Adoptive transfer of murine syngeneic graft-vs.-host disease by CD4+ T cells

Abstract

Syngeneic graft-vs.-host disease (SGVHD) develops in rodents following the treatment of lethally irradiated, bone marrow (BM) reconstituted animals with a short course of the immunosuppressive agent cyclosporine A (CsA). Using an in vivo depletion approach, we recently demonstrated that CD4(+), but not CD8(+), T cells participated in inducing SGVHD. Studies were therefore undertaken to adoptively transfer SGVHD into lethally irradiated, syngeneic BM reconstituted secondary recipients. Whole T cell populations as well as purified CD4(+)T cells isolated from SGVHD, but not normal or transplant control, animals mediated the transfer of SGVHD into secondary recipients. These cells have an apparent specificity for enteric bacterial antigens. The pathologic process that developed was identical to that observed in the animals with de novo SGVHD after syngeneic BMT and CsA therapy. It was shown that a radiation-sensitive mechanism prevented the transfer of SGVHD into normal, nonirradiated secondary recipients. The ability to reproducibly transfer SGVHD into secondary recipients will enhance our ability to study regulatory mechanisms that are altered during CsA therapy and permit the development of murine CsA-induced SGVHD.

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

“…It has been observed that proportions of CD4 ϩ T cells are increased in colons of SGVHD mice compared with BMT controls and that CD4 ϩ T cells were responsible for the induction of murine SGVHD (3,4,9). The role of CD4 ϩ T cells as effector cells in the induction of murine SGVHD was demonstrated in two sets of experimental studies.…”

“…First, CD4 ϩ , but not CD8 ϩ , T cell depletion during the 21 days of CsA therapy inhibited SGVHD-induced colitis (9). Additional studies showed that murine SGVHD could be transferred to secondary recipients with CD4 ϩ , but not CD8 ϩ , T cells isolated from diseased animals (4). Given the role of CD4 ϩ T cells in the induction of SGVHD, studies were designed to follow up on the observation that CD4 ϩ T cells accumulate in the colon during CsA therapy (9) and to study potential mechanisms involved in trafficking of these cells into the colon of CsA-treated mice.…”

“…SGVHD is an inducible syndrome that develops after lethal irradiation and reconstitution with syngeneic BM followed by 21 days of treatment with the immunosuppressive agent CsA. Pretransplant radiation and CsA therapy are absolute requirements for induction of SGVHD (4,6,15,23,28). Radiation conditioning has been shown to induce the upregulation of transcription factors and proinflammatory cytokines (30,48,50).…”

“…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…”