4-Year NIH Grant in Immune Regulation of Tissue Homeostasis

Xiaozhe Han, D.M.D., Ph.D., principal investigator (PI) from College of Dental Medicine’s Department of Oral Science and Translational Research (OSTR) were recently awarded a four-year $2,338K NIH grant titled “Regulatory B Cell in the Amelioration of Immune-Mediated Periodontal Disease.” Together with the co-investigator on the grant, Dr. Toshi Kawai, D.D.S., Ph.D., at the same Department, the research team will strive to understand the mechanisms underlying B10-mediated immune regulation within the coordinated immune network that maintain tissue homeostasis. In particular, the studies will broaden insights into role of Breg-macrophage interaction in inflammation resolution in periodontal disease.

IL-10 expressing regulatory B cells (B10 cells) have been implicated in the regulation of autoimmune and inflammatory diseases in animal models, and evidence is accumulating of their relevance in analogous human diseases. Despite the considerable advances made toward understanding of B10 biology, the regulatory activities of B10 cells during different stages of inflammation and their potential role in the resolution of inflammation, is still not well understood. Gaining this complete picture is essential to therapeutically harness local B10 functions.

Recent findings indicate that direct cell-cell interaction also play important role in B10 function and immune regulation. Based on the literature and preliminary data from Dr. Han’s research, the specific hypotheses of the current studies are: i) that activated B10 cells induced pro-resolving macrophage differentiation and specialized pro-resolving mediators (SPM) production via PD-L1/PD-1 ligation, and ii) that actions of SPM derived from B10-macrophage interaction enhance B10 cell differentiation to antibody-secreting cells and pro-resolving macrophage function to alleviate neutrophil-mediated, RANKL-dependent periodontal inflammation and bone loss.

To test these hypotheses, Dr. Han and his collaborators will determine the role of PD-L1/PD-1 ligation on B10-mediated regulation of macrophage phenotype switch and production of lipid mediators; actions of SPM on B10 differentiation and function during B10-macrophage interaction; and the role of B10-macrophage interaction on pro-resolving macrophage function, neutrophil activity, and the resolution of periodontal inflammation.

If successful, this NIH funded project will provide novel mechanistic insights into the coordination of immune regulatory cells that reflect the dynamic process of inflammation. It will also enhance scientific understanding of the actions of SPM and their roles on innate and adaptive immune responses in the resolution of periodontal inflammation. Results of this study will lay the ground for identification of diagnostic markers and therapeutic targets to facilitate treatment of periodontal disease and potentially other immune-mediated osteolytic conditions such as osteoporosis or rheumatoid arthritis.