The objectives of these new NIDCR Funding Opportunity Announcements (FOAs) are to expand contemporary, systematic research approaches to elucidate the role of immune system plasticity in health and in the pathogenesis of dental, oral, and craniofacial (DOC) diseases as well as to develop novel tools and technologies to treat and prevent disease based on precise modulation of the immune system. Plasticity, for the purposes of this initiative, is defined as the ability of the immune system to undergo changes in both characteristics and functions in response to the environment.
Recent advances in our understanding of diseases and conditions involving DOC tissues, including periodontal disease, peri-implantitis, oral cancers, Sjögren’s Syndrome (SS), and orofacial pain, revealed substantial involvement of the immune system in disease onset, progression, and persistence. For example:
- In periodontal disease and peri-implantitis, the immune system-mediated destruction of oral bone compromises bone volume as well as the integrity of the supporting tissues.
- In oral cancer, the normal clearance of cancer cells by oral and systemic immune surveillance processes breaks down as cancer cells acquire mechanisms to evade the immune system, resulting in cancer progression and metastasis.
- In SS, several genetic loci predisposing to the disease appear to be related to innate and adaptive immune responses, as identified by a recent genome-wide association study (GWAS).
- In orofacial pain, peripheral tissue damage or nerve injury stimulates local and systemic immune responses interfacing with the central nervous system (CNS), and this process is likely to be involved in the transition of acute to chronic pain as well as in the persistence of chronic pain.
While progress to date has been encouraging, critical scientific knowledge gaps still exist regarding our understanding of the role that immune system plasticity plays in predisposition to and pathogenesis of DOC diseases. Moreover, few clinically-relevant strategies are currently available to allow for predictable modulation of immune system plasticity and functions to prevent undesirable consequences and for restoring health in these disease conditions. These FOAs will address these gaps by capitalizing on recent discoveries of the immunological basis of DOC diseases and technological progress in the field. For example:
- Cancer immunotherapy is an emerging therapeutic option for some patients with specific types of cancers (e.g., melanomas and lung cancers). Existing studies have shown upregulation of the checkpoint inhibitory protein, programmed cell death protein-1 ligand 1 (PD-L1), in head and neck cancers and HPV-associated oropharyngeal cancers, thus providing a strong rationale for this treatment approach. Monoclonal antibodies targeting the receptor, PD-1, are already being tested for treatment of head and neck cancers.
- Studies of osteoimmunology focus on the interplay of bone homeostasis with the immune system. Molecular details of how genetic mutations disrupt protein activity and interactions leading to pathogenesis have been elucidated for some inflammatory craniofacial bone conditions, including cherubism. Recent advances in this area have identified potential therapeutic targets.
- Inflammation and bone loss are hallmarks of periodontal disease. Identification of the connection between periodontal disease and certain components of the complement system as well as discovery of new endogenous inflammatory mediators of periodontal disease warrant further mechanistic dissection of these novel findings.
- Recent GWAS for SS have implicated a number of loci as genetic risk factors including immune-related genes. In addition, evidence exists for the effectiveness of immunosuppressive therapy for SS. B-cell and T-cell targeted therapies of SS have shown promise, but further investigation in this area is needed. To facilitate this line of research, NIDCR supports the Sjögren’s International Collaborative Clinical Alliance (SICCA) Biorepository that provides access to specimens and data from subjects, and their family members, with SS and other autoimmune diseases.
- Peripheral tissue damage or nerve injury stimulates local and systemic immune responses interfacing with the central nervous system (CNS). Initial activation of CNS microglia results in an inflammatory cascade of cytokine and chemokine release and recruitment of immune cells leading to a persistent sensory neuron hypersensitivity to both normal and noxious stimuli. Aberrant innate and adaptive immune responses in the CNS may play a role in the chronic pain that accompanies many complex DOC diseases.
- Advances in bioengineering, material science, and nanotechnology generated a multitude of novel tools and approaches, which permit precise and predictable temporal and spatial patterning of the tissue microenvironment in vivo, including modulation of immune system responses. These findings have strong potential to enable predictable modulation of the immune system in DOC diseases to restore health.
These and other critical developments identified a strong need to: 1) advance knowledge of the immunological basis of DOC diseases, and 2) further develop and adapt novel tools and technologies for precise modulation of immune system plasticity to restore health for DOC diseases. The expectation is that the outcomes of this effort will be instrumental in development of immunomodulatory therapies for prevention and treatment of a broad range of DOC diseases and conditions.
Deadlines: standard dates apply
- R01 version PAR-15-192
- R21 version: PAR-15-193
Filed Under: Funding Opportunities