HPV-Specific, Immune Suppression in Patients with RRP

描述（由申请人提供）：由人乳头瘤病毒（HPV）6型和11型引起的复发性呼吸道乳头瘤病（RRP）的特征是恶性前肿瘤的反复生长，具有显著的发病率和死亡率。标准治疗是手术切除，但患者可能需要>100次手术来维持他们的气道，每年花费> 1亿美元。推动我们研究的主要问题是：是什么阻止了RRP患者对HPV产生有效的免疫反应？这些HPV在乳头状瘤组织中诱导极高水平的促炎细胞因子IL-36 β，这矛盾地未能触发有效的激活先天性反应和随后对这些病变的免疫清除。我们目前正在进行塞来昔布治疗RRP的IIB期临床试验， 拟议的研究将使我们能够在体内解决这一机制。我们的长期目标是利用我们对RRP免疫反应的了解，为这种疾病开发更好的治疗方法。这些研究也可能提供关键的见解，为什么一些患有口咽部高危HPV感染的患者无法清除感染并最终发展为癌症。具体目标：RRP患者在IL-36 β介导的先天免疫应答的激活方面存在缺陷，这至少部分是由气道中PGE 2的表达引起的，这一假设的三个目的是：1A）确定IL-36 β对RRP患者喉角质形成细胞表达和释放细胞因子/趋化因子的影响，以及升高的考克斯-2/PGE 2对这种调节的影响; 1B）确定IL-36 β和外源性PGE 2对朗格汉斯细胞成熟和促/抗炎细胞因子/趋化因子表达的影响; 2）：确定介导喉角质形成细胞和朗格汉斯细胞中IL-36 β表达和释放的信号转导途径，以及并行PGE 2信号传导对这些途径的影响;和3）。确定Aim I中促炎/抗炎细胞因子/趋化因子表达的改变模式是否与入选正在进行的塞来昔布治疗IIB期临床试验的RRP患者的血清和喉组织中的模式相似。创新：我们将 首次测试了宿主特异性、组成性和升高的PGE 2表达抑制局部HPV诱导的炎症反应并导致RRP患者先天免疫信号传导偏倚的新概念。通过塞来昔布的临床试验，我们有独特的机会比较我们的体外研究与体内反应。这些研究应该确定新的目标，可以改变现有的手术方法，以治疗RRP患者，以医学免疫为基础的治疗，成本更低，降低发病率，有可能治愈这种疾病，并提供关键和急需的洞察力，为什么一些高危HPV感染的患者发展口咽癌。

DESCRIPTION (provided by applicant): Recurrent respiratory papillomatosis (RRP), caused by human papillomavirus (HPV) types 6 and 11, is characterized by repeated growth of pre-malignant tumors, with significant morbidity and mortality. Standard treatment is surgical removal but patients can require >100 surgical procedures to maintain their airway, at a cost of >$100 million U.S. dollars yearly. The major question driving our studies is: what prevents RRP patients from mounting an effective immune response to HPV? These HPVs induce extremely high levels of the pro-inflammatory cytokine IL-36� in papilloma tissues, which paradoxically fails to trigger an effective activating innate response and the subsequent immune clearance of these lesions. We are currently conducting a phase IIB clinical trial of celecoxib in RRP, and this proposed study will permit us to address this mechanism in vivo. Our long-term goal is to use our knowledge of the immune response in RRP to develop better therapies for this disease. These studies may also provide critical insight into why some patients with high risk HPV infections of the oropharynx fail to clear the infection and ultimately develop cancer. Specific Aims: Three aims will test the hypothesis that RRP patients have a defect in IL-36� mediated activation of the innate immune response caused, at least in part, by expression of PGE2 in the airway are: 1A) Determine the effect of IL-36� on the expression and release of cytokines/chemokines by laryngeal keratinocytes from RRP patients, and the effects of elevated COX-2/PGE2 on this modulation; 1B) Determine the effect of both IL-36� and exogenous PGE2 on maturation and the expression of pro/anti-inflammatory cytokine/chemokines by Langerhans cells; 2): Determine the signal transduction pathways that mediate expression and release of IL-36� in laryngeal keratinocytes and Langerhans cells, and the impact of concurrent PGE2 signaling on those pathways; and 3). Determine if patterns of altered pro/anti-inflammatory cytokine/chemokine expression in Aim I parallel those in serum and laryngeal tissue from RRP patients enrolled in an ongoing, phase IIB clinical trial of celecoxib therapy. Innovation: We will test for the first time, the novel concept that a host-specific, constitutive, and elevated expression of PGE2 suppresses the local HPV-induced inflammatory response and contributes to a bias in innate immune signaling in RRP patients. We have the unique opportunity through our clinical trial of celecoxib to compare our in vitro studies with in vivo responses. These studies should identify novel targets that could change the existing surgical approach to treat RRP patients to medical immune-based therapies that would be less costly, reduce morbidity, have the potential to cure this disease, and also provide critical and much needed insight into why some patients with high risk HPV infection develop cancer of the oropharynx.