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.

评估皮肤和肛门生态HPV相关疾病患者的临床和调节基础设施已扩大，尤其是对特发性CD4淋巴细胞减少症（ICL）和HIV/AIDS的患者。这样的研究强调了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细胞的耗竭或重建损害的新机制。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/caspase-1激活或端粒缩短与ICL，HIV/AIDS和AUTOMMMUNE淋巴淋巴结剂综合征（Alps）中的CD4 T细胞的耗竭和/或CD4 T细胞的重新分解有关。在免疫功能低下的宿主中需要有效的治疗方法启发了难治性HPV介导的高级发育不良或坦率地与HPV相关疾病的免疫治疗的发展。特别是，在ICL患者和患有新型IL-2RG失误变体的受试者中，具有复发性HPV相关的侵入性鳞状细胞癌的降低强度调节同种异体骨髓移植方案（BMT）导致了复发性HPV相关的浸润性鳞状细胞癌的稳定回归。