Clinical Investigations In Infectious And Autoimmune Diseases

干燥综合征的治疗方法： 舍维斯综合征（SS）是一种常见的自身免疫性疾病，主要影响女性在第四和第五个十年的生活。该疾病的自身免疫特征由外分泌腺的局灶性淋巴细胞浸润和自身抗体的产生证实。临床范围从损害生活质量的外分泌腺特异性疾病扩展到发病率和死亡率增加的系统性过程，主要是由于发生B细胞淋巴瘤的风险增加。此外，几乎所有自身免疫性风湿性疾病的患者都经常遇到SS的特征。该综合征的病因仍在很大程度上未知，治疗是经验性的，主要是对症治疗。为了解决在SS中观察到的免疫介导的破坏，最近已经评估了免疫调节药物如沙利度胺和抗TNF α在控制疾病的超免疫表型中的潜在有效性。 在用TNF抑制剂依那西普治疗之前，唾液腺炎性病灶评分与循环TNF水平无关。抑制TNF并没有改善pSS的临床疾病参数。与缺乏显著临床获益进一步一致的是，依那西普治疗后，免疫活化标志物增强、细胞亚群频率和异常TH 1、TH 2或TH 17细胞因子谱均未恢复至正常水平。值得注意的是，治疗后循环TNF水平显著增加。因此，依那西普在pSS中是无效的治疗药物，反映了在该患者人群中不存在TNF抑制和其他免疫活化指标。这些数据表明，TNF可能不是pSS发病机制中的关键细胞因子，促使继续对疾病参数进行分子表征，以确定适当的干预靶点。 口腔粘膜创伤性和感染性组织炎症和损伤： 人类口腔粘膜的组织损伤激活了炎症和愈合过程中重要的级联转录事件，这些事件尚未明确定义。基于这些事件的表征和在组织损伤的临床模型中使用cDNA表达阵列鉴定基因模式（第三磨牙拔除）和感染组织中（牙周病）时，我们开始鉴定在正常口腔粘膜中组成型表达的基因和创伤性或感染性粘膜组织损伤后的转录事件，这将为临床干预策略提供生理和病理途径之间的差异以及潜在的基因靶点。 进一步了解牙周病的病理生理学基础包括研究单核细胞，树突状细胞和巨噬细胞与牙周病原体刺激的基因组和蛋白质组学分析确定的贡献。 鳞状细胞癌 口腔癌和咽癌仍然是世界上10种最常见的癌症之一，预后不良。重要的是确定与治疗抗性相关的细胞、分子和生化机制，以及确定不仅影响转移发生而且可以预测转移性疾病可能性的预后因素。 在我们对生长因子及其与肿瘤状态相关的参数进行初步评估后，我们扩大了研究范围，包括蛋白水解级联反应和免疫调节途径。在合作研究中，我们已经确定了蛋白水解/抗蛋白水解失衡与SLPI水平的相关性，影响弹性蛋白酶、MMP和其他与侵袭和转移活性相关的下游蛋白酶，提示了潜在的预后标志物以及干预靶点。

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.