T helper17 Cells Are Sufficient But Not Necessary to Induce Acute Graft-Versus-Host Disease

Abstract

T helper (Th)1 cells were considered responsible for the induction of graft-versus-host disease (GVHD), but recently the concept has been challenged. Th17 cells play a critical role in mediating autoimmune diseases, but their role in the pathogenesis of GVHD remains unclear. Herein we compare the ability of in vitro generated Th1 and Th17 cells from C57BL/6 mice to induce GVHD in lethally irradiated BALB/c recipients. Allogeneic Th17 cells had superior expansion and infiltration capabilities in GVHD target organs, which correlated with their increased pathogenicity when compared with naïve or Th1 controls. Th17 cells caused no pathology in the syngeneic recipients, indicating that antigen-activation was required for their pathogenicity. Polarized Th17 cells could not maintain their phenotype in vivo as they produced a significant amount of interferon (IFN)-γ after being transplanted into allogeneic recipients; however, IFN-γ was not required for Th17 cell-induced GVHD. Further, we evaluated the pathogenesis of Th17 cells in GVHD by using polyclonal nonprimed CD4 T cells in a clinically relevant allogeneic bone marrow transplantation (BMT) setting. We found that disruption of Th17-differentiation alone by targeting RORγt (Th17-specific transcription factor) had no significant effect on GVHD development. We conclude that Th17 cells are sufficient but not necessary to induce GVHD.

A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT

“…Several mouse model experiments have revealed that transfer of IL-17-producing cells induced acute GVHD, [33][34][35] whereas in contrast there is a report 31 showing that donor IL-17-producing cells ameliorated acute GVHD. Host DCs are critical in the initiation of acute GVHD, [52][53][54] leading to a hypothesis that IL-17-producing cells could modify the function of host DCs through unknown mechanisms.…”

“…[21][22][23][24][25][26][27][28][29] Moreover, several reports have so far shown that Th17 cells and IL-17 has a significant impact on the development of acute GVHD in mouse models. [30][31][32][33][34][35] Recent reports have shown association of SNPs in the IL-17 gene with autoimmune diseases such as rheumatoid arthritis and ulcerative colitis. [36][37][38][39] The promoter SNP of the IL-17 gene, rs2275913 (G197A), was found to be associated with the susceptibility of rheumatoid arthritis in the Norwegian population 38 as well as that of ulcerative colitis in the Japanese population.…”

Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease

“…7 We hypothesized that Th17 cells could preferentially accumulate within the target tissues of aGVHD. Thus, gastrointestinal biopsies obtained from a cohort of 23 allo-SCT patients (n ¼ 5 without and 18 with histologically proven GI aGVHD taken before starting corticosteroids) were analyzed for Th17 cell infiltration.…”

“…Some data suggested that interleukin (IL)-17 is protective, 5 while others indicated a pathogenic role. 6,7 Of note, transplantation of Th17 cells caused lethal GVHD hallmarked by extensive tissue damage. 8 Finally, blockade of both Th1 and Th17 differentiation is required to prevent GVHD in mice.…”

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

“…The role of IL-17-producing Thelper cells is increasingly being recognized in GvHD. [63][64][65][66][67] Tournadre et al 68 recently showed by analyzing muscle biopsies of patients with inflammatory myopathies that IVIG could mediate their immunomodulation by acting on the Th17 pathway. One could speculate that IVIG exert their modulatory effect on GvHD by impairing the Th17 pathway, although more analysis on other Th17-family cytokines and on the nature of IL-17 secreting cells in our model will be required to confirm this hypothesis.…”