The objectives of this program focus on the cellular, molecular and biochemical characterization of the underlying pathologic events in inflammatory, infectious, neoplastic and autoimmune diseases, with the long-term intent to develop novel approaches to therapeutic intervention. Our basic research program fuels this clinical focus based on our characterization of in vitro immunoregulatory pathways and animal model studies in disease pathogenesis. Nonhealing mucosal and cutaneous lesions due to infection, inflammation or neoplasia can become chronic and debilitating. Despite the profound health effects that chronic wound healing problems and excessive scarring pose, the mechanisms underlying normal and pathologic healing are little understood. Moreover, mucosal epithelial healing is typically more rapid and nearly scarless, prompting a comparison of cutaneous and oral mucosal wound inflammation and repair to identify controlling factors which may be of benefit in clinical delayed healing responses. In recent studies, not only were the kinetics, cellular composition, and outcome of the healing response found to be substantially altered between cutaneous and oral wounds, but secretory leukocyte protease inhibitor (SLPI) was identified as a pivotal regulatory factor in cutaneous and mucosal wounds using pre-clinical models, setting the stage for determining clinical efficacy. In clinically-derived chronic inflammatory lesions, perpetuated by bacteria and/or their products (periodontal tissues, etc.), viruses (HIV-1), other pathogens, or autoimmune responses (Sjogren's Syndrome), our characterization of the systemic immune response, as well as the local lesion cellular constituents and their products, using laser capture microdissection, proteomic and transcriptome profiles, offers new insight into targets for amelioration of tissue degradation and delayed repair. ? ? Traumatic and infectious tissue inflammation and injury in oral mucosa:? Tissue injury in the oral mucosa of humans activates a cascade of transcriptional events important during inflammation and the healing process that are not yet clearly defined. Based on characterization of these events and identification of gene patterns using cDNA expression arrays in a clinical model of tissue injury (3rd molar extraction) and in infected tissues (periodontal disease), we began to identify genes constitutively expressed in normal oral mucosa and transcriptional events following traumatic or infectious mucosal tissue injury, which will offer insight into differences between physiologic and pathologic pathways and potential gene targets for clinical intervention strategies. Further understanding of the pathophysiology underlying periodontal diseases includes investigation of the contributions of monocytes, dendritic cells and macrophages stimulated with periodontopathogens as determined by genomic and proteomic analyses.? ? Therapeutic approaches to Sjogren?s Syndrome:? Sjogren?s Syndrome (SS) is a common autoimmune disorder affecting primarily females in the fourth and fifth decade of their life. The autoimmune hallmarks of the disease are attested by the focal lymphoid cell infiltration of the exocrine glands and the production of autoantibodies. The clinical spectrum extends from an exocrine gland specific disorder which compromises quality of life to a systemic process with increased morbidity and mortality, mainly due to the increased risk of developing B cell lymphomas. In addition, features of SS are frequently encountered in patients with nearly all autoimmune rheumatic disorders. The etiology of the syndrome remains largely unknown and therapy is empirical and mainly symptomatic. In an effort to address the immune-mediated destruction observed in SS, immunomodulatory drugs such as thalidomide and anti-TNFa have recently been evaluated for potential effectiveness in controlling the hyperimmune phenotype of the disease.. ? ? In the last decade, thalidomide has been reinvented as a potential anti-inflammatory, immunomodulatory and anti-angiogenic agent for the treatment of a variety of conditions ranging from dermatological disorders and autoimmune diseases to cancer. Given the central role of TNF in immune and inflammatory conditions, the ability of thalidomide to down-regulate TNF may, in large part, explain its clinical usefulness in other immune-mediated disorders. To this end, thalidomide was tested as a potential therapy for SS and its lack of clinical efficacy was unanticipated. However, evaluation of systemic immunological parameters that may serve as potential prognostic markers of treatment outcome revealed that prior to treatment, HLA-DR, TNFRI, CXCRI and CXCRII were elevated in the patients compared to healthy controls. After three weeks of thalidomide treatment, phenotypic changes began to emerge in the patient peripheral blood mononuclear cells. Although no significant changes were evident in multiple PBMC subsets, the number of B cells decreased after treatment and HLA-DR expression decreased on PBMC of treated patients, as did cell surface expression of the adhesion molecule L-selectin and TNFRI. Finally, expression of CXCRI and II chemokine receptors was reduced in the treated patients, possibly reflecting reduced recruitment potential to areas of disease. Evidence of multiple systemic immunological consequences within weeks after the onset of thalidomide treatment, despite lack of quantifiable clinical efficacy during this short treatment interval, may offer insight into the immunoregulatory actions of thalidomide, but may point to a nonessential role for TNF in this disease. Similarly, the failure of the TNF inhibitor etanercept to ameliorate SS symptoms provides additional support for alternative mechanisms of pathology, currently under study in our laboratory and in collaboration with international investigators.? ? Squamous Cell Carcinoma? Oral and pharyngeal cancer remains one of the 10 most frequently occurring cancers worldwide with a poor prognosis. It is vital to identify cellular, molecular and biochemical mechanisms associated with treatment resistance as well as to identify prognostic factors that not only influence the occurrence of metastasis, but can predict the likelihood of metastatic disease. Following our initial assessment of growth factors and their correlative parameters with tumor status, we have expanded our studies to include proteolytic cascades and immunoregulatory pathways. In collaborative studies, we have identified an association with a proteolytic/antiproteolytic imbalance, SLPI levels and TGF-beta expression, suggesting potential prognostic markers, as well as interventional targets.
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