Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option in the treatment of aggressive malignant and non-malignant blood disorders. However, the benefits of allo-HSCT can be compromised by graft-versus-host disease (GvHD), a prevalent and morbid complication of allo-HSCT. GvHD occurs when donor immune cells mount an alloreactive response against host antigens due to histocompatibility differences between the donor and host, which may result in extensive tissue injury. The reprogramming of cellular metabolism is a feature of GvHD that is associated with the differentiation of donor CD4+ cells into the pathogenic Th1 and Th17 subsets along with the dysfunction of the immune-suppressive protective T regulatory cells (Tregs). The activation of glycolysis and glutaminolysis with concomitant changes in fatty acid oxidation metabolism fuel the anabolic activities of the proliferative alloreactive microenvironment characteristic of GvHD. Thus, metabolic therapies such as glycolytic enzyme inhibitors and fatty acid metabolism modulators are a promising therapeutic strategy for GvHD. We comprehensively review the role of cellular metabolism in GvHD pathogenesis, identify candidate therapeutic targets, and describe potential strategies for augmenting immunometabolism to ameliorate GvHD.
Highlights
Allogeneic hematopoietic stem cell transplantation has the potential to cure multiple hematological disorders, including aggressive malignancies [1]
We comprehensively review the role of cellular metabolism in graft-versus-host disease (GvHD) pathogenesis, identify candidate therapeutic targets, and describe potential strategies for augmenting immunometabolism to ameliorate GvHD
While intracellular glutamine metabolism may support pathogenic T cell proliferation in GvHD, target tissue cells in the gastrointestinal tract rely on glutamine for survival under stress from allogeneic immune attack [113]. This was demonstrated in a haploidentical (C57BL/6-> B6D2F) model in which oral glutamine supplementation was associated with reduced jejunum TNF-α expression and reduced histological GvHD scores in the same tissue [114]
Summary
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has the potential to cure multiple hematological disorders, including aggressive malignancies [1]. The curative potential of allo-HSCT, the graft-versus-leukemia (GvL) effect, can be mediated by several immune subsets [2,3,4]. First-line therapeutic interventions aim to provide global immune suppression via the administration of systemic corticosteroids with or without calcineurin inhibitors [27,32]. These measures increase the risk of infection, relapse, and secondary malignancies [32,33]. An ideal GvHD therapeutic intervention would suppress pathogenic allogeneic immune reactivity while preserving the graft-versus-leukemia (GvL) effect and maintain functional anti-infection immunity [2,36].
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