An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition

Forcade, Édouard; Paz, Katelyn; Flynn, Ryan; Griesenauer, Brad; Amet, Tohti; Li, Wei; Liu, Liangyi; Bakoyannis, Giorgos; Jiang, Di; Chu, Hong Wei; Lobera, Mercedes; Yang, Jianfei; Wilkes, David S.; Du, Jing; Gartlan, Kate H.; Hill, Geoffrey R.; MacDonald, Kelli P. A.; Espada, Eduardo; Blanco, Patrick; Serody, Jonathan S.; Koreth, John; Cutler, Corey; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jérôme; Paczesny, Sophie; Blazar, Bruce R.

doi:10.1172/jci.insight.92111

Cited by 66 publications

(53 citation statements)

References 61 publications

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“…Our novel observations regarding the relationship between IL-22 and IL-17 suggest that an additional strategy may be to target IL-17 directly in the skin using small molecule inhibition. 38 These data provide insight for rational therapeutic strategies to inhibit IL-22 secreting T-cells late after transplant, particularly for the treatment of cutaneous chronic GVHD.…”

Section: Discussionmentioning

confidence: 96%

“…Intriguingly, Bronchiolitis Obliterans (BO), a manifestation of chronic GVHD that mirrors BO after lung transplant, was not IL-22-dependent. Given that we have recently established the importance of IL-17A and Th17 cells in driving BO, 38,54 this would suggest that IL-17A rather than IL-22 is the most appropriate therapeutic target for inhibition of BO after stem cell or solid organ transplant.…”

Section: Discussionmentioning

confidence: 99%

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

Gartlan

Bommiasamy

Paz

et al. 2018

American Journal of Transplantation

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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.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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

Gartlan

Bommiasamy

Paz

et al. 2018

American Journal of Transplantation

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“…Additionally, TMP778 significantly alleviated murine lung cGVHD. The use of anti-IL-17 antibody showed similar results [65]. In cGVHD, activation of STAT3 and production of IL-21 by pathogenic T cells is also important for the pathogenesis.…”

Section: Biomarkers As Potential Therapeutic Targetmentioning

confidence: 85%

“…Recently, a CD4 T-cell population, expressing CD146, an adhesion molecule and CCR5, a chemokine receptor, was identified in cGVHD patients. More importantly, this T-cell population is TH17-prone [65]. Another subset of T cells, CXCR3+ T cells were identified in two studies, where their levels were significantly decreased in cGVHD patients compared to non-GVHD patients [46,48].…”

Section: Useful Cgvhd Biomarkersmentioning

confidence: 99%

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The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease

Ren

Adom

Paczesny

2018

Expert Review of Clinical Immunology

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Introduction Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary We focus on biomarkers that play an essential role in target identification.

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