NOVEL TREATMENTS FOR HIV-1 RELATED PSORIASIS

描述(申请人摘要)：牛皮癣是一种常见而神秘的疾病 皮肤病通常发生在其他健康的人身上。 然而，自艾滋病流行以来，牛皮癣显然是 HIV-1感染的皮肤表现之一。这一现象 提出了皮肤科医生在病理生理学之外的几个难题 问题，包括对替代治疗的考虑。自.以来 大多数成功的银屑病治疗都是免疫抑制的，它 在艾滋病毒-1的背景下使用这种药物是一个挑战。 基于这些考虑，很明显，新的治疗方法 应对临床治疗挑战的策略是必要的 HIV-1阳性的银屑病患者。我们建议使用一种创新的模式 一种将牛皮癣斑块移植到SCID小鼠身上的系统 确定新的治疗策略。SCID小鼠不能排斥 移植了人类皮肤，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的皮肤之间检查的异常 都保留在这个模型中。初步数据表明，我们可以 有效治疗并完全消除移植的银屑病斑块 使用环孢素A(CyA)，与先前发表的类似 HIV-1阴性银屑病患者的研究。使用的主要优势是 这个动物模型是，没有患者直接接触到 治疗，从而避免任何医源性影响患者的 免疫状态，或对抗机会性感染的风险。这个 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，可以抑制 已知银屑病患者1型细胞因子的产生增加 以及抑制细胞介导的免疫反应。这个 IL-10的疗效将与其他两种药物进行比较/对比 已经知道对牛皮癣有用。此外，这些特工 最近也被发现对HIV-1有抗病毒作用，以及 因此可能能够通过两种方法改善感染HIV-1的牛皮癣 抑制皮肤的局部免疫过度活动，以及通过 阻止HIV-1复制。所有治疗都将接受检查，以确定其疗效 对表皮角质形成细胞增殖、免疫细胞活化的影响 和HIV-1复制。 如果这些疗法中的任何一种或所有疗法都能改善移植的牛皮癣斑块， 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模型的积极结果很可能是 将为利用生物技术加速生产铺平道路 可以与皮肤科医生一起使用的IL-I0行业 对人类受试者的提法，并确保机构审查委员会 可能会产生有益的结果，以平衡潜在的风险 以及副作用。通过设计和优化新的治疗策略 使用SCID模型，将为HIV-1带来的临床红利 被感染的患者也可能延伸到未被感染的牛皮癣患者 携带HIV-1病毒。

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.