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Graft-versus-host disease (GvHD) remains a major cause of morbidity and mortality in patients that have received allogeneic hematopoietic stem cell transplant (allo-HSCT). Conditioning with pretransplant chemotherapy or irradiation causes widespread cell death, release of endogenous danger signals, and epithelial barrier dysfunction leading to bacterial translocation, all of which promote the induction of a proinflammatory cytokine storm. These signals drive the activation of antigen-presenting cells (APCs) and the differentiation of alloreactive donor T cells, which cause damage to various host tissues, a characteristic of GvHD.1
Stimulator of interferon genes (STING) is an innate immune sensor that can contribute to the inflammatory response and was recently reported to protect against gastrointestinal GvHD after major histocompatibility complex (MHC)-mismatched allo-HSCT. However, its role in MHC-matched GvHD remains unexplored. Therefore, in in vivo/preclinical experiments, Cameron S. Bader and colleagues investigated whether STING could influence CD8- versus CD4-mediated GvHD and whether STING-dependent effects were related to the donor/recipient MHC-matched versus MHC-mismatched genetic disparity. The results were published in the journal Science Translation Medicine.1
Table 1. mRNA expression of proinflammatory cytokines in the colon of STING-deficent vs WT mice1
Ifnb1, interferon beta 1; Il6, interleukin 6; Tnf, tumor necrosis factor. |
||
Inflammatory cytokine |
C3H.SW donor p value |
LP/J donor p value |
Ifnb1 |
< 0.01 |
< 0.01 |
Tnf |
< 0.01 |
0.077 |
Il6 |
< 0.05 |
< 0.01 |
STING deficiency in the nonhematopoietic compartment of the recipient reduces GvHD after MHC-matched allo-HSCT by downregulation of MHC class I expression and reduced donor CD8+ activation. Conversely, in MHC-mismatched allo-HSCT, which is induced by donor CD4+ cells, deficiency of STING does not result in decreased GvHD. This indicates that STING deficiency reduces donor CD8+ T cell-mediated GvHD (as seen in matched allo-HSCT), while it has no impact on CD4+ T cell-mediated GvHD response (as seen in mismatched allo-HSCT). Therefore, the authors suggest that targeting the STING pathway in a clinical setting of matched allo-HSCT could potentially improve the outcomes of patients.
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