Work

Th17 Recruitment and Interferon Pathway Activation in Oral Chronic Graft-Versus-Host Disease Tissues

Year: 2016

Type: article

Abstract: Chronic graft-versus-host disease (cGVHD) manifests in multiple organ systems, including the oral cavity where buccal mucosa (BM) and minor salivary glands (MSG) are affected. The oral cavity is a highly-accessible mucosal site with its own local biofluid – saliva – but little is known about the immune network that drives pathogenesis of cGVHD in oral tissues. This study used a systems approach to query the relationship between salivary gland gene expression, salivary proteins and the immune cell network within oral tissues with regard to oral cGVHD severity. Patients enrolled in NIH cGVHD trials (NCT00331968, NCT00520130, NCT01851382) were evaluated after cGVHD onset. Self-organizing cluster analysis of microarray data from MSG distinguished cGVHD status from controls with a clear differential pattern of gene expression. The significantly-changed gene list was explored using Ingenuity Pathway Analysis (IPA). IPA analysis of 1645 significantly altered genes in the MSG microarray identified canonical pathways implicating induction of innate immune pathways, and IFN, IL-17 and IL-22-induced processes. Whole saliva from individual oral cGVHD patients (n=58) and healthy controls (n=10) was analyzed for a 13-plex panel of immune-related analytes and revealed elevated expression of tissue remodeling factors and IFN- and IL-17-induced chemokines that correlated with clinical scoring of cGVHD severity in a multivariate analysis. Confocal microscopy was performed to assess the presence of immune cells in BM and MSG biopsy tissues. Extending our laboratory’s prior observations of Th1 effectors in BM, Th17 cells (CD4+/CD161+/IL-17+) and Type I IFN-induced factors were identified in the majority of available BM and MSG of cGVHD patients, but not in unaffected post-transplant controls from the saliva cohort. Current analyses in cGVHD patient samples implicate activation of IFN pathways and Th17 cell recruitment to oral tissues in the pathogenesis of oral cGVHD.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2015.11.390