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Compensatory mechanisms of estrogen mediated protection from EAE in IL-10 KO mice

IL-10 KO 小鼠雌激素介导的 EAE 保护的补偿机制

基本信息

批准号：
10263144
负责人：
Halina Offner
金额：
$ 15.75万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263144
关键词：
Address Autoimmune Diseases B-Lymphocytes CNS autoimmune disease Cells Chronic Clinical Demyelinations Disease Disease Progression Disease model Dose Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogens Evaluation Experimental Autoimmune Encephalomyelitis Female Financial compensation Gonadal Steroid Hormones Histologic Immune Immune system Immunization Implant Individual Inflammatory Interleukin-10 Investigation Knockout Mice Laboratories Lead Mediating Monitor Mouse Strains Multiple Sclerosis Mus Neuraxis Neurologic Deficit Pathway interactions Peripheral Play Postpartum Period Pregnancy Property Proteins Recurrent disease Regulatory Pathway Relapse Research Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Spinal Cord Spleen Symptoms Therapeutic Effect Time Tissues Wild Type Mouse Woman Work base chemokine cytokine experience experimental study immunoregulation lymph nodes male men multiple sclerosis treatment neuroinflammation neuron loss neutralizing antibody programmed cell death ligand 1 programmed cell death protein 1 protective effect recruit relating to nervous system

项目摘要

Research Summary Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system that results in neurological deficits from demyelination and neuron loss from chronic neuroinflammation. MS is more prevalent in women yet improvement in clinical symptoms occurs during pregnancy followed by disease exacerbations post-partum. It is well accepted that sex hormones have immunoregulatory properties and may protect individuals with MS during pregnancy. Our previous work has shown pretreatment with low dose estrogen (17β- estradiol, E2) protects mice from developing experimental autoimmune encephalomyelitis (EAE) and promotes regulatory B cells. We have demonstrated that E2 protects mice by inducing regulatory B cells that express PD- L1 and/or IL-10. Recently we showed E2 can protect IL-10 KO mice from developing EAE (indicating that IL-10 is not required for protection) and that these mice up regulate proteins in the PD-1/PD-L1/2 pathway as well as increasing different subsets of regulatory B cells. In this proposal we thus will examine in detail these two major pathways through which E2 appears to protect IL-10 KO mice during EAE in order to address our hypothesis that IL-10 knockout mice are protected from EAE by E2 through compensatory mechanisms. Aim 1, will define the role of the PD-1/PD-L pathway in protecting IL-10 knockout mice compared to wild type mice. PD-L1, PD-L2, and PD-1 will be inhibited with neutralizing antibodies to determine the extent of compensation provided by each protein in E2 pretreated IL-10 KO mice with EAE; Aim 2, will determine which subsets of regulatory B cells are compensating for the loss of IL-10 secreting regulatory B cells in E2 mediated protection of IL-10 knockout mice. Regulatory B cells from the spleen and lymph nodes will be examined in E2 pretreated wild type and IL-10 KO EAE mice to determine which regulatory B cells are produced in each strain of mouse; Aim 3, will identify which cytokine and chemokine pathways are up/down-regulated in E2 pretreated mice lacking IL-10 compared to wild type mice. Spinal cords will be evaluated using a cytokine array and RT-PCR analysis at 21 days post immunization in four groups of mice: wild type + E2, wild type + sham, IL-10 KO + E2, and IL-10 + sham. Overall this proposal will provide a more comprehensive understanding of the immunoregulatory properties of E2 and could lead to the identification of dominant pathways that could be activated or expanded for the treatment of MS.

研究总结