Induction of Murine Syngeneic Graft-Versus-Host Disease by Cells of Recipient Origin

Brandon, J. Anthony; Jennings, C. Darrell; Perez, Jacqueline; Caywood, Betty E.; Alapat, Daisy; Kaplan, Alan M.; Bryson, J. Scott

doi:10.1097/01.tp.0000266995.93463.0c

Cited by 3 publications

(7 citation statements)

References 26 publications

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“…Previous studies had demonstrated a significant skewing of the CD4 + T cell population to the CD62L 2 subset (17)(18)(19). This response suggested that the responsive cells were activated in vivo and that few naive precursor cells were present in either the control or SGVHD animals, as evidenced by lack of reactivity of the CD62L + subset.…”

Section: Discussionmentioning

confidence: 94%

“…In addition to the increase of in vitro reactivity of SGVHD CD4 + T cells against microbial Ags, we have demonstrated that an increase in Th1 and Th17 immunity was observed in SGVHD animals (11,12,(17)(18)(19)(20)(21). Th1 and Th17 effector CD4 + T cells have been shown to participate in a variety of models of colon and liver inflammation.…”

Section: Antibiotic Treatment Alters the Immune Responses Associated mentioning

confidence: 90%

“…Histologic analysis of tissue samples from SGVHD mice demonstrated lymphocytic infiltration of the target organs, with increases in CD4 + T cells being observed in the intestinal lesions (17). Similarly, increased numbers of intraepithelial and lamina propria CD4 + T lymphocytes were present in the colons of SGVHD versus control BMT mice (17)(18)(19). Based on these studies, it was shown by in vivo depletion and adoptive transfer studies that CD4 + , but not CD8 + T cells played a dominant role in the development of murine SGVHD-associated colon and liver inflammation (17,19).…”

mentioning

confidence: 99%

“…CD8 + effector T cells have been shown to mediate the induction and development of rat SGVHD (2,13,14), with CTLs specific for the CLIP being shown to be the predominant effector cell (15,16). Where autoreactive CD8 + T cells are responsible for disease induction in the rat (1,14,15), CD4 + T cells were shown to be the major effector cell in murine SGVHD (17)(18)(19). Histologic analysis of tissue samples from SGVHD mice demonstrated lymphocytic infiltration of the target organs, with increases in CD4 + T cells being observed in the intestinal lesions (17).…”

mentioning

confidence: 99%

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Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Brandon

Jennings

Kaplan

et al. 2011

The Journal of Immunology

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Murine syngeneic graft-versus-host disease (SGVHD) initiates colon and liver inflammation following lethal irradiation, reconstitution with syngeneic bone marrow transplantation, and therapy with the immunosuppressive agent cyclosporine A. Previous studies have demonstrated that the inducible disease is mediated by CD4+ T cells with increased reactivity of peripheral and liver-associated lymphocytes against intestinal microbial Ags. In the current report, studies were performed to analyze the specificity of the CD4+ T cell response of T cells isolated from diseased animals and to determine the in vivo role of the microbiota to the development of SGVHD. Increased major histocompatibility Ag (MHC) class II-restricted responsiveness of SGVHD CD4+ T cells against microbial Ags isolated from the ceca of normal animals was observed. The enhanced proliferative response was observed in the CD62L− memory population of CD4+ T cells. To determine the role of the bacterial microbiota in the development of murine SGVHD, control and CsA-treated bone marrow transplantation animals were treated with broad-spectrum antibiotics (metronidazole, ciprofloxacin) after transplantation. Cyclosporine A-treated animals that were given antibiotic therapy failed to develop clinical symptoms and pathological lesions in the target tissues characteristic of SGVHD. Furthermore, the reduction in intestinal bacteria resulted in the elimination of the enhanced antimicrobial CD4+ T cell response and significantly reduced levels of the inflammatory cytokines, IFN-γ, IL-17, and TNF-α. The elimination of the disease-associated inflammatory immune responses and pathology by treatment with broad-spectrum antibiotics definitively links the role of the microbiota and microbial-specific immunity to the development of murine SGVHD.

