Immunobiology and therapy of oral mucosal and salivary gland chronic graft-versus-host disease

National Institute Of Dental & Craniofacial Research

Investigators

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Abstract

Our initial studies have focused on patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy primarily for hematological malignancies. More than 50% of HSCT recipients develop chronic Graft-Versus-Host-Disease (cGVHD), a multi-organ autoimmune-like disorder, and the oral cavity (oral mucosa or salivary glands) is affected in a majority of cGVHD patients. While mucosal manifestations are readily evaluable, pathologic changes in salivary glands progress silently from periductal and diffuse lymphocytic infiltrates to destruction of secretory acini and irreversible glandular fibrosis, with severe consequences on oral health, nutrition and quality of life. Understanding the mechanisms underlying salivary gland destruction may contribute to development of targeted therapies and non-invasive methods for serial screening and treatment of post-transplant patients prior to glandular destruction. We are investigating immune and physiologic causes of salivary gland dysfunction following allogeneic hematopoietic stem cell transplant using mouse and human models and are conducting clinical trials directed toward advancing cGVHD therapy. Our recent work has identified immune cell populations in cGVHD-affected oral mucosa and salivary glands including CD4, CD8+T cells, and IL17-producing cells. Analysis of the local biofluid of the oral cavity, saliva, shows close association between Th1 cytokines and chemokines and clinical disease severity in humans along with a decrease in specific salivary proteins with onset of salivary gland GVHD. Using immunohistochemistry, we have detected production of the interferon-induced GTPase protein MxA (myxoma resistance protein A) in human salivary glands and oral mucosa, providing direct evidence for active type 1 interferon signaling in cGVHD-affected oral tissues. These assays were recently extended to analysis of skin lesions taken from patients exposed to the SARS-CoV-2 virus and affected with pernio or chilblains lesions at acral sites also known as COVID toes. In a mouse model of cGVHD, we have identified GVHD-like infiltration of lymphocytes in the salivary gland accompanied by structural alteration and fibrosis, suggesting that this system could be a powerful tool for mechanistic and interventional laboratory studies focused on cGVHD salivary gland pathogenesis. These studies are ongoing and are contributing to a clear characterization of the pathogenic process of oral cGVHD in the salivary glands and oral mucosa that will lead to identification of additional therapeutic targets. Ongoing clinical trial work includes characterization and sampling of the oral cavity in patients following HSCT in conjunction with the NIH interdisciplinary cGVHD group. In summary, our current scientific investigation has identified specific immune cell populations active in the cGVHD salivary gland, salivary protein perturbations that indicate salivary gland damage and analysis of their role in post-transplant tissue damage. In the past year, we have also reported a novel nuclear dye, atto465, and demonstrated its utility in multiplex immunohistochemistry panels. This project involves research on human coronavirus, novel coronavirus, COVID-19, Severe Acute Respiratory Syndrome coronavirus disease, SARS coronavirus, SARS-coronavirus-2, SARS-cov-2, SARS-cov2, SARS-related coronavirus 2, Severe acute respiratory syndrome coronavirus 2, SARS-Associated Coronavirus, SARS-cov, or SARS-Related Coronavirus.