权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neural Immunoregulation of Post-Traumatic Autoimmunity

创伤后自身免疫的神经免疫调节

基本信息

批准号：
9765423
负责人：
DAVID J. CLARK
金额：
$ 33.48万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765423
关键词：
Adrenergic Agents Affect Antibodies Antibody Formation Antigen-Presenting Cells Antigens Antinuclear Antibodies Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Binding Biopsy Bone callus Calcitonin-Gene Related Peptide Receptor Cell Proliferation Cells Chronic Clinical Trials Complement Activation Complex Regional Pain Syndromes Consensus Contralateral Cutaneous Dendritic Cells Deposition Dermal Development Distal Edema Etiology Exhibits Extravasation FDA approved Foundations Fracture Functional disorder Future Goals Hindlimb Immobilization Immunity Immunoglobulin M Immunoglobulins Inflammatory Intravenous Immunoglobulins Investigation Label Langerhans cell Lead Limb structure Maintenance Maps Mediating Microvascular Permeability Modeling Molecular Molecular Target Mus Natural Immunity Nerve Neuroimmune Neuropeptides Nociception Nuclear Nuclear Antigens Pain Pathogenesis Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacology Play Proliferating Quality of life Reporting Role Sensory Serum Signal Pathway Signal Transduction Skin Skin Temperature Spinal Cord Spinal cord injury Substance P Symptoms Syndrome System Testing Tissues Transgenic Mice Transgenic Organisms Trauma Work adaptive immune response adaptive immunity allodynia beta-2 Adrenergic Receptors bone loss chronic pain cohort cytokine effective therapy experimental study fluorophore genetic association immunoregulation improved injured keratinocyte limb fracture lymph nodes mouse model neoantigens novel pain reduction recruit relating to nervous system rituximab sciatic nerve therapeutic target tibia trafficