IL-17 contributes to CD4-mediated graft-versus-host disease

Abstract

IntroductionThus far, 3 subsets of proinflammatory helper T cells have been described: Th1, Th2, and Th17 cells. 1 Naive T cells exposed to interleukin-12 1 (IL-12) differentiate into Th1 cells, resulting in expression of Tbet and STAT4, and secretion of interferon (IFN)-␥. 2 Th1 cells are essential for the clearance of intracellular bacteria and negatively regulate the development of Th2 and Th17 cells. 2 IL-4 activates a Th2 program, characterized by expression of STAT6 and GATA3 and secretion of IL-4, IL-5, and IL-13, which is important for humoral immunity. 2 Finally, naive T cells exposed to TGF-␤, IL-6, and IL-21 differentiate into Th17 cells by activating ROR␥t, ROR␣, STAT3, STAT4, and IRF4 transcription factors. [3][4][5][6] Th17 cells produce high levels of IL-17A (IL-17), IL-17F, IL-21, and IL-22, and have been shown to contribute to mucosal immunity. [7][8][9] Specifically, IL-17 is important in the control or clearance of various pathogens, including Klebsiella pneumoniae, 10 Citrobacter rodentium, 3 Borrelia burgdorferi, 11 and Candida albicans. 12 In addition, Th17 cells have been implicated in allograft rejection of solid organs [13][14][15] and several autoimmune diseases. 1,[16][17][18][19] IL-17, otherwise known as IL-17A, is the bestcharacterized member of the IL-17 family (IL-17A through F). IL-17 is a disulfide-linked homodimeric glycoprotein consisting of 155 amino acids with a molecular weight of 35 kDa. 20 IL-17F shares the greatest homology with IL-17 (55%). Th17 cells produce IL-17 and IL-17F while innate immune cells produce other IL-17 family members. IL-17 and IL-17F can exist as homodimers or heterodimers. 21 IL-17 homodimers are efficient at inducing chemokine production by epithelial cells. The IL-17 receptor (IL-17RA) is a type 1 transmembrane protein, and its mRNA is expressed in the lungs, kidneys, liver, and spleen as well as in isolated fibroblasts, epithelial cells, mesothelial cells, and various myeloid cells in rats and mice. 20 Th17 cells have been identified as the primary source of IL-22, an IL-10 family member. 8,22 IL-22 can stimulate proliferation, abnormal differentiation, and migration of various epithelial cells. 23 Its up-regulation has been associated with several autoimmune diseases, including psoriasis, Crohn's disease, and ulcerative colitis, as well as murine models of inflammatory bowel disease. [24][25][26][27] Allogeneic bone marrow transplantation (BMT) is a potentially curative therapy for various hematopoietic malignancies and immunologic diseases. 28,29 GVHD is a major complication of allogeneic BMT and causes significant morbidity and mortality. GVHD is the result of alloreactive donor T cells recognizing alloantigens on normal host tissues and mounting an attack against the host. 28,30 During GVHD, donor T cells specifically target the intestines, skin, and liver, 28 however, alloreactive T cells also contribute to graft-versus-tumor (GVT) activity, which may prevent tumor relapse. 28 During the early stages after BMT, alloreactive CD4 ϩ T cells sec...

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.…”

New perspectives on the biology of acute GVHD

“…116 In contrast, a second study using a similar model showed that IL-17 contributes to CD4-mediated GVHD without affecting the OS rates. 117 In addition, the differentiation of Th17 cells in vitro appears to cause lethal acute GVHD with severe cutaneous and pulmonary damage. 118 These conflicting results may be due to variations among the model systems, and further analyses are required to define the role of Th17 cells in GVHD.…”

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

“…12 This could be relevant as Th17 responses were shown to be involved in GvHD. 13 The application of Syk inhibitors has been successfully tested in murine models of glomerulonephritis, 14 lupus 15,16 and rheumatoid arthritis. 17 Although initial studies were performed with broader protein tyrosine kinase inhibitors such as Curcumin or Piceatannol, recently more specific Syk kinase inhibitors, such as Syk Inhibitor I to IV or R406, of which the orally bioavailable prodrug is R788 (Fostamatinib) have been developed and safely tested in humans.…”