Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease.

Abstract

Lethally irradiated mice were injected with semiallogeneic, T-depleted bone marrow cells and an amount of peripheral T lymphocytes sufficient to induce graft-vs.-host disease (GVHD) becoming apparent on the second week after the graft and leading to an increasing mortality rate within the following weeks (greater than 90% mortality within 80 d). Mice receiving bone marrow cells alone had no GVHD and were used as controls. Beginning on day 8, mice with GVHD were injected weekly with 2 mg of either rabbit anti-mouse recombinant tumor necrosis factor/cachectin (TNF-alpha) IgG, or normal rabbit IgG. On the 16-18th d, mice were killed to examine the skin and intestinal lesions of the acute phase of GVHD. The anti-TNF treatment resulted in an almost complete prevention of the severe lesions seen in the mice treated with normal rabbit IgG, i.e., the skin epidermal cell necrosis, foci of lichenoid hyperplastic reactions, and loss of the hypodermic fat; in the gut dilatation with marked flattening of the villi and elevation of the crypts, with increased numbers of mitoses and isolated crypt cell necrosis. In addition to preventing these acute lesions, anti-TNF treatment resulted in a significantly decreased mortality (approximately 70% survival at 80 d). These results suggest that during acute GVHD, the activation of grafted lymphocytes leads to a local release of TNF in the cutaneous and intestinal mucosae, which induces epithelial cell alterations and increases the inflammatory reaction.

Peptide vaccination of mice immune to LCMV or vaccinia virus causes serious CD8+ T cell-mediated, TNF-dependent immunopathology

“…In at least 3 separate experiments, mice that had received the peptide mix showed visible dilation of the small intestines, which were filled with yellow, viscous fluid. These observations are consistent with acute TNF toxicity (20,21), in which intestinal changes can occur with extraordinary speed, being detectable within 30 minutes of injection of recombinant TNF (22). Histological sections of the small intestines from acutely infected mice, without and with peptide injection (200 μg NP 396 plus GP 33 peptide mix), are shown in the top row of Figure 5B.…”

“…Therefore, a group of microchip-implanted C57BL/6 mice were infected with vaccinia virus. As reported, these mice develop strong CD8 + T cell responses, with approximately 11.5% of splenic CD8 + T cells responding to in vitro incubation with the dominant peptide, B8R [20][21][22][23][24][25][26][27] ( Figure 3A). Most relevant to the present study, the injection of 100 μg of the B8R 20-27 peptide 8 days after vaccinia infection resulted in a very rapid hypothermia ( Figure 3B), although all mice recovered.…”

Infliximab for steroid‐refractory acute GVHD: A case series

“…Case #1 is a good example of a patient whose main GVHD manifestation was gastrointestinal, with severe diarrhea, and he clearly responded to infliximab. Results of animal data suggest that TNF-a is a major mediator of GI GVHD [18], whereas it is much less important in hepatic GVHD, where FasL-mediated cytotoxicity appears to play a greater role. Both TNFa and FasL appear to be important mediators of cutaneous GVHD [25].…”

“…In addition, high levels of TNF-a can directly damage the GI tract, thus leading to amplification of the cascade described [17][18][19]. Given that TNF-a appears to enhance acute GVHD on a variety of levels, it is rational to target in treatment of acute GVHD.…”

Serum tumor necrosis factor-.ALPHA. levels in allogeneic bone marrow transplant recipients with acute leukemia.

“…237 induce the destruction of some malignant cells both in vivo and in vitro, and also has a wide variety of biological actions (Carswell et al 1975;Sugarman et al 1985;Beutler and Cerami 1986). Recently, TNF has been shown to play an important role in acute GVHD in murine models crossing major histocompatibility antigen barriers (Piguet et al 1987). The present study was conducted to determine whether TNF activity was detected in serum after human allogeneic bone marrow transplantation, and whether serum TNF levels were associated with GVHD.…”