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Attenuation of acute graft-versus-host disease in the absence of the transcription factor ROR?t.

ABSTRACT: Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR)?t. In this study, we have evaluated the role of Th17 cells in murine acute GVHD by infusing donor T cells lacking RORC and as a consequence the isoform ROR?t. Recipients given donor CD4(+) and CD8(+) T cells lacking RORC had significantly attenuated acute GVHD and markedly decreased tissue pathology in the colon, liver, and lung. Using a clinically relevant haploidentical murine transplantation model, we showed that RORC(-/-) CD4(+) T cells alone diminished the severity and lethality of acute GVHD. This was not found when CD4(+) T cells from RORC(-/-) mice were given to completely mismatched BALB/c mice, and it was correlated with absolute differences in the generation of TNF in the colon after transplant. Thus, CD4(+) T cell expression of RORC is important in the pathogenesis of acute GVHD.

SUBMITTER: Fulton LM

PROVIDER: S-EPMC3411855 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt.

Fulton LeShara M LM Carlson Michael J MJ Coghill James M JM Ott Laura E LE West Michelle L ML Panoskaltsis-Mortari Angela A Littman Dan R DR Blazar Bruce R BR Serody Jonathan S JS

Journal of immunology (Baltimore, Md. : 1950) 20120709 4

Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR)γt. In this study, we have evaluated the role of Th17 cells in murine acute GVHD by inf ...[more]

PMID: 22778391

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Project description:Acute gut graft-versus-host disease (aGVHD) is a leading threat to the survival of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Abnormal gut microbiota is correlated with poor prognosis in allo-HSCT recipients. A disrupted intestinal microenvironment exacerbates dysbiosis in GVHD patients. We hypothesized that maintaining the integrity of the intestinal barrier may protect gut microbiota and attenuate aGVHD. This hypothesis was tested in a murine aGVHD model and an in vitro intestinal epithelial culture. Millipore cytokine array was utilized to determine the expression of proinflammatory cytokines in the serum. The 16S rRNA sequencing was used to determine the abundance and diversity of gut microbiota. Combining Xuebijing injection (XBJ) with a reduced dose of cyclosporine A (CsA) is superior to CsA alone in improving the survival of aGVHD mice and delayed aGVHD progression. This regimen also reduced interleukin 6 (IL-6) and IL-12 levels in the peripheral blood. 16S rRNA analysis revealed the combination treatment protected gut microbiota in aGVHD mice by reversing the dysbiosis at the phylum, genus, and species level. It inhibited enterococcal expansion, a hallmark of GVHD progression. It inhibited enterococcal expansion, a hallmark of GVHD progression. Furthermore, Escherichia coli expansion was inhibited by this regimen. Pathology analysis revealed that the combination treatment improved the integrity of the intestinal tissue of aGVHD mice. It also reduced the intestinal permeability in aGVHD mice. Besides, XBJ ameliorated doxorubicin-induced intestinal epithelial death in CCK-8 assay. Overall, combining XBJ with CsA protected the intestinal microenvironment to prevent aGVHD. Our findings suggested that protecting the intestinal microenvironment could be a novel strategy to manage aGVHD. Combining XBJ with CsA may reduce the side effects of current aGVHD prevention regimens and improve the quality of life of allo-HSCT recipients.

Dataset Information

Attenuation of acute graft-versus-host disease in the absence of the transcription factor ROR?t.

Publications

Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt.

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