NOVEL TREATMENTS FOR HIV-1 RELATED PSORIASIS

描述（申请人的摘要）：Psaponism是一种常见的和神秘的 通常发生在健康人身上的皮肤病。 然而，自从艾滋病流行以来，很明显牛皮癣是 HIV-1感染的皮肤表现之一。这种现象 提出了几个难题，皮肤科医生超越病理生理学 问题，包括考虑替代治疗办法。以来 大多数成功的银屑病治疗是免疫抑制的， 在HIV-1的情况下使用这些药物是一个挑战。 基于这些考虑，很明显，新的治疗方法是可行的。 应对临床挑战的策略是必要的， HIV-1阳性银屑病患者。我们建议采用一种创新的模式 该系统采用移植到SCID小鼠上的银屑病斑块， 确定新的治疗策略。SCID小鼠不能排斥 移植的人类皮肤，我们已经验证了所有可测量的 迄今为止，在移植前和移植后皮肤之间检查到的异常 保留在这个模型中。初步数据显示我们可以 有效治疗并彻底消除移植性银屑病斑块 使用类似于早期公开的损伤内环孢菌素A（CyA） HIV-1阴性银屑病患者的研究。使用的主要优点 该动物模型是没有患者直接暴露于 治疗，从而避免对患者的任何医源性影响 免疫状态或对抗机会性感染的风险。的 我们将重点关注的治疗药物包括IL-10、CsA和维甲酸。 选择IL-10是因为它是一种2型细胞因子， 已知银屑病患者中1型细胞因子的产生增加 斑块，以及抑制细胞介导的免疫反应。的 IL-10的有效性将与其他2种药物进行比较/对比， 已知对牛皮癣有效。此外，这些代理人 最近也发现对HIV-1有抗病毒作用， 因此，可能能够通过以下两种方式改善银屑病伴HIV-1 抑制皮肤局部免疫功能亢进，以及 阻断HIV-1复制将检查所有治疗的 对表皮角质细胞增殖，免疫细胞活化， HIV-1复制 如果这些治疗中的任何一种或全部改善了移植的银屑病斑块， 那么这些数据将为推进第一阶段提供支持， 临床试验使用SCID模型的积极结果可能是 将为生物技术加速生产铺平道路 IL-10的工业，可以与皮肤病 对人类受试者的制剂，并确保机构审查委员会 一个可能的有益结果将发生平衡潜在的风险 和副作用通过设计和优化新的治疗策略 使用联合免疫缺陷模型， 受感染的患者也可扩展至未受感染的银屑病患者 HIV-1

DESCRIPTION (applicant's Abstract): Psoriasis is a common and enigmatic skin disease that generally occurs in otherwise healthy individuals. However, since the AIDS epidemic, it has become clear that psoriasis is one of the cutaneous manifestations of HIV-1 infection. This phenomenon presents several dilemmas for dermatologists beyond pathophysiological issues, to include consideration of treatment alternatives. Since the majority of successful psoriatic treatments are immunosuppressive, it is a challenge to use such drugs in the setting of HIV-1. Based on these considerations, it is clear that novel therapeutic strategies are necessary to meet the clinical challenge of treating HIV-1 positive psoriasis patients. We propose to use an innovative model system that employs psoriatic plaques transplanted onto SCID mice to identify novel treatment strategies. SCID mice cannot reject the transplanted human skin, and we have validated that all measurable abnormalities examined to date between pre- and post-transplanted skin are retained in this model. Preliminary data indicate that we can effectively treat and completely resolve transplanted psoriatic plaques using intralesional cyclosporin A (CyA) analogous to earlier published studies in HIV-1 negative psoriatic patients. The main advantage of using this animal model is that no patient is directly exposed to the treatments, thereby avoiding any iatrogenic impact on the patient's immune status, or risk for combating opportunistic infections. The treatment agents we will focus on include IL-10, CsA, and retinoic acid. IL-10 was chosen because it is a type 2 cytokine that inhibits production of type 1 cytokines known to be elevated in psoriatic plaques, as well as inhibiting cell-mediated immune reactions. The effectiveness of IL-10 will be compared/contrasted to 2 other drugs that are already known to be useful in psoriasis. Furthermore, these agents have also recently been found to have antiviral effects on HIV-1, and hence may be capable of improving psoriasis with HIV-1 by both inhibiting the local immune hyperactivity in skin, as well as by blocking HIV-1 replication. All treatments will be examined for their effects on epidermal keratinocyte proliferation, immune cell activation, and HIV-1 replication. If any or all of these treatments improve transplanted psoriatic plaques, then this data would provide support for moving ahead with phase I clinical trials. It is likely that positive results using the SCID model will pave the way for accelerating production by the biotechnology industry of IL-I0 that could be administered with a dermatological formulation to human subjects, and assuring institutional review boards that a possible beneficial result would occur to balance potential risks and side effects. By devising and optimizing new therapeutic strategies using the SCID model, clinical dividends that will result for HIV-1 infected patients may also extend to psoriatic patients not infected with HIV-1.