Clinical Investigations In Infectious And Autoimmune Diseases

干燥综合征的治疗方法： Sjvgrens综合征(SS)是一种常见的自身免疫性疾病，主要影响女性生命的第四和第五个十年。这种疾病的自身免疫特征表现为外分泌腺的局灶性淋巴样细胞浸润和自身抗体的产生。临床范围从影响生活质量的外分泌腺特异性疾病扩展到全身性过程，发病率和死亡率增加，主要是由于发展为B细胞淋巴瘤的风险增加。此外，几乎所有自身免疫性风湿病的患者都会出现SS的特征。该综合征的病因在很大程度上仍不清楚，治疗是经验性的，主要是对症。为了解决SS中观察到的免疫介导的破坏，最近对免疫调节药物如沙利度胺和抗TNFa在控制疾病的高免疫表型方面的潜在有效性进行了评估。 在使用肿瘤坏死因子抑制剂依那西普治疗之前，唾液腺炎性病灶评分与循环中的肿瘤坏死因子水平无关。抑制肿瘤坏死因子并不能改善PSS的临床疾病参数。进一步与缺乏显著临床益处一致的是，依那西普治疗后免疫激活增强的标志物、细胞亚群的频率以及异常的TH1、TH2或TH17细胞因子谱未恢复到正常水平。治疗后外周血中肿瘤坏死因子水平明显升高。因此，依那西普在PSS中是一种无效的治疗剂，反映了在这一患者群体中缺乏对肿瘤坏死因子和其他免疫激活指标的抑制。这些数据表明，肿瘤坏死因子可能不是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。 口腔黏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一系列在炎症和愈合过程中重要的转录事件，这些事件尚未明确定义。基于对这些事件的描述和在组织损伤(拔除第三磨牙)和感染组织(牙周病)的临床模型中使用基因表达阵列鉴定基因模式，我们开始识别正常口腔黏膜和创伤或感染性黏膜损伤后转录事件的组成性表达基因，这将为临床干预策略提供生理和病理途径之间的差异和潜在的基因靶点。进一步了解牙周疾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在牙周病原体刺激下的作用，这是通过基因组和蛋白质组分析确定的。 鳞状细胞癌 口腔和咽癌仍然是世界上最常见的10种癌症之一，预后很差。识别与化疗耐药相关的细胞、分子和生化机制，以及识别不仅影响转移发生而且可以预测转移疾病可能性的预后因素是至关重要的。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降解/抗蛋白分解失衡和SLPI水平之间的关系，影响了弹性蛋白酶、基质金属蛋白酶和其他与侵袭和转移活性相关的下游蛋白酶，提出了潜在的预后标记物和干预靶点。

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.