IL-21 accelerates xenogeneic graft-versus-host disease correlated with increased B-cell proliferation

Abstract

Graft-versus-host disease (GVHD) is a prevalent and potential complication of hematopoietic stem cell trans-plantation. An animal model, xenogeneic GVHD (X-GVHD), that mimics accurately the clinical presentation of GVHD would provide a tool for investigating the mechanism involved in disease pathogenesis. Murine models indicated that inhibiting IL-21 signaling was a good therapy to reduce GVHD by impairing T cell functions. We sought to investigate the effect of exogenous human IL-21 on the process of X-GVHD. In this study, human IL-21 was expressed by hydrodynamic gene delivery in BALB/cRag2 −/− IL-2Rγc −/− (BRG) immunodeficient mice which were intravenously transplanted human peripheral blood mononuclear cells (hPBMCs). We found that human IL-21 exacerbated X-GVHD and resulted in rapid fatality. As early as 6 days after hPBMCs transplanted to BRG mice, a marked expansion of human CD19 + B cells, but not T cells, was observed in spleen of IL-21-treated mice. Compared with control group, IL-21 induced robust immunoglobulin secretion, which was accompanied by increased accumulation of CD19 + CD38 high plasma cells in spleen. In addition, we demonstrated that B-cell depletion was able to ameliorate X-GVHD. These results are the fi rst to fi nd in vivo expansion and differentiation of human B cells in response to IL-21, and reveal a correlation between the expansion of B cells and the exacerbation of xenogeneic GVHD. Our fi ndings show evidence of the involvement of B cells in X-GVHD and may have implications in the treatment of the disease.

Interleukin-21 promotes thymopoiesis recovery following hematopoietic stem cell transplantation

“…More specifically, IL-21 promotes the expansion of ST-HSCs and MPPs within the BM-resident LSK population, which represents the source of building blocks required for rapid immune recovery [ 49 , 51 – 55 ]. Although not directly assessed in our studies, we presume that such increase in the pool of BM progenitors enhances thymic seeding [ 60 , 73 ]. In parallel, we demonstrated that IL-21 stimulates intrathymic T cell development directly by boosting the count of thymic progenitor cells while enhancing TEC recovery.…”

“…This is counterintuitive as GVT is usually associated with GVHD induction [ 65 ]. Furthermore, the IL-21/IL-21R signaling axis was previously reported to exacerbate GVHD in a CD4-dependent manner involving B cell expansion and production of autoantibodies [ 73 , 90 , 91 ]. Our study puts at play two important factors, which may help depict the discrepancy between our observations and those reported by others.…”

Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD

“…Although most studies were performed in the isolated murine setting, IL-21 has not only been shown to be a key mediator of murine acute GVHD 39,40 but also of xenogeneic GVHD induced by human lymphocytes. 21,41 Here, we show that a blockade of the common g chain, which is required for the function of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, reduced acute GVHD significantly in mice with respect to survival, inflammatory cytokine levels, and histopathological GVHD severity. In line with this potent reduction of acute GVHD in the mouse model, in patients, the plasma levels of IL-7 and IL-15 measured 30 days after both myeloablative 35 and nonmyeloablative allo-HCT 42 were highly predictive biomarkers of acute GVHD.…”

Cellular and molecular mechanisms in graft-versus-host disease

“…The inhibition of IL-21 signaling was a good therapy to reduce GVHD by impairing T cell functions. Compared with the control group, IL-21 induced robust Ig secretion, which was accompanied by increased accumulation of CD19 + CD38 high plasma cells in spleen [63]. IL-22, which produced by Th22, Th1, and Th17 cells, plays a pathogenic role in the GVHD process.…”