Tumor necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease

Brown, Geri; Lindberg, Guy; Meddings, Jon; Silva, Maria João; Beutler, Bruce; Thiele, Dwain L.

doi:10.1016/s0016-5085(99)70181-2

Cited by 93 publications

(63 citation statements)

References 24 publications

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“…In previous studies, TNF blockade has been noted to ameliorate the development of intestinal GVHD in the DBA3 B6D2F 1 MHC class I and II disparate model (11). TNF and its family members appear to influence intestinal inflammation induced by GVHD by promoting a Th1 cytokine profile (IL-2, IFN-␥) (12).…”

Section: Tnf Enhances Cd4mentioning

confidence: 94%

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

Brown

Lee

Thiele

2003

The Journal of Immunology

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Inhibition of TNF/TNFR2 interactions ameliorates intestinal graft-vs-host disease (GVHD) and Th1 cytokine responses induced by transfer of B6 CD4+ spleen cells into irradiated MHC class II disparate B6.C-H-2bm12 (bm12) × B6 F1 recipients. The present studies examined whether these effects of TNF are IL-12 dependent. T cell proliferative responses of B6.129S1-IL-12rb2tm1Jm (B6.IL-12R−/−) responder spleen cells were found to be comparable to those of control B6 spleen cells. TNF inhibition reduced T cell proliferation and IFN-γ production in supernatants of MLC using either B6.IL-12R−/− or control B6 responder cells. GVHD induced wasting disease in recipients of B6.IL-12R−/− CD4+ spleen cells that received a TNF inhibitor-encoding adenovirus (5.4 ± 6.5% weight loss (n = 7)) was significantly reduced compared with levels of weight loss observed in recipients that had received a control adenovirus (25.7 ± 12.2% weight loss (n = 11), p = 0.001). Furthermore, TNF inhibition was associated with a reduction in colonic GVHD scores (p = 0.039) and in the percentage of the splenic CD4+ T cells that expressed IFN-γ (16 vs 6%). These findings indicate that TNF promotes CD4+ T cell alloproliferation, IFN-γ responses, and intestinal GVHD by IL-12-independent mechanisms.

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Section: Tnf Enhances Cd4mentioning

confidence: 94%

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

Brown

Lee

Thiele

2003

The Journal of Immunology

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“…TNF-a, which is an important pro-inflammatory cytokine, contributes to T cell activation and differentiation in GVHD, and directly amplifies organ injury [36]. Treatment with an anti-TNF antibody has been shown to ameliorate murine GVHD [6,37]. Since the level of TNFa was higher in the gut tissues of Allo-p38a +/--grafted GVHD mice than in Allo-WT-grafted mice, it is possible that increased levels of TNF-a accelerate intestinal injury in p38a +/--grafted mice.…”

Section: Discussionmentioning

confidence: 99%

“…3D). TNF-a is one of the most well known cytokines that promotes various inflammatory responses and is implicated in the severity and mortality of GVHD [4,6]. The TNF-a concentrations in the colon homogenates analyzed by ELISA on day 21 were elevated in both groups of GVHD-induced mice but not in the syngeneic-grafted mice, while the TNF-a levels Fig.…”

Section: Reduced P38a In Donor Cells Induces More Severe Gvhd Phenotymentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…However, there are contradictory reports on the effectiveness of inhibiting p38 in experimental colitis [25] and in an infectious disease model. Although GVHD is also an inflammatory disease involving various cytokines [6,26], the function of the p38 in intestinal GVHD has not been explored. In this report, we established the experimental model using p38 gene-targeted mice [13,27] and analyzed the pathological role of p38 in acute intestinal GVHD.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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The gastrointestinal tract is a major target of graft-versus-host disease (GVHD), which constitutes a life-threatening complication of bone marrow transplantation. GVHD is mainly caused by the activation of donor-derived lymphocytes, in which cytokine cascades play essential roles. Since p38 MAPK (p38) has been identified as a regulator of cytokine reactions and proposed as a molecular target for anti-inflammatory therapy, we investigated the contribution of p38 to the severity of murine intestinal GVHD. Unexpectedly, p38a +/-donor graft induced more acute GVHD-related mortality and more severe gut injury. The survival of p38a +/-donor-derived intestinal intraepithelial lymphocytes (IEL) was prolonged in vitro and in vivo, and TNF-a expression in the p38a +/-donor-derived IEL was also increased compared with wild-type cells. In contrast, the p38a +/-grafted mice resulted in decreased expansion of donor lymphocytes in mesenteric lymph nodes, and the up-regulation of IL-12p40 and IL-18 was diminished. These findings suggest that p38 has dichotomous effects for inflammatory response in vivo; not only regulates inflammatory cytokine expression and lymphocyte expansion, but also has distinct regulatory functions for IEL in intestinal GVHD. In conclusion, the inhibition of p38 may not be a suitable antiinflammatory strategy for GVHD due to the associated intestinal injury.

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Enhancement of MHC class I-stimulated alloresponses by TNF/TNF receptor (TNFR)1 interactions and of MHC class II-stimulated alloresponses by TNF/TNFR2 interactions

Brown

Thiele

2000

Eur. J. Immunol.

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In vivo TNF inhibition has been observed to ameliorate the disease process attributed to T cell‐dependent immune responses such as those generated during graft‐vs.‐host disease. The present studies were designed to evaluate whether TNF/TNF receptor (TNFR)1 and TNF/TNFR2 interactions were involved in the generation of allospecific T cell responses. Splenic lymphocyte populations were obtained from TNFR1‐ or TNFR2‐deficient B6 mice and from control B6 mice. These responder cells were cultured with irradiated MHC class II‐disparate B6.C‐H‐2bm12 (bm12) or MHC class I‐disparate B6.C‐H‐2bm1 (bm1) or irradiated syngeneic stimulator cells for 3 days before assay of [3H]thymidine incorporation. IL‐2 levels of the mixed lymphocyte culture (MLC) supernatants were assessed by enzyme‐linked immunosorbent assay. With MHC class II‐disparate bm12 stimulator cells, a significant reduction in T cell proliferation was observed utilizing TNFR2‐deficient CD4+ responder T cells, but not when using TNFR1‐deficient CD4+ responder T cells. A significant decrease in proliferation of TNFR1‐deficient CD8+ responder cells, but not of TNFR2‐deficient CD8 responder T cells was observed after stimulation with MHC class I‐disparate bm1 stimulator cells. IL‐2 levels were lower in MLC utilizing MHC class I stimulators and TNFR1‐deficient responders or MHC class II stimulators and TNFR2‐deficient responders. These results indicate that TNF/TNFR2 interactions promote MHC class II‐stimulated alloresponses, while TNF/TNFR1 interactions promote MHC class I‐stimulated alloresponses.

show abstract

Tumor necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease

Cited by 93 publications

References 24 publications

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

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

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

Enhancement of MHC class I-stimulated alloresponses by TNF/TNF receptor (TNFR)1 interactions and of MHC class II-stimulated alloresponses by TNF/TNFR2 interactions

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