幼年型复发性呼吸道乳头状瘤 （JO-RRP）的T细胞免疫机制研究

Juvenile Onset Recurrent Respiratory Papillomatosis (JO-RRP) is a chronic disease caused by Human Papillomavirus (HPV) infection. The papillomas in children's respiratory track impair the respiratory function and affect children's growth physically and psychologically. Surgical remove of the papillomas introduces new lesions HPV can reinfect, which is one of the main causes for the recurrence of the disease. Other treatments such as antivirus drug, retinoids and gene therapy either exert limited effect or bear undesirable side effects. The respiratory papillomas in children likely converts into malignant tumor at certain conditions if leave untreated. This necessitates an effective and less harmful approach being developed. Based on our long-term clinical observation, JO-RRP has a trend of alleviation and extended surgical interval along with children's age increase. As T-cell is the major immune component for combating HPV in adult papillomas, we propose that age-related spontaneous alleviation of JO-RRP is a result from the gradually maturing T cells. We test this possibility through comparing JO-RRP patients at different age groups regarding their T-cell differentiation, function, polarity as well as thymopoiesis. Proliferation of tumor cells and MHC expression will also be assessed to understand the immune-suppression and immune-escape of the papillomatosis. The ultimate goal is to understand what is the key feature of T-cell-mediated immunity effectively eliminating papillomas of JO-RRP patients. This will pave the road to develop a potent immunotherapy for complete remission of recurrent respiratory papillomatosis in children.

幼儿型复发性呼吸道乳头状瘤(JO-RRP)由人类乳头状瘤(HPV)病毒引发的呼吸道疾病，表现为呼吸道堵塞，严重影响儿童呼吸功能及个体发育。手术切除是目前唯一较有效的干扰手段，但面临着新创伤面的重复感染和病情向深度组织扩展的问题。抗病毒药物等辅助治疗手段效果非常有限。基于我们长期的临床观察，JO-RRP的发病及复发率随着年龄增长而减小，术后恢复也和年龄增长成正相关性。研究表明T细胞在对抗HPV相关的成人型乳头状瘤中起重要的作用，但随幼儿年龄增长而增强的T细胞免疫在JO-RRP的增龄性自发遏制中的作用目前还不清楚。本课题将利用北京儿童医院的样本优势系统研究不同年龄组的JO-RRP患儿的T细胞分型及功能、胸腺T细胞生发能力、肿瘤细胞增殖及免疫逃避能力、HPV病毒亚型及是否存在其他病毒共感染。回答何种增龄性T细胞免疫变化是对抗JO-RRP的关键。为开发针对JO-RRP的T细胞免疫治疗提供理论基础。

幼儿型复发性呼吸道乳头状瘤(JORRP)是由人类乳头状瘤(HPV)病毒引发的呼吸道疾病，表现为呼吸道堵塞，严重影响儿童呼吸功能及个体发育。手术切除是目前唯一较有效的干扰手段，但面临着新创伤面的重复感染和病情向深度组织扩展的问题。抗病毒药物等辅助治疗手段效果非常有限。基于我们长期的临床观察，JORRP的发病及复发率随着年龄增长而减小，术后恢复也和年龄增长成正相关性。研究表明T细胞在对抗HPV相关的成人型乳头状瘤中起重要的作用。本课题利用北京儿童医院的样本优势系统研究JORRP患儿的T细胞分型及功能、HPV病毒亚型、HLA-DRB1和HLA-DQB1的基因型、胸腺T细胞生发能力等，以探索JORRP发病机制及T淋巴细胞在JORRP中的作用。结果表明：（1）JORRP病人中Tf h细胞分泌IL-21的能力受损导致B细胞成熟发生障碍，JORRP病人T细胞依赖的体液免疫受损；（2）JORRP组HLA-DRB1 *03:01和HLA-DQB1*02:01等位基因频率明显增加，HLA-DRB1*03:01等位基因阳性与侵袭性JORRP具有较强的正相关性；（3）JORRP病人外周血T细胞受体重排删除环(sjTRECs)的拷贝数降低，T细胞生发能力较弱。这加深了我们对T细胞介导的细胞免疫是如何来抑制JORRP的理解，为将来发展针对JORRP的免疫疗法提供理论基础。