Salivary Biology and Immunology Program, Integrative Biology and Infectious Diseases Branch, DER, NIDCR
This initiative will encourage contemporary, systematic research approaches to elucidate the role of immune system plasticity in health and in the pathogenesis of dental, oral, and craniofacial diseases. The expectation is that new knowledge derived from this research will facilitate development of novel immunomodulatory-based therapies to prevent or reverse disease progression. Plasticity, for the purposes of this concept, is defined as the ability of the immune system to undergo changes in both phenotype and function in response to a dynamic environment.
Recent advances in understanding diseases and conditions involving dental, oral, and craniofacial tissues – periodontal disease, peri-implantitis, oral cancers, Sjögren’s Syndrome, and HIV/AIDS with its associated oral opportunistic infections - highlight that substantial changes occur in the immune system and contribute to disease onset, progression, and persistence. However, critical scientific gaps exist regarding our understanding of the relationship between the immune system and disease pathogenesis. In periodontal disease and peri-implantitis, the immune system exerts detrimental effects on oral bone, compromising bone volume as well as integrity of the surrounding 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. Recent genome-wide association studies on Sjögren’s Syndrome have identified variants at several loci involved with innate and adaptive immunity. Recent research on chronic HIV infection has uncovered substantial information regarding oral and systemic effects of residual inflammation, immune activation, and microbial translocation in subjects treated with a combination of antiretroviral therapies. However, little is known about the impact of and mechanisms by which these effects play a role on the development and persistence of oral diseases. In addition, pain may accompany these 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 be responsible for the chronic pain that accompanies many complex diseases of the orofacial region.
Recent basic science and clinical research advances have shown that the innate immune system can regulate gene networks in a cell-, environment-, and even time-dependent manner contributing to disease complexity. These advances create an unprecedented opportunity to apply these discoveries towards treatments for dental, oral, and craniofacial diseases. For example, cancer immunotherapy has evolved into a successful therapeutic option for a substantial fraction of patients with immunogenic cancers (e.g., melanomas). Recent studies have shown the upregulation of the checkpoint inhibitory protein, PD1 ligand 1, in head and neck cancers and HPV-associated oropharyngeal cancers, providing a strong rationale for this approach. In addition, monoclonal antibodies targeting PD-1 are being developed for the treatment of cancer. Molecular details of how genetic mutations disrupt protein activity and interactions leading to pathogenesis have recently been elucidated for some inflammatory craniofacial bone conditions where large areas of bone are eventually destroyed. In periodontal disease where there is highly localized chronic inflammation in response to pathogens, discovery of certain components in the complement system and of new endogenous mediators warrant further dissection of their mechanisms of action. While bone resorption is carried out by osteoclast activity, these cells are in the same lineage as macrophages and discoveries of disrupted signaling pathways common to both present a unique opportunity to study their interplay. Furthermore, recent studies indicate that macrophage-specific Toll-Like Receptor (TLR-2) signaling mediates pathogen-induced cytokine-dependent inflammatory oral bone loss. Similarly, other pathways such as Wnt5a or PD-1, may serve as potential targets for immunomodulatory therapy in periodontitis
NIDCR’s investment in the Sjögren’s International Collaborative Clinical Alliance (SICCA) Biorepository supports research on Sjögren’s Syndrome and related autoimmune diseases by providing access to specimens and data from affected individuals and family members. These and other critical advances identified a strong need to: 1) advance knowledge of the immunological basis of oral diseases, and 2) develop tools and technologies for precise and robust modulation of the immune system to restore health. This initiative will pursue both goals, with the recognition that some efforts may move faster than others, depending on tool availability and knowledge available on a disease or condition.
Opportunities for Research Include:
- Identification of genetic loci of inflammatory diseases and environmental factors that contribute to immune dysfunction associated with these diseases utilizing a variety of approaches, including genome wide association studies (GWAS), phenotype/genotype correlation studies, and modeling human inflammatory diseases using disease-specific induced pluripotent stem cells models.
- Derivation of systems biology approaches to understand innate and adaptive immune responses within the context of tissue homeostasis in health and disease, identification of key signaling molecules and networks that can serve as effective diagnostic and therapeutic targets, and development of tools and technologies to permit precise manipulation of these targets to restore health
- Development of new and improvement of existing large animal models reflecting the pathogenesis of human diseases to validate and optimize therapeutic strategies that have shown promise in small animals; assessment of the safety and therapeutic efficacy of these strategies demonstrated through the use of clinically relevant outcomes
- Development of experimental tools and technologies for precise and predictable modulation of immune system function to understand the transition from normal tissue homeostasis to pathology and prevention of disease progression; these tools and technologies include, but are not limited to, temporal and spatial biomolecule delivery and release, efficient genetic and epigenetic modification of immune cells, directed immune cell homing and activation, amplification/suppression of specific immune cell subsets, and non-invasive real-time imaging of immune system function
- Enhanced understanding of endogenous cellular and molecular mediators that maintain normal tissue homeostasis, prevent inflammatory disease progression, and initiate and control inflammatory responses, immune activation, and microbial translocation in oral infections, including those that control transition from acute to chronic inflammation.
- Development of clinically-applicable strategies to treat or prevent oral and craniofacial disease based on precise modulation of immune system plasticity and on the identification of the optimal conditions for fighting infection, pathological immune activation and aberrant inflammation
Current Portfolio Overview
Within the NIDCR extramural research portfolio, understanding the dynamic nature of the immune system is a common interest to several programs. A search of recent NIDCR grants (2011-2014) associated with immune response demonstrates the broad interest in immune system function within the NIDCR mission. Sixty-five research project grants, mostly R01s, were identified in this search and were assigned to ten different NIDCR programs. A more focused search, specifically targeting immune system plasticity demonstrates the need to consider this concept proposal - only six RPGs were funded across five programs; three of these were R01s.
Alignment with Institute Goals and Strategic Plan
This concept aligns with the goals and objectives of NIDCR Strategic Plan 2014-2019: Goal I, Objective 1-1: Enable basic research to advance knowledge of dental, oral, and craniofacial health; Goal 2, Objective 2-1: Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease; and Goal 3, Objective 3-1: Support multidisciplinary, multilevel research and research training to overcome oral health disparities.
Overlapping Interests with Other NIH Institutes and Centers
Explorations as addressed by this initiative will stimulate interest and the potential for partnerships with other NIH Institutes and Centers such as NCI, NIAID, NIAMS, NINDS, and NICHD, which share common interests with NIDCR in several diseases.
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