Recent Metabolic Advances for Preventing and Treating Acute and Chronic Graft Versus Host Disease

Fathima A. Mohamed, Govindarajan Thangavelu, Stephanie Rhee, Peter T. Sage, Roddy S. O’Connor, Jeffrey C. Rathmell, Bruce R. Blazar

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number757836
JournalFrontiers in immunology
Volume12
DOIs
StatePublished - Oct 12 2021

Bibliographical note

Funding Information:
This work was supported by grants from National Institutes of Health, National Institute of Allergy, and Infectious Diseases R37 AI34495 (BB), R01 AI153124 (PS), R01 AI153167 (JR), and T32 AI007313 (FM, SR); National Heart, Lung, and Blood Institute R01 HL56067 (BB), R01 HL11879 (BB), R01 HL115114 (BB) and R01 HL136664 (JR); National Institute for Diabetes and Digestive and Kidney Diseases R01 DK 105550 (JR); National Cancer Institute P01 CA065493 (BB) and R01 CA226983 (RO); Lupus Research Alliance Innovator Award (JR); Canadian Institutes of Health Research Fellowship (GT).

Publisher Copyright:
© Copyright © 2021 Mohamed, Thangavelu, Rhee, Sage, O’Connor, Rathmell and Blazar.

Keywords

  • alloreactive T-cells
  • graft-versus-host disease
  • graft-versus-tumor
  • intestinal epithelial cells
  • metabolism

PubMed: MeSH publication types

  • Journal Article
  • Review

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