Anti–interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice

Fuss, Ivan J.; Marth, Thomas; Neurath, Markus F.; Pearlstein, Glen R.; Jain, Ashish; Strober, Warren

doi:10.1016/s0016-5085(99)70392-6

Cited by 253 publications

(167 citation statements)

References 37 publications

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“…Although IFN-c up-regulation was maintained in the p38a +/--grafted mice, Th1 differentiation by IL-12 may have been reduced by the decreased p38 activity, as reported previously [31]. Moreover, since IL-12 is considered to be essential for the viability of Th1 CD4 + T cells [32][33][34][35], the expansion of activated CD4 + T cells may be suppressed in p38a +/--grafted mice. If this is true, then it is interesting to note the discrepancy between the numbers of expanded donor-derived IEL and MLNL.…”

Section: Discussionsupporting

confidence: 59%

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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Section: Discussionsupporting

confidence: 59%

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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“…12,17,29,44 In contrast, it has been anticipated that the use of antibody agent could induce the production of an anti-drug antibody such as an antiidiotype antibody. We think that IL-12 p40 would not induce the synthesis of an unwelcome antibody because it exists naturally in vivo.…”

Section: Discussionmentioning

confidence: 99%

IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice

Shiraki

Aihara

Kinouchi

et al. 2004

Laboratory Investigation

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T-helper-1 (Th1) cytokines play an important role in Crohn's disease, and interleukin-12 (IL-12), which is composed of two subunits, p40 and p35, drives Th1 differentiation. In previous reports, IL-12 p40 was shown to prevent IL-12 from binding to the receptor. We demonstrate here the effect of IL-12 p40 overexpression in intestinal epithelia on enterocolitis mediated by Th1 cells in IL-10-deficient (IL-10 À/À ) mice on a C57BL/6J background. IL-10 deficient (IL-10 À/À )/T3 b -IL-12 p40 þ (IL-12 p40 þ ) mice and IL-10 À/À /T3 b -IL-12 p40 À (IL-12 p40 À ) mice were generated by crossing T3 b -IL-12 p40 transgenic mice and IL-10 À/À mice. At 8 weeks of age, IL-12 p40 þ mice did not show any clinical manifestations of colitis. The colon length of IL-12 p40 À mice became shorter than that of IL-12 p40 þ mice. The histological score of IL-12 p40 þ mice was lower. Interferon-gamma (IFN-c) production was suppressed in both the mesenteric lymph node cell culture and colon tissue culture of IL-12 p40 þ mice. There was no significant difference in IL-4 production and tumor necrosis factor-alpha (TNF-a) production between the two groups. These results show that overexpression of IL-12 p40 in intestinal epithelia prevents enterocolitis in IL-10 À/À mice by suppressing IFN-c production, and suggest a potential clinical application of IL-12 p40 for Crohn's disease. Furthermore, these results also suggest that local gene transduction in the intestinal epithelium may be a potent therapeutic approach for Crohn's disease.

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“…In the course of Th1 differentiation, production of IFN-␥ is enhanced and IL-2 is diminished. Because IL-2 is a potent growth factor and IFN-␥ is antiproliferative, IL-12 could function to sustain cell growth and viability (23) or to prevent apoptosis of CD4 ϩ IFN-␥ T cells (24,25). Moreover, recent experiments studying how CD8 ϩ memory T cells Groups of wild-type BALB/c or IL-12 Ϫ/Ϫ mice (n ϭ 8 per group) were infected with L. major and were treated with IL-12 (1 g) at the time of infection (day 0) and for the following 4 days for a total treatment of 5 days.…”

Section: Discussionmentioning

confidence: 99%

The role of antigen and IL-12 in sustaining Th1 memory cellsin vivo: IL-12 is required to maintain memory/effector Th1 cells sufficient to mediate protection to an infectious parasite challenge

Stobie

Gurunathan

Prussin

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

181

125

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Anti–interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice

Cited by 253 publications

References 37 publications

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

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

IL-12 p40 prevents the development of chronic enterocolitis in IL-10-deficient mice

The role of antigen and IL-12 in sustaining Th1 memory cellsin vivo: IL-12 is required to maintain memory/effector Th1 cells sufficient to mediate protection to an infectious parasite challenge

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