Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 18, Issue 4, Pages 810-820Publisher
WILEY
DOI: 10.1111/ajt.14513
Keywords
basic (laboratory) research; science; bone marrow; hematopoietic stem cell transplantation; bronchiolitis obliterans (BOS); cytokines; cytokine receptors; graft-versus-host disease (GVHD); immunobiology; lymphocyte biology: differentiation; maturation; T cell biology
Categories
Funding
- Rio Tinto Ride to Conquer Cancer
- National Health and Medical Research Council
- National Institutes of Health
- NATIONAL CANCER INSTITUTE [T32CA009138, P30CA016086, P01CA142106, R01CA166794] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL056067] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [T32AI007313, P01AI056299] Funding Source: NIH RePORTER
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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. This study demonstrates a tissue-specific role for IL-22 in mediating chronic cutaneous graft-versus-host disease, confirming parallel but symbiotic pathways of Th22 and Th17 differentiation, and highlights potential new therapeutic approaches.
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