Human Th17 activity profile in oral chronic Graft-versus-Host Disease

Abstract

Abstract Immunotherapy using allogeneic hematopoietic stem cell transplantation (alloHSCT) is highly effective; however, its use is limited by the incidence of chronic graft-versus-host disease (cGVHD). The oral cavity, which is affected by cGVHD, is a highly accessible mucosal site with its own local biofluid – saliva – but little is known about the pathogenic progression of cGVHD in oral tissues. This study examined the relationship between salivary gland gene expression, salivary proteins and the immune cell network within oral tissues at onset of oral cGVHD. Patients enrolled in NIH cGVHD trials (NCT00331968, NCT00520130, NCT01851382) were evaluated after cGVHD onset. 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. Microarray of patient MSG indicated canonical pathway expression including innate immune pathways, and IFN, IL-17 and IL-22-induced processes. Confocal microscopy confirmed the presence of immune cells in oral 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. Current analyses in cGVHD patient samples implicate activation of IFN pathways and presence of Th17 cells in oral tissues in the pathogenesis of oral cGVHD, though the specific sequence and role of these cells in salivary gland pathogenesis during cGVHD remain to be determined.