Immunopathogenesis of skin and mucosal Human Papillomavirus (HPV)-related diseases

皮肤和粘膜人乳头瘤病毒（HPV）相关疾病的免疫发病机制

• 批准号: 10690334
• 负责人: Andrea Lisco
• 金额: $ 55.02万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10690334
• 关键词: Ablation; Allogeneic Bone Marrow Transplantation; Blood Cells; Bone Marrow Transplantation; CD4 Antigens; CD4 Positive T Lymphocytes; Cells; Chemicals; Clinical; Clinical Protocols; Defect; Development; Disease; Epidemiology; Epithelial; Gene Expression Profiling; Genetic; Genetic Determinism; Genotype; Goals; HIV-1; HIV/AIDS; Human; Human Characteristics; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; IL7 gene; Image; Immune; Immune Targeting; Immunization; Immunocompromised Host; Immunologics; Infrastructure; Intervention; Lesion; Lymphopenia; Malignant Neoplasms; Mediating; Metagenomics; Modeling; Molecular Epidemiology; Morbidity - disease rate; Mucous Membrane; Natural History; Natural Killer Cells; Operative Surgical Procedures; Pathogenesis; Patients; Prevention strategy; Proteins; Recombinants; Recurrence; Refractory; Reporting; Role; Site; Skin; T cell response; Variant; Virion; Woman; acquired immunodeficiency; antiretroviral therapy; clinical efficacy; conditioning; congenital immunodeficiency; cytotoxic; cytotoxicity; exome sequencing; genetic variant; immune function; immune reconstitution; men who have sex with men; novel; recruit; tool; trafficking; treatment strategy

The studies on the immunological and genetic determinants of HPV-related diseases have further elucidated the role of CD4 T cells and NK cells in the development and clinical progression of HPV-related skin and mucosal diseases. In particular, we have been investigating the epidemiological and immunological characteristics of HPV anogenital colonization in HIV-1 infected women and man who have sex with man (MSM). In parallel, we delineated the immunological determinants of HPV pathogenesis in clinical models of primary immunodeficiencies with discrete genetic immunological defects. We reported on the clinical and immunological defects associated with a novel genetic variant causing a complete multilineage loss of expression of the CD4 molecule and the role NK mediated cytotoxicity in the context of a novel IL-2RG missense variant with somatic reversion. Such studies illustrated the role of specific immunological effector functions as well as the role of a reduced intensity conditioning allogeneic bone marrow transplantation (BMT) in leading to stable regression of recurrent HPV-related diseases. Novel metagenomic tools for HPV genotyping have been integrated with studies on the immunological function associated with control of HPV replication in the skin and in the anogenital compartment. The clinical and regulatory infrastructure to evaluate patients with skin and anogenital HPV-related disease has been further expanded focusing on patients with primary immunodeficiencies, idiopathic CD4 lymphopenia (ICL) and HIV/AIDS while a novel clinical protocol using long-acting rhIL-7 has been launched in a patient with ICL and refractory skin and mucosal HPV-related diseases.

HPV相关疾病的免疫学和遗传决定因素的研究进一步阐明了CD4 T细胞和NK细胞在HPV相关皮肤粘膜疾病发生和临床进展中的作用。特别是，我们一直在调查 HIV-1 感染女性和男男性行为者 (MSM) 中 HPV 肛门生殖器定植的流行病学和免疫学特征。与此同时，我们在具有离散遗传免疫缺陷的原发性免疫缺陷临床模型中描述了 HPV 发病机制的免疫决定因素。我们报道了与导致 CD4 分子表达完全多谱系丧失的新型遗传变异相关的临床和免疫学缺陷，以及 NK 在具有体细胞逆转的新型 IL-2RG 错义变异背景下介导的细胞毒性的作用。此类研究阐明了特异性免疫效应功能的作用以及降低强度调节同种异体骨髓移植 (BMT) 在导致复发性 HPV 相关疾病稳定消退中的作用。用于 HPV 基因分型的新型宏基因组工具已与与控制皮肤和肛门生殖器中 HPV 复制相关的免疫功能研究相结合。 评估皮肤和肛门生殖器 HPV 相关疾病患者的临床和监管基础设施已进一步扩展，重点关注原发性免疫缺陷、特发性 CD4 淋巴细胞减少症 (ICL) 和 HIV/AIDS 患者，同时使用长效 rhIL-7 的新型临床方案已已在患有 ICL 和难治性皮肤和粘膜 HPV 相关疾病的患者中启动。