macrophages (25,26), and T cells (4,8,9). Bryson et al (9) demonstrated a role for CD4…”

“…Previously published studies report an increase in colonic CD4 ϩ T cells in CsA-treated mice by day 21 post-BMT, suggesting enhanced T cell migration into the colon during the CsA treatment period (9). Studies were undertaken to investigate CD4 ϩ T cell migration into the colon during the induction of SGVHD.…”

A gut feeling about murine syngeneic GVHD

“…in the mouse by Cheney and Sprent 4 and while SGVHD is induced via a similar induction protocol in both rats and mice, 5 we have shown that a dichotomy exists between the effector cell phenotype and specificity between these two species. CD4 + T cells were shown to be the effector cell responsible for induction of murine SGVHD, 6,7 and in contrast to rats, autoreactive T-cell responses have not been detected in SGVHD mice.…”