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: 10683252
• 负责人: Diana J Goode
• 金额: $ 34.17万
• 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/10683252
• 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; Cell secretion; Cells; Chemotherapy-induced peripheral neuropathy; Coculture Techniques; Color; Communication; Conflict (Psychology); Confocal Microscopy; Data; Data Set; Dose Limiting; Estradiol; Estrogen Receptor alpha; Estrogen Therapy; Estrogen decline; Estrogen deficiency; 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; Neuroglia; Neuroimmunomodulation; Neuronal Injury; Neurons; Neuropathy; Non-Small-Cell Lung Carcinoma; Ovarian; Paclitaxel; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Postmenopause; Preventive measure; Production; Proliferating; 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; Visualization; Woman; aluminum sulfate; antinociception; cancer therapy; chemotherapeutic agent; copolymer 1; cytokine; experimental study; in vivo; male; malignant breast neoplasm; neuroprotection; 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/文摘