Novel expression of MHC class II on DRG neurons and its role in promoting antinociceptive CD4+ T cells in females during chemotherapy-induced peripheral neuropathy

MHC II 类在 DRG 神经元上的新表达及其在化疗引起的周围神经病变期间促进女性抗伤害 CD4 T 细胞的作用

• 批准号: 10522294
• 负责人: Diana J Goode
• 金额: $ 34.22万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522294
• 关键词: Affective; Afferent Neurons; Aftercare; Analgesics; Anti-Inflammatory Agents; Antibodies; Binding; Blocking Antibodies; Blood; Breast; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cell Communication; Chemotherapy-induced peripheral neuropathy; Color; Communication; Conflict (Psychology); Confocal Microscopy; Data; Data Set; Dose-Limiting; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Female; Flow Cytometry; Histocompatibility Antigens Class II; Hormones; Hypersensitivity; Immune; In Vitro; Inflammation; Injury; Interleukin-10; Interleukin-4; Intravenous; Lead; MHC Class II Genes; Malignant neoplasm of ovary; Measures; Mechanics; Methods; Motivation; Multiple Sclerosis; Mus; Neuroimmunomodulation; Neuronal Injury; Neurons; Neuropathy; Non-Small-Cell Lung Carcinoma; Ovarian; Paclitaxel; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Postmenopause; Preventive measure; Production; Proteins; Publishing; Reporting; Risk; Role; Severities; Sex Differences; Signal Transduction; Source; Spinal Ganglia; System; T cell response; T-Cell Activation; T-Cell Depletion; T-Cell Proliferation; T-Lymphocyte; Tactile; Testing; Therapeutic Intervention; Woman; aluminum sulfate; cancer therapy; chemotherapeutic agent; copolymer 1; cytokine; experimental study; in vivo; male; malignant breast neoplasm; novel; painful neuropathy; paracrine; prevent; prophylactic; response; screening; transcriptome sequencing

Project Summary/Abstract Chemotherapeutic agents are often dose limiting due to the emergence of a debilitating and painful neuropathy, posing a major challenge to the successful treatment of cancer. Recent reports demonstrate that male mice lacking T cells have prolonged mechanical hypersensitivity after treatment with paclitaxel (PTX), and only the intravenous transfer of CD8+, but not CD4+, T cells reduced the hypersensitivity. Our preliminary in vivo data demonstrates female mice have 2-fold more CD4+ T cells in the DRG than male and ovariectomized (OVX) female mice, and neuronal injury induced by PTX robustly increases anti-inflammatory CD4+ T cells in the DRG only in estrogen-competent female mice. CD4+ T cell depletion in female mice prior to PTX results in an increase in mechanical hypersensitivity 3 days post-PTX. Our results suggest a previously unexplored hormone and sex difference in CD4+ T cells and the severity of chemotherapy-induced peripheral neuropathy (CIPN). PTX is primarily used to treat ovarian, breast, and non-small cell lung cancer with post- menopausal patients at an increased risk of CIPN; therefore, preventative measures would be invaluable for women. The mechanism by which CD4+ T cells reduce the severity of PIPN is unknown. In our preliminary studies, DRG neurons from female mice have the capacity to activate CD4+ T cells to secrete anti- inflammatory cytokines. Published RNA-seq datasets of DRG neurons show that DRG neurons express MHCII, a protein directly involved in T cell activation. Our central hypothesis is that PTX administration in female mice increases MHCII on sensory neurons to stimulate the paracrine release of anti-inflammatory cytokines by resident CD4+ T cells to suppress CIPN. In Aim 1, we will determine the extent to which estrogen- driven CD4+ T cells reduce the severity of PTX-induced peripheral neuropathy. Estrogen is known to induce proliferation of blood CD4+ T cells, but it is unknown if this occurs in the DRG. We predict that estrogen signaling in CD4+ T cells will increase the number of resident CD4+ T cells in the DRG to secrete anti- inflammatory cytokines in response to PTX. We expect CD4+ T cells to ameliorate CIPN in female, but not male mice. In Aim 2, we will quantify the extent PTX can enhance MHCII on DRG neurons to induce anti- inflammatory CD4+ T cell cytokine production. We predict PTX-induced inflammation will increase neuronal MHCII to elicit an anti-inflammatory CD4+ T cell response in the DRG of female, but not male mice. In Aim 3, we will determine the degree in vivo activation of neuroprotective CD4+ T cells can reduce and reverse PTX- induced peripheral neuropathy. We predict that activated CD4+ T cells will dampen and reverse CIPN in female, but not male mice, unless pre-treated with estrogen. Completion of these aims will provide compelling evidence that CD4+ T cells in the DRG of females are neuroprotective and anti-nociceptive, and can be exploited to prevent or resolve CIPN. Neuronal MHCII-dependent activation of CD4+ T cells represents a novel mechanism for neuro-immune communication that could be utilized for therapeutic intervention.

