Graft-versus-host disease (GVHD) is the major cause of nonrelapse morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). Prevention and treatment of GVHD remain inadequate and commonly lead to end-organ dysfunction and opportunistic infection. The role of interleukin (IL)-17 and IL-22 in GVHD remains uncertain, due to an apparent lack of lineage fidelity and variable and contextually determined protective and pathogenic effects. We demonstrate that donor T cell-derived IL-22 significantly exacerbates cutaneous chronic GVHD and that IL-22 is produced by highly inflammatory donor CD4+ T cells posttransplantation. IL-22 and IL-17A derive from both independent and overlapping lineages, defined as T helper (Th)22 and IL-22+ Th17 cells. Donor Th22 and IL-22+ Th17 cells share a similar IL-6-dependent developmental pathway, and while Th22 cells arise independently of the IL-22+ Th17 lineage, IL-17 signaling to donor Th22 directly promotes their development in allo-SCT. Importantly, while both IL-22 and IL-17 mediate skin GVHD, Th17-induced chronic GVHD can be attenuated by IL-22 inhibition in preclinical systems. In the clinic, high levels of both IL-17A and IL-22 expression are present in the skin of patients with GVHD after allo-SCT. Together, these data demonstrate a key role for donor-derived IL-22 in patients with chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation.
|Authors||Gartlan, Kate H; Bommiasamy, Hemamalini; Paz, Katelyn; Wilkinson, Andrew N; Owen, Mary; Reichenbach, Dawn K; Banovic, Tatjana; Wehner, Kimberly; Buchanan, Faith; Varelias, Antiopi; Kuns, Rachel D; Chang, Karshing; Fedoriw, Yuri; Shea, Thomas; Coghill, James; Zaiken, Michael; Plank, Maximilian W; Foster, Paul S; Clouston, Andrew D; Blazar, Bruce R; Serody, Jonathan S; Hill, Geoffrey R|
|Journal||AMERICAN JOURNAL OF TRANSPLANTATION|
|Grant ID||P01 CA142106|
|Funding Body||NCI NIH HHS|