Published on May 07, 2025
DHODH inhibition alters T cell metabolism limiting acute graft-versus-host disease while retaining graft-versus-leukemia response
by Alex Kadhim
In a recent study published in The Journal of Immunology, researchers from Ohio State University have demonstrated that inhibition of dihydroorotate dehydrogenase (DHODH) selectively modulates T cell metabolism, significantly reduces effector T cell responses, and effectively limits graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. Using the selective DHODH inhibitor HOSU-53, they showed significant attenuation of acute GVHD severity and improved survival (p<0.01) in a xenogeneic mouse model, highlighting DHODH as a promising therapeutic target.
The rationale behind this study lies in addressing the unmet clinical need to mitigate GVHD without compromising the beneficial anti-leukemic (GVL) response following allogeneic hematopoietic cell transplantation (allo-HCT). Prior research indicates that activated alloreactive T cells depend heavily on oxidative phosphorylation (OXPHOS) for energy demands and pyrimidine biosynthesis for proliferation and cytokine production. Given that DHODH is critical for these processes, the investigators hypothesized that DHODH inhibition could selectively impair T cell activation and proliferation, thereby mitigating GVHD pathology. To test this, the researchers used human T cells activated in vitro, and NSG mouse models transplanted with human peripheral blood mononuclear cells (PBMCs), treated with the DHODH inhibitor HOSU-53.
In vitro experiments revealed that DHODH inhibition during initial T cell activation significantly reduced T cell proliferation, interferon-gamma (IFNγ, p<0.01), tumor necrosis factor-alpha (TNFα, p<0.05) cytokine production, and mitochondrial respiration (OXPHOS, p<0.005) without impairing cell viability. Interestingly, post-activation DHODH inhibition reduced OXPHOS (p<0.005) but did not affect cytokine production (p=0.5). In vivo, treatment with HOSU-53 significantly decreased pathogenic T cell infiltration into GVHD target organs, including IFNγ+ Th1, IL-17+ Th17, TNFα+ CD4+, and IFNγ+ CD8+ T cells (p<0.05), while expanding immunoregulatory double-negative (DN) T cells. Crucially, DHODH inhibition preserved the anti-leukemic GVL effect, significantly improving survival in mice receiving human leukemia cells (p<0.0001). Thus, DHODH inhibition emerges as a targeted therapeutic strategy to reduce GVHD while maintaining critical anti-leukemic immunity.
Reference:
Kumar R, Ranganathan P, Braunreiter K, et al. DHODH inhibition alters T cell metabolism limiting acute graft-versus-host disease while retaining graft-versus-leukemia response. The Journal of Immunology, 2025.
https://doi.org/10.1093/jimmun/vkaf023
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