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• W2041569269 abstract "The diagnosis of GvHD currently relies on clinical criteria coupled with histopathologic analysis of biopsy samples. However, the sickest patients are often too ill to permit GI or liver biopsy, resulting in significant diagnostic uncertainty for the patients who are at most risk for GvHD morbidity and mortality. Thus, there is a pressing need to develop a sensitive and specific test for GvHD that is amenable to routine monitoring in the peripheral blood. Using the Primate GvHD Model we have determined that Granzyme B expression is massively upregulated in T cells causing GvHD. We analyzed the T cell phenotype in a cohort of Rhesus macaques who had received MHC-mismatched HSCT in the absence of immunosuppression, and who had histopathologically-proven GvHD. One of the most striking phenotypic changes that correlated with GvHD was the massive upregulation of Granzyme B on both CD4+ and CD8+ T cells: The per-cell Mean Fluorescence Intensity (MFI) for Granzyme B during GvHD increased by as much as 10-25-fold for both CD4+ and CD8+ T cells compared to pre-transplant expression levels. Importantly, Granzyme B upregulation was independent of T cell proliferation: Animals that had undergone autologous transplant and who were undergoing T cell reconstitution by homeostatic proliferation did not upregulate Granzyme B on either CD4+ or CD8+ T cells. Thus, while the average Granzyme B MFI was 1.97x105 and 1.15x105 for CD8+ and CD4+ T cells causing GvHD, the MFI in CD4+ and CD8+ T cells expanding after autologous transplant was 9.6-fold and 11.7-fold lower, despite ongoing T cell proliferation in these animals (p < 0.0001). Immunosuppressed animals reactivating CMV also did not upregulate Granzyme B on either CD4+ or CD8+ T cells (Granzyme B MFI0.24x105 and 0.074x105, respectively, corresponding to a 8.2-fold and 15.5-fold reduction compared to T cells causing GvHD, p < 0.0001). Our results suggest that Granzyme B expression may be a highly discriminating phenotypic marker of GvHD, able to distinguish T cells causing GvHD from those undergoing homeostatic expansion or those activated during CMV viremia. This observation could be translated into a flow-cytometric test for GvHD in the peripheral blood, which could significantly improve our ability to accurately diagnose this devastating disorder. These observations also implicate Granzyme B in the pathogenesis of GvHD, and identify this enzyme as a potential target for GvHD prevention and treatment." @default.
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• W2041569269 date "2011-02-01" @default.
• W2041569269 modified "2023-09-24" @default.
• W2041569269 title "Diagnosing GvHD With a Simple Blood Test? CD4+ and CD8+ T Cell Granyzme B Expression May Hold the Key" @default.
• W2041569269 doi "https://doi.org/10.1016/j.bbmt.2010.12.520" @default.
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