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Abstract
IL-Y, a synthetic member of IL-12 cytokine family, was found to exert potent immunosuppressive effects by inhibiting the differentiation and activation of Th1 and Th17 cells. However, the role of IL-Y in the development of chronic graft-versus-host disease (cGVHD) remains unknown. Here, using murine models of scleroderma-like and lupus-like cGVHD, we examined the function of IL-Y in the pathogenesis of cGVHD by hydrodynamically injecting minicircle-IL-Y expressing plasmids (MC IL-Y). In contrast with the reported immune suppressive function of IL-Y, administration of MC IL-Y enhanced cGVHD severity reflected by deteriorated multi-organ pathologic damages. In lupus-like cGVHD model, urine protein and the serum anti-dsDNA antibody (IgG) were significantly upregulated by IL-Y treatment. Further study demonstrated that IL-Y impacts both donor T and B cell response. In T cells, IL-Y inhibited the generation of CD4+Foxp3+ regulator T (Treg) cells during the development of cGVHD. IL-Y may also increase the infiltration of pathogenic TNF-α producing CD4+ and CD8+ T cells through IL-27Rα in recipient spleens, as this effect was diminished in IL-27Rα deficient T cells. Moreover, IL-Y enhanced the differentiation of ICOS+ T follicular helper (Tfh) cells. In B cells, the percentage of germinal center (GC) B cells in recipient spleens was significantly upregulated by MC IL-Y plasmid administration. The levels of co-stimulatory molecules, MHC-II and CD86, on B cells were also enhanced by IL-Y expression. Taken together, our data indicated that IL-Y promoted the process of cGVHD by activating pathogenic T and B cells.
Highlights
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains a cornerstone curative therapy for hematological malignancy
There was no difference in the subgroup of T follicular Regulatory (Tfr) cells. These results suggested that IL-Y selectively inhibited Treg cell differentiation and promoted T follicular helper (Tfh) activation to facilitate the development of Chronic graft-versus-host disease (cGVHD)
With the decrease of mortality in the early stage of transplantation, the increase of the upper limit of the recipients’ age, the application of unrelated donors and peripheral blood hematopoietic stem cells, the incidence of cGVHD gradually increases, which adversely affects the life quality of allo-HSCT patients. cGVHD has become an important cause of non-recurrent death in the late stage of transplantation [7, 31]
Summary
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains a cornerstone curative therapy for hematological malignancy. Chronic graft-versus-host disease (cGVHD) continues to be a common cause of non-relapse morbidity and mortality after allo-HSCT [1,2,3,4]. CGVHD prophylaxis and treatment with a calcineurin inhibitor may promote the development of cGVHD by blocking thymic central tolerance and peripheral Treg-cell function [5, 6]. It is closely associated with increased risk of infection and malignancy recurrence [2, 7]. New therapeutic strategies are urgently needed to improve curative effect of cGVHD
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