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Translational and clinical advances in acute graft-versus-host disease.

ABSTRACT: Acute graft-versus-host disease (aGvHD) is induced by immunocompetent alloreactive T lymphocytes in the donor graft responding to polymorphic and non-polymorphic host antigens and causing inflammation in primarily the skin, gastrointestinal tract and liver. aGvHD remains an important toxicity of allogeneic transplantation, and the search for better prophylactic and therapeutic strategies is critical to improve transplant outcomes. In this review, we discuss the significant translational and clinical advances in the field which have evolved based on a better understanding of transplant immunology. Prophylactic advances have been primarily focused on the depletion of T lymphocytes and modulation of T-cell activation, proliferation, effector and regulatory functions. Therapeutic strategies beyond corticosteroids have focused on inhibiting key cytokine pathways, lymphocyte trafficking, and immunologic tolerance. We also briefly discuss important future trends in the field, the role of the intestinal microbiome and dysbiosis, as well as prognostic biomarkers for aGvHD which may improve stratification-based application of preventive and therapeutic strategies.

SUBMITTER: Gooptu M

PROVIDER: S-EPMC7604566 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Translational and clinical advances in acute graft-versus-host disease.

Gooptu Mahasweta M Koreth John J

Haematologica 20201101 11

Acute graft-versus-host disease (aGvHD) is induced by immunocompetent alloreactive T lymphocytes in the donor graft responding to polymorphic and non-polymorphic host antigens and causing inflammation in primarily the skin, gastrointestinal tract and liver. aGvHD remains an important toxicity of allogeneic transplantation, and the search for better prophylactic and therapeutic strategies is critical to improve transplant outcomes. In this review, we discuss the significant translational and clin ...[more]

PMID: 33054103

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Project description:The therapeutic efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the development of graft-versus-host disease (GVHD). In GVHD, rigorous pre-conditioning regimen resets the immune landscape and inflammatory milieu causing immune dysregulation, characterized by an expansion of alloreactive cells and a reduction in immune regulatory cells. In acute GVHD (aGVHD), the release of damage- and pathogen- associated molecular patterns from damaged tissue caused by the conditioning regimen sets the stage for T cell priming, activation and expansion further exacerbating tissue injury and organ damage, particularly in the gastrointestinal tract. Studies have shown that donor T cells utilize multiple energetic and biosynthetic pathways to mediate GVHD that can be distinct from the pathways used by regulatory T cells for their suppressive function. In chronic GVHD (cGVHD), donor T cells may differentiate into IL-21 producing T follicular helper cells or tissue resident T helper cells that cooperate with germinal center B cells or memory B cells, respectively, to produce allo- and auto-reactive antibodies with subsequent tissue fibrosis. Alternatively, donor T cells can become IFN- γ/IL-17 cytokine expressing T cells that mediate sclerodermatous skin injury. Patients refractory to the first line standard regimens for GVHD treatment have a poor prognosis indicating an urgent need for new therapies to restore the balance between effector and regulatory immune cells while preserving the beneficial graft-versus-tumor effect. Emerging data points toward a role for metabolism in regulating these allo- and auto-immune responses. Here, we will discuss the preclinical and clinical data available on the distinct metabolic demands of acute and chronic GVHD and recent efforts in identifying therapeutic targets using metabolomics. Another dimension of this review will examine the changing microbiome after allo-HSCT and the role of microbial metabolites such as short chain fatty acids and long chain fatty acids on regulating immune responses. Lastly, we will examine the metabolic implications of coinhibitory pathway blockade and cellular therapies in allo-HSCT. In conclusion, greater understanding of metabolic pathways involved in immune cell dysregulation during allo-HSCT may pave the way to provide novel therapies to prevent and treat GVHD.

Dataset Information

Translational and clinical advances in acute graft-versus-host disease.

Publications

Translational and clinical advances in acute graft-versus-host disease.

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