Fas ligand mediated killing by intestinal intraepithelial lymphocytes: Participation in graft-versushost disease

Lin, Tiejun; Madsen, Jill; Reaves, Miriam; Green, Douglas

doi:10.1016/s0016-5085(98)84159-0

Cited by 8 publications

(8 citation statements)

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“…Furthermore, the inhibition of IFN-g (37), TNF-a (64), IL-1 (63), or NO (65) can reduce GI tract histopatholog y in animals with GVHD. In contrast, CTL effectors do not appear to play a dominant role in experimental GVHD of the GI tract (17,(66)(67)(68)(69)(70), despite the ability of intraepithelial lymphocytes to induce Fas-mediated apoptosis of host-type tumor cells (71).…”

Section: Phase Three: Inflammatory Effectorsmentioning

confidence: 99%

Pathogenesis of Acute Graft-Versus-Host Disease: Cytokines and Cellular Effectors

Ferrara

2000

Journal of Hematotherapy & Stem Cell Research

151

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The pathogenesis of acute graft versus host disease (GVHD) is multistep process. This review considers acute GVHD in three sequential steps: conditioning regimen, donor T cell activation, and effector mechanisms. In step one, the conditioning regimen simultaneously damages and activates host tissues, amplifying antigen presentation to allogeneic donor T cells. In step two, donor T cells, activated by host alloantigens, proliferate and secrete a variety of cytokines. Type 1 cytokines (interleukin-2 and interferon-y) are critical for acute GVHD, but several regulatory mechanisms of tissue damage include inflammatory cytokines and cytolytic cellular effectors. The gastrointestinal (GI) tract is a principal target organ because damage to the GI mucosa can release inflammatory mediators such as endotoxin that amplify systemic disease. The inflammatory processes of acute GVHD can be considered as a distortion of the cellular responses to viral and bacterial infections. Cell-mediated toxicity is critical to other GVHD target organs, particularly the liver, where Fas-mediated injury predominates. The cytolytic pathways (e.g., perforin) clearly intensify acute GVHD, although they are not necessary for systemic disease in several model systems. Many of these insights come from animal models using mutant mouse strains that can clarify the role of individual proteins or cell types in the disease process. These insights should allow the testing of new classes of drugs and inhibitors in clinical bone marrow transplantation.

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Section: Phase Three: Inflammatory Effectorsmentioning

confidence: 99%

Pathogenesis of Acute Graft-Versus-Host Disease: Cytokines and Cellular Effectors

Ferrara

2000

Journal of Hematotherapy & Stem Cell Research

151

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“…Mice deficient in Fas (i.e., lpr mice) were described as a result of retrotransposon insertion in the Fas locus, and have a phenotype similar to that of gld mice (i.e., lymphoproliferative disease) (Watanabe-Fukunaga et al, 1992). The lpr mice have been an important tool in understanding the role of Fas±FasL interactions in regulation of viral infections, autoimmune diseases, and immunological privilege (Green and Ware, 1997;Griffith and Ferguson, 1997;Lin et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Fas-Fas Ligand Interactions Play a Major Role in Effector Functions of Cytotoxic T Lymphocytes after Adenovirus Vector-Mediated Gene Transfer

Chirmule

Moscioni²,

Qian³

et al. 1999

Human Gene Therapy

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Adenovirus vectors transduce liver hepatocytes with extreme efficiency; however, transgene expression is eliminated within 2 weeks. Extinction of transgene expression has been attributed to infiltrating cytotoxic T lymphocytes (CTLs) in the liver in a process that resembles a number of human diseases, including viral and autoimmune hepatitis. In this study we investigated the role of Fas-Fas ligand interactions in killing of vector-transduced hepatocytes in vitro and in vivo. Intrahepatic lymphocytes (IHLs) isolated from livers of mice administered adenovirus vector demonstrated cytolytic activity against vector-infected primary hepatocytes. The in vitro CTL activity of the IHLs involving both CD4+ and CD8+ T cells was MHC class I restricted and could be blocked by soluble Fas-IgG. Adoptive transfer of IHLs from immune-competent mice immunized with Ad-lacZ into Ragl-deficient mice previously infused with Ad-lacZ resulted in rapid elimination of beta-galactosidase-transduced hepatocytes. Transfer of these cells into Fas-deficient mice (B6-lpr) failed to eliminate lacZ expression; likewise IHLs from immunized FasL-deficient mice (B6-gld) failed to eliminate lacZ expression in Rag1-deficient mice. Finally, in vivo administration of soluble Fas-IgG abrogated the ability of Ad-lacZ-primed IHLs to eliminate transgene expression. These studies establish an essential role for Fas-Fas ligand interactions in the mechanism of elimination of adenoviral vector-mediated transgene expression in the liver.

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“…The ability of IEL to induce the cytotoxic killing of human Jurkat T cells (primarily through a Fas-mediated mechanism) has been previously described (32 Figure 3). As shown in Figure 3 …”

Section: Introductionmentioning

confidence: 72%

Autospecific γδ thymocytes that escape negative selection find sanctuary in the intestine

Lin

Yoshida²,

Matsuzaki³

et al. 1999

J. Clin. Invest.

Self Cite

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αβ or γδ thymocytes whose T-cell receptors (TCRs) recognize endogenously expressed antigens (Ag) are autospecific and, thus, potentially self-reactive. In the thymus, such T cells are eliminated during T-cell development through a process known as negative selection. As a model of negative selection of γδ T cells, we have used G8 γδ-T cell transgenic mice, which express a γδ TCR that recognizes the nonpolymorphic MHC class I TL b molecule. Here, we demonstrate that negative selection of autospecific γδ T cells is almost complete in the adult thymus but is markedly attenuated in the neonatal thymus.A consequence of this attenuated negative selection is that potentially self-reactive γδ thymocytes are allowed to escape negative selection, undergo extrathymic differentiation, and find sanctuary in the intestinal epithelium. Interestingly, the ability of these potentially self-reactive γδ T cells to find sanctuary requires both the intestinal epithelial environment and the extrathymic presence of the self-Ag. The implications of these findings on the development and persistence of autoreactive T cells in autoimmune disease are discussed.

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Fas ligand mediated killing by intestinal intraepithelial lymphocytes: Participation in graft-versushost disease

Cited by 8 publications

References 0 publications

Pathogenesis of Acute Graft-Versus-Host Disease: Cytokines and Cellular Effectors

Pathogenesis of Acute Graft-Versus-Host Disease: Cytokines and Cellular Effectors

Fas-Fas Ligand Interactions Play a Major Role in Effector Functions of Cytotoxic T Lymphocytes after Adenovirus Vector-Mediated Gene Transfer

Autospecific γδ thymocytes that escape negative selection find sanctuary in the intestine

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