Intestinal graft-versus-host disease is initiated by donor T cells distinct from classic cytotoxic T lymphocytes.

Abstract

In these studies, the role of T helper and T cytotoxic cells in generating intestinal graft-vs.-host disease (GVHD) was examined. Treatment of C57BL/6J (B6) splenocytes with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) selectively removes natural killer cells, cytotoxic T lymphocyte (CIL) precursors, and the capacity to cause lethal GVHD in irradiated B6xDBA/2 Fl (B6D2Fl) mice while preserving T helper cell function. Neither control nor Leu-Leu-OMe-treated DBA/2 donor spleen and bone marrow cells were found to induce lethal GVHD in B6D2F1 recipients. However, extensive colonic GVHD developed in B6D2F1 recipients of DBA/2 bone marrow and spleen cells. Enteropathic GVHD in DBA/2 -* B6D2F1 mice was reduced in severity after anti-L3T4 + C treatment of donor cells, and was eliminated by anti-Thyl.2 + C or the combination of anti-L3T4 and anti-Lyt2 + C treatment of the donor cell inoculum. However, neither antiLyt2 + C, Leu-Leu-OMe, nor anti-Lyt2 + C and Leu-LeuOMe treatment of donor cells significantly decreased severity of gut GVHD. Leu-Leu-OMe treatment of DBA/2 or B6 SpC was comparably effective in preventing in vitro or in vivo generation of B6D2Fl-specific CiL. These findings, therefore, demonstrate that histologically severe enteropathic GVHD does not require participation of CIL and is not always associated with high mortality rates.

TNF Enhances CD4+ T Cell Alloproliferation, IFN-γ Responses, and Intestinal Graft-Versus-Host Disease by IL-12-Independent Mechanisms

“…In studies conducted in other mouse strain combinations, we have noted previously that severity of intestinal GVHD, especially colonic GVHD, does not correlate well with GVHD mortality (2). In all strain combinations examined to date (11,13), the most impressive effect of TNF inhibition is its effects on colonic GVHD and associated IFN-␥ responses.…”

“…Animal models of GVHD have been used in determining the pathogenesis of intestinal GVHD. In many murine models of intestinal GHVD, including the DBA/2J3 B6D2F 1 and the B63 B6 ϫ bm12 F 1 GVHD models, CD4 ϩ T cells play a prominent role in the pathogenesis (2)(3)(4).…”

The CCL3/Macrophage Inflammatory Protein-1α–Binding Protein Evasin-1 Protects from Graft-versus-Host Disease but Does Not Modify Graft-versus-Leukemia in Mice

“…A series of experiments were then carried out to understand the mechanisms by which a blockade of CCL3 with evasin-1 would protect from GVHD. CD8 + and CD4 + cells, as well as macrophages, are leukocytes known to play an effector role in GVHD (7,25,(27)(28)(29)(30)(31)(32). In evasin-1-treated animals, there was significant inhibition of the influx of these leukocytes to the intestine of mice subjected to GVHD.…”

“…Control group (n), n = six mice/group; GVHD group (:), n = eight mice/group; evasin-1 group (3), n = 9 mice/group; and CCL3 2/2 group microscope with a resolution of 720 3 480 pixels (Cool SNAP-Procf Color, Media Cybernetics, Bethesda, MD) and evaluated using the program Image ProExpress version 4.0 for Windows (Media Cybernetics). Histopathological scores were determined according to the criteria previously established (11,24,25). Samples were obtained from mice at days 3, 10, and 20 posttransplantation, which correspond to the following phases of clinical disease in mice: latency, onset of clinical disease, and mortality, respectively.…”

Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice

“…Although the mechanism of intestinal GVHD is complex, this disease is considered to be the result of host antigenmediated donor T cell responses, which are activated by pro-inflammatory cytokines and endotoxins [4,5]. Several studies have suggested that intestinal lesions are initiated by the activation of donor T cells by allogeneic antigen presentation, while the disease is exacerbated by cytokine release from the activated T cells [6,7].…”