Therapeutic approaches to Sjogrens Syndrome:? Sjvgrens 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.. ? ? Prior to treatment with the TNF inhibitor, etanercept, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Inhibition of TNF did not ameliorate clinical disease parameters in pSS. Further consistent with lack of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations, and aberrant TH1, TH2 or TH17 cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNF were significantly increased after treatment. Consequently, Etanercept is an ineffective therapeutic agent in pSS reflecting the absence of suppression of TNF and other indicators of immune activation in this patient population. These data suggest that TNF may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterization of disease parameters to define appropriate intervention targets.? ? 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.? ? 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 and SLPI levels, impacting on elastase, MMP and other downstream proteases associated with invasion and metastatic activity, suggesting potential prognostic markers, as well as interventional targets.
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