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

基本信息

批准号：
10272304
负责人：
Andrea Lisco
金额：
$ 42.91万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/10272304
关键词：
AIDS/HIV problem Ablation Allogeneic Bone Marrow Transplantation Antiviral Agents Autoantibodies Bone Marrow Transplantation CASP1 gene CD4 Positive T Lymphocytes Cells Chemicals Clinical Development Disease Epithelial Epithelium Gene Expression Profiling Goals High grade dysplasia Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Immune Immune Targeting Immunization Immunocompromised Host Immunologics Impairment Inflammasome Infrastructure Intervention Lesion Lymphocyte Lymphopenia Malignant - descriptor Malignant Neoplasms Mediating Molecular Epidemiology Morbidity - disease rate Mucous Membrane Natural History Natural Killer Cells Operative Surgical Procedures Patients Prevention strategy Proteins Protocols documentation Recurrence Refractory Role Skin Squamous cell carcinoma T cell response Telomere Shortening Treatment Efficacy Variant Virion Work acquired immunodeficiency antiretroviral therapy autoimmune lymphoproliferative syndrome clinical efficacy conditioning congenital immunodeficiency cytotoxic exome sequencing immune reconstitution novel reconstitution trafficking treatment strategy virology

项目摘要

The clinical and regulatory infrastructure to evaluate patients with skin and anogenital HPV-related disease has been expanded focusing in particular on patients with idiopathic CD4 lymphopenia (ICL) and HIV/AIDS. Such studies emphasized the role of CD4 T cells and NK cells in controlling HPV-related diseases and identified novel mechanisms leading to depletion or impaired reconstitution of CD4 T cells. In particular, our work revealed that the presence of anti-lymphocytes autoantibodies, persistent inflammasome/caspase-1 activation or telomeres shortening was implicated in depletion and/or impaired reconstitution of CD4 T cells in ICL, HIV/AIDS and Autoimmune Lymphoproliferative syndrome (ALPS). The need for effective therapeutic approaches in immunocompromised hosts inspired the development of immunological treatments for refractory HPV-mediated high-grade dysplasia or frankly malignant HPV-related diseases. In particular, the development of a reduced intensity conditioning allogeneic bone marrow transplantation protocol (BMT) resulted in the stable regression of recurrent HPV-related invasive squamous cell carcinoma in ICL patients and in a subject with a novel IL-2RG missense variant with somatic reversion.

用于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得到扩展，特别关注特发性 CD4 淋巴细胞减少症 (ICL) 和 HIV/AIDS 患者。此类研究强调了 CD4 T 细胞和 NK 细胞在控制 HPV 相关疾病中的作用，并确定了导致 CD4 T 细胞耗竭或重建受损的新机制。特别是，我们的工作表明，抗淋巴细胞自身抗体的存在、持续的炎症小体/caspase-1激活或端粒缩短与ICL、HIV/AIDS和自身免疫性淋巴增殖综合征（ALPS）中CD4 T细胞的耗竭和/或重建受损有关。）。免疫受损宿主对有效治疗方法的需求激发了针对难治性 HPV 介导的高度不典型增生或明显恶性 HPV 相关疾病的免疫治疗的发展。特别是，降低强度调理同种异体骨髓移植方案（BMT）的开发导致 ICL 患者和具有体细胞逆转的新型 IL-2RG 错义变异的受试者中复发性 HPV 相关浸润性鳞状细胞癌的稳定消退。