A critical role for donor-derived IL-22 in cutaneous chronic GVHD

Abstract

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.

The role of IL-22 in intestinal health and disease

“…Yet, as in IBD, there are also some preclinical results that tell a cautionary tale. Specifically, one study demonstrated that inflammation, skin epidermal thickness, and fibrosis were all reduced when IL-22 was neutralized in a model of cutaneous GVHD (Gartlan et al, 2018), assigning a disease-promoting role to IL-22 during chronic inflammation. Such a role would be consistent with other observations of a disease-promoting role of IL-22 in the skin.…”

B-cell targeting in chronic graft-versus-host disease

“…In a consecutive step activated B-cells can promote tissue injury via antibody and cytokine production and release, leading to the clinical manifestations of cGVHD ( Figure 1A, step 4). IgG-induced macrophage activation may contribute to cGVHD via secretion of pro-inflammatory cytokines such as IL-6 and IL-22 22 , which maintain inflammation. Tissue stiffness in cGVHD can be enhanced by copious Ig production and deposition together with fibroblast-derived extracellular matrix molecules including collagen and proteoglycans (Figure 1A, step 4).…”

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

“…There is also a growing focus in the field in identifying cellular biomarkers of this disease. This work has been driven by detailed flow cytometric evaluation of the T-and B-cell subpopulations driving both acute and chronic disease, [86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102] as well as increasing use of systems-based transcriptomic approaches to identifying the pathways associated with GVHD, both in preclinical models and clinical samples. 50, [103][104][105][106][107] This work is identifying a new cohort of targetable pathways for GVHD control, many of which are amenable for clinical translation.…”