项目总结/摘要 化疗药物通常是剂量限制性的，因为出现了使人衰弱和疼痛的症状。 神经病变，对癌症的成功治疗构成重大挑战。最近的报告表明， 缺乏T细胞的雄性小鼠在用紫杉醇（PTX）治疗后具有延长的机械超敏性， 仅静脉输注CD 8 + T细胞而非CD 4 + T细胞可减轻超敏反应。我们的初步 体内数据表明，雌性小鼠DRG中的CD 4 + T细胞是雄性小鼠的2倍， 卵巢切除（OVX）雌性小鼠，PTX诱导的神经元损伤强烈增加抗炎作用。 仅雌激素感受态雌性小鼠DRG中的CD 4 + T细胞。给药前雌性小鼠中的CD 4 + T细胞耗竭 PTX导致PTX后3天机械超敏反应增加。我们的研究结果表明， 未探索的激素和性别差异的CD 4 + T细胞和化疗诱导的外周血淋巴细胞的严重程度 神经病变（CIPN）。PTX主要用于治疗卵巢癌、乳腺癌和非小细胞肺癌， 绝经期患者CIPN的风险增加;因此，预防措施将是无价的， 妇女CD 4 + T细胞降低PIPN严重程度的机制尚不清楚。在我们的初步调查中 研究表明，来自雌性小鼠的DRG神经元具有激活CD 4 + T细胞分泌抗- 炎性细胞因子已发表的DRG神经元的RNA-seq数据集显示，DRG神经元表达 MHCII是一种直接参与T细胞活化的蛋白质。我们的中心假设是， 雌性小鼠增加感觉神经元上的MHCII，以刺激抗炎药的旁分泌释放 细胞因子通过驻留的CD 4 + T细胞来抑制CIPN。在目标1中，我们将确定雌激素- 驱动的CD 4 + T细胞降低PTX诱导的周围神经病变的严重性。雌激素会导致 血液CD 4 + T细胞的增殖，但尚不清楚这是否发生在DRG中。我们预测雌激素 CD 4 + T细胞中的信号传导将增加DRG中驻留的CD 4 + T细胞的数量，以分泌抗CD 4 + T细胞。 炎症细胞因子对PTX的反应。我们预期CD 4 + T细胞可以改善女性CIPN，但不能 雄性老鼠在目标2中，我们将量化PTX可以增强DRG神经元上的MHCII以诱导抗-MHCII的程度。 炎性CD 4 + T细胞细胞因子产生。我们预测PTX诱导的炎症会增加神经元 MHCII在雌性而非雄性小鼠的DRG中引发抗炎性CD 4 + T细胞应答。在目标3中， 我们将确定神经保护性CD 4 + T细胞的体内活化可以减少和逆转PTX的程度。 诱发周围神经病变。我们预测，活化的CD 4 + T细胞将抑制和逆转CIPN。 雌性，但不是雄性小鼠，除非用雌激素预处理。完成这些目标将提供令人信服的 有证据表明，女性DRG中的CD 4 + T细胞具有神经保护作用和抗伤害性， 用于预防或解决CIPN。CD 4 + T细胞的神经元MHCII依赖性活化代表了一种新的 神经免疫通讯的机制，可用于治疗干预。