Granzymes A and B serum levels in allo-SCT

Kircher, Brigitte; Schumacher, Petra B.; Nachbaur, David

doi:10.1038/bmt.2008.395

Cited by 9 publications

(10 citation statements)

References 33 publications

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“…In human HCT patients, granzymes have been used as biomarkers of aGVHD and a predictor of disease severity. In an 86-patient cohort, Kircher et al (52) demonstrated that serum GrA was detected at higher levels than GrB and was a better predictor of disease severity than HLA mismatch or donor/ recipient age. Earlier studies by this same group indicated that GrA, but not GrB, produced in mixed lymphocyte reactions between donor and host PBMCs significantly correlated with GVHD grade posttransplant.…”

Section: Discussionmentioning

confidence: 99%

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

et al. 2020

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Intestinal GrA + Th cells in aGVHD represent a distinct Th lineage. Although the cellular sources were not defined, enhanced Gzma expression was previously observed in the intestines during aGVHD but only minimally in the skin and lymphoid organs (11). At 10 days post-HCT, we observed significantly increased expression of Gzma in both the small intestine (SI) and large intestine (LI) of mice that received allogeneic bone marrow and T cells as compared with syngeneic controls (P = 0.01 and P < 0.0001, respectively, Figure 1A). We observed a population of GrA + CD8 + T cells in all organs examined in allogeneic recipients that was present in lower percentages in syngeneic recipients (Figure 1, B and C). Unexpectedly, CD4 + T cells also produced GrA in allogeneic recipients and were the dominant population of GrA-producing T cells within the small and large intestines, the latter being where CD4 + T cells accounted for approximately 75% of the GrA-producing cells (Figure 1, B-D). A limited proportion of intestinal GrA + Th cells coexpressed GrB in the SI or LI, indicating that these cells did not acquire a classic cytotoxic phenotype (Figure 1E) (12-15). GrA + cells did not coexpress FOXP3 or IL-17A (Figure 1E) but exhibited partial coexpression of IFN-γ, which was slightly more pronounced in the LI versus the SI (~40% vs. ~30%, Figure 1E). To determine if GrA + Th cells were related to IFN-γ-producing Th1 cells, we analyzed lineage-specific cytokine and transcription factor expression (Supplemental Table 2; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.124465DS1) within intestinal CD3 + CD4 + T cells using time-of-flight cytometry (CyTOF). GrA + Th cells were spatially clustered, indicating that GrA expression is limited to a distinct population of Th cells and is not shared by multiple Th subsets (Figure 1F). In contrast, IFN-γ + Th cells were distributed between 2 major populations, those that spatially segregated with TNF + IL-2 + cells (i.e., prototypic Th1 cells) and those that partially overlapped with GrA + Th cells (Figure 1F). Cells that expressed high levels of GrA exhibited minimal overlap with other lineage-specific cytokines, many of which were expressed in low amounts (Supplemental Figure 1). These data indicate that GrA + Th cells are not typical Th1 cells and may represent a novel Th cell type that responds to signals involved with intestinal damage or inflammation. GrA is expressed by human Th cells in a PBMC-induced model of GVHD. Our data indicate that CD4 + Th cells are an important source of GrA and thus may be relevant to human GVHD. To examine this further, we adopted an established model (16) of human PBMC-induced GVHD in immune-compromised NRG mice. Briefly, human PBMCs from 2 individual donors were injected into NRG mice, and mice were monitored until they reached 20% body weight loss or a significant clinical score (>3). At this endpoint, mice were euthanized, and immune cells were isolated from the spleen, liver, SI, and LI and analyzed fo...

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Section: Discussionmentioning

confidence: 99%

Granzyme A–producing T helper cells are critical for acute graft-versus-host disease

et al. 2020

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“…Recently, investigators from the University of Michigan spearheaded an effort to evaluate the prognostic value of a panel of biomarkers comprised of TNFR1, IL-2Ra, IL-8, HGF, elafin and reg3a. Samples T-cell growth factor, stimulates production of TNF-a and IFN-g Activated NK cells, induces IFN-g production Nakamura et al 16 Fujimori et al 17 Shaiegan et al 18 Mohty et al Visentainer et al 12 Visentainer et al 12 Liem et al 13 Other circulating molecules Uguccioni et al 20 Okamoto et al 21 Luft et al 22 Seidel et al 23 Kircher et al 24 Hubel et al 26 Chen et al 25 Lymphocytetrafficking molecules a4b7 integrin…”

Section: Moving Toward Risk-adapted Approachesmentioning

confidence: 99%

“…23 Granzymes A and B are products of cytotoxic T cells and natural killer cells, and serum levels appeared to parallel the incidence and severity of acute GVHD, although there was an association with CMV infection as well. 24 CD30, a member of the TNFR superfamily, is expressed on the surface of certain activated T cells. Recent studies have shown that CD30 expression appears to be higher on memory T cells in patients with acute GVHD, 25 and soluble CD30 levels have been shown to be increased in the setting of GVHD, 26 possibly revealing a novel target for therapeutic intervention.…”

Section: Il-2mentioning

confidence: 99%

Biomarkers for acute GVHD: can we predict the unpredictable?

2012

Bone Marrow Transplant

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Acute GVHD remains an important complication after allogeneic hematopoietic cell transplantation (HCT). Many efforts have been devoted to identifying potential noninvasive peripheral blood biomarkers to help improve the diagnosis or management of acute GVHD while avoiding invasive tissue biopsies. Early attempts to identify biomarkers focused on inflammatory cytokines, especially IL-2 or TNF-a, however, both of these and others were not specific for GVHD, often being elevated in the setting of generalized inflammation, accompanying other major complications of HCT as well. More recent efforts have focused on additional cytokines and other cell-surface molecules, which function in leukocyte trafficking and activation with the hope that these can also serve as targets for novel therapeutic approaches. Modern proteomic methods have allowed the screening of large numbers of patient samples and yielded several novel candidate biomarkers, including elafin and reg3a, which may not be directly involved in the immunological pathogenesis of GVHD, but may be unique biomarkers for end-organ injury. Combining these new molecules with traditionally identified cytokines to form an acute GVHD biomarker panel has recently shown the ability to predict outcomes in patients who develop acute GVHD. The ultimate goals of identifying a specific biomarker are to refine diagnosis, guide therapy and develop risk-adapted approaches in order to better treat patients and improve outcomes after allogeneic HCT. These approaches include differential treatment for patients who develop acute GVHD with a high-risk biomarker profile as well as pre-emptive therapy in patients after HCT prior to the development of symptoms. With the recent progress summarized below, these goals may soon be realized.

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“…41,42 Increased gene expression of granzyme B was detected in patients with aGVHD 43 and an elevated serum level of granzyme B post-HSCT was highly predictive of the risk and severity of aGVHD. 44 However, inter-individual variability in the baseline expression and activity of granzyme B may result from variations in the granzyme B gene. Espinoza et al reported that donors and/or patients with the granzyme B +55 G-allele positive genotype were associated with improved overall survival after unrelated HLA-fully matched T-cell-replete bone marrow transplantation, but failed to find any significant association with aGVHD.…”

confidence: 99%