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Section: Discussionmentioning

confidence: 94%

Section: Antibiotic Treatment Alters the Immune Responses Associated mentioning

confidence: 90%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Brandon

Jennings

Kaplan

et al. 2011

The Journal of Immunology

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“…It has been observed that proportions of CD4 ϩ T cells are increased in colons of SGVHD mice compared with BMT controls and that CD4 ϩ T cells were responsible for the induction of murine SGVHD (3,4,9). The role of CD4 ϩ T cells as effector cells in the induction of murine SGVHD was demonstrated in two sets of experimental studies.…”

Section: Discussionmentioning

confidence: 99%

Accumulation of CD4⁺T cells in the colon of CsA-treated mice following myeloablative conditioning and bone marrow transplantation

Perez

Brandon

Cohen

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Syngeneic graft vs. host disease (SGVHD) was first described as a graft vs. host disease-like syndrome that developed in rats following syngeneic bone marrow transplantation (BMT) and cyclosporin A (CsA) treatment. SGVHD can be induced by reconstitution of lethally irradiated mice with syngeneic bone marrow cells followed by 21 days of treatment with the immunosuppressive agent CsA. Clinical symptoms of the disease appear 2–3 wk following cessation of CsA therapy, and disease-associated inflammation occurs primarily in the colon and liver. CD4+T cells have been shown to play an important role in the inflammatory response observed in the gut of SGVHD mice. Time-course studies revealed a significant increase in migration of CD4+T cells into the colon during CsA therapy, as well as significantly elevated mRNA levels of TNF-α, proinflammatory chemokines, and cell adhesion molecules in colonic tissue of CsA-treated animals compared with BMT controls, as early as day 14 post-BMT. Homing studies revealed a greater migration of labeled CD4+T cells into the gut of CsA-treated mice at day 21 post-BMT than control animals via CsA-induced upregulation of mucosal addressin cell adhesion molecule. This study demonstrates that, during the 21 days of immunosuppressive therapy, functional mechanisms are in place that result in increased homing of CD4+T effector cells to colons of CsA-treated mice.

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Long-term skin-resident memory T cells proliferate in situ and are involved in human graft-versus-host disease

et al. 2020

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The skin contains a population of tissue-resident memory T cells (Trm) that is thought to contribute to local tissue homeostasis and protection against environmental injuries. Although information about the regulation, survival program, and pathophysiological roles of Trm has been obtained from murine studies, little is known about the biology of human cutaneous Trm. Here, we showed that host-derived CD69+ αβ memory T cell clones in the epidermis and dermis remain stable and functionally competent for at least 10 years in patients with allogeneic hematopoietic stem cell transplantation. Single-cell RNA sequencing revealed low expression of genes encoding tissue egress molecules by long-term persisting Trm in the skin, whereas tissue retention molecules and stem cell markers were displayed by Trm. The transcription factor RUNX3 and the surface molecule galectin-3 were preferentially expressed by host T cells at the RNA and protein levels, suggesting two new markers for human skin Trm. Furthermore, skin lesions from patients developing graft-versus-host disease (GVHD) showed a large number of cytokine-producing host-derived Trm, suggesting a contribution of these cells to the pathogenesis of GVHD. Together, our studies highlighted the relationship between the local human skin environment and long-term persisting Trm, which differs from murine skin. Our results also indicated that local tissue inflammation occurs through host-derived Trm after allogeneic hematopoietic stem cell transplantation.

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Induction of Murine Syngeneic Graft-Versus-Host Disease by Cells of Recipient Origin

Abstract: These results demonstrate that after lethal irradiation and in the absence of donor T cells, T cells of recipient origin can expand and mediate the induction of CsA-induced SGVHD.

Cited by 3 publications

References 26 publications

Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Accumulation of CD4⁺T cells in the colon of CsA-treated mice following myeloablative conditioning and bone marrow transplantation

Long-term skin-resident memory T cells proliferate in situ and are involved in human graft-versus-host disease

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Induction of Murine Syngeneic Graft-Versus-Host Disease by Cells of Recipient Origin

Abstract: These results demonstrate that after lethal irradiation and in the absence of donor T cells, T cells of recipient origin can expand and mediate the induction of CsA-induced SGVHD.

Cited by 3 publications

References 26 publications

Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Murine Syngeneic Graft-Versus-Host Disease Is Responsive to Broad-Spectrum Antibiotic Therapy

Accumulation of CD4+T cells in the colon of CsA-treated mice following myeloablative conditioning and bone marrow transplantation

Long-term skin-resident memory T cells proliferate in situ and are involved in human graft-versus-host disease

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Accumulation of CD4⁺T cells in the colon of CsA-treated mice following myeloablative conditioning and bone marrow transplantation