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

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications & trials

Abstract

The Oral Immunobiology Unit is dedicated to solution-oriented approaches to improve scientifically valid, measurable health outcomes in cancer survivors with chronic autoimmune disease. I use bedside-to-bench clinical research to study dysregulated exocrine gland and mucosal immunity in allogeneic hematopoietic stem cell transplant patients in the context of chronic graft versus host disease (cGVHD) to improve understanding of the biology of and treatment for oral cGVHD to improve the lives of cancer patients. In parallel, I build the pipeline of excellent biomedical dental clinician scientists through a merit-based fellowship training program that teaches trainees to design and conduct the highest quality scientific studies to expand the contributions of the oral health sciences to biomedical research. Our initial studies have focused on patients who have undergone allogeneic hematopoietic cell transplantation (HCT, alloHCT) as curative therapy primarily for hematological malignancies. Approximately 15% of allogeneic HCT 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 and quality of life. Understanding the mechanisms underlying salivary gland destruction and influences of the local oral environment on the immune response 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 oral mucosa and salivary gland dysfunction following alloHCT 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 and alterations in the local environment of the oral cavity. In patients with cGVHD, we have identified infiltration of specific lymphocyte subsets in the oral mucosa that appear to be dysregulated and could represent therapeutic targets. We analyzed data from sixty participants enrolled in a contemporary alloHCT natural history study (ClinicalTrials.gov ID: NCT03602599) and reported oral health problems and reductions in oral health-related quality of life through two years after alloHCT. These findings support a tailored approach to oral healthcare among recipients of alloHCT. Providing comprehensive and sustained oral health care for this patient population is essential. Work from a multi-center clinical trial (ROCKstar study, registered at www.clinicaltrials.gov as NCT03640481) assessed tissue-level immune dynamics in 20 subjects with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSG], and skin) and peripheral blood. Belumosudil (KD025), is an oral, selective, Rho-associated, coiled-coil containing protein kinase 2 (ROCK2) inhibitor, that is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Following belumosudil treatment, reduction in collagen was observed in OM in parallel with decreased IL-17+ cell frequency in both OM (n = 14 pairs) and MSG (n = 11 pairs). IL-17 was primarily produced by non–T cells in the oral tissues. Immune cell frequencies in the OM decreased following treatment, while CD4 Tregs increased in both MSG and blood. Per overall or mouth-specific clinical response criteria, responders to belumosudil exhibited a reduction in collagen type I and IL-17 in OM. Additionally, salivary transforming growth factor β1 (TGF)-β1, a critical driver of fibrosis, decreased significantly, with a strong correlation observed between TGF-β1 and IL-17 levels. These findings illustrate the tissue-level response to belumosudil therapy and suggest that there is a reduction in tissue fibrosis and inflammation, thereby highlighting the therapeutic impact of ROCK2 inhibition in mitigating cGVHD. Clinical and translational 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 HCT (NCT03602599) at NIDCR and in conjunction with the NIH interdisciplinary cGVHD group, and a multi-center randomized placebo-controlled trial to treat oral cGVHD using photobiomodulation (NCT05675930) along with collaboration with transplant teams across the NIH Clinical Center to study and care for the oral cavity in the peri- and post-HCT period. In summary, our current scientific investigation has identified microenvironmental changes, specific immune cell populations active in the cGVHD oral mucosa and salivary gland, and effector-site immune perturbations that are linked to post-transplant tissue damage. In the past year, we have contributed to work in patient advocacy and education and academic review of cGVHD clinical care for dental, dermatology and transplant care providers.