The Expression of Th17-Associated Cytokines in Human Acute Graft-versus-Host Disease

Abstract

The role of Th17 cells and Th17-associated cytokines in the development of acute graft-versus-host disease (aGVHD) in clinical allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is not well established. In the current study, a cohort of 69 allo-HSCT patients was examined for the percentages of Th17 and FoxP3(+) Treg cells and the expressions of RORγt and FoxP3 in peripheral blood mononuclear cells (PBMCs). The Th17 percentage and RORγt expression were significantly higher, whereas Treg percentage and FoxP3 expression were significantly lower in severe aGVHD (grade 3 to 4) and mild aGVHD (grade 1 to 2) patients than in patients without aGVHD (grade 0) and healthy donors. We then investigated the expressions of Th17-associated cytokines, including TGF-β, IL-6, IL-1β, IL-17, IL-21, IL-22, IL-23, as well as IL-23R in the PBMCs of patients after allo-HSCT. The expressions of IL-17 and IL-22 in CD4(+) T cells were also examined. The results showed that the expressions of IL-6, IL-1β, IL-17, IL-21, IL-23, and IL-23R were all increased, whereas IL-22 expression was decreased in aGVHD patients. The changes were also correlated with the severity of aGVHD. We also investigated the dynamic changes of Th17/Treg cells and Th17-associated cytokines in patients during the onset and resolution of aGVHD. The results demonstrated a reciprocal relationship between Treg and Th17 cells. Th17-associated cytokine expressions, namely IL-17 and IL-23, were closely related to the occurrence and resolution of aGVHD. We conclude that the dynamic balance between the Th17 and FoxP3(+) Treg cells and the changes of Th17-associated cytokines could be the indicators of the disease progression and promising candidates of prognostic biomarkers of aGVHD.

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

“…[1][2][3][4]38,39 In nontransplant settings, Th17 have in turn been described as protective in response to fungal infections and other pathogens, 40 pathogenic in multiple human autoimmune diseases, 41 and regulatory during inflammation resolution. 13 This heterogeneity in Th17 function has been attributed to their high degree of plasticity such that Th17 have been reported to transdifferentiate between these functional roles.…”

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

“…Whether these cells are also involved in the pathophysiology of alloimmune inflammation in aGVHD has remained an open question. In fact, although a growing amount of data support a role of Th17 cells in aGVHD in preclinical mouse models [6][7][8][9][10][11], studies in humans have reported conflicting results, suggesting [12][13][14][15] or dismissing [16][17][18] their involvement.…”

Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease

“…1,7 The role of T helper (Th)1-induced cytotoxic T lymphocytes as effector cells of aGVHD has been challenged by numerous mouse studies demonstrating an involvement of not only Th1 [7][8][9][10][11][12] but also Th2 8,9,12,13 and Th17 cells. 8,11,14,15 Studies in aGVHD patients investigating either circulating 12,[16][17][18][19][20][21] or skin-localized [17][18][19]22 T-cell subsets have yielded conflicting results. In aGVHD skin, either increased 17,22 or decreased numbers 18,19 of Th17 cells were reported to occur.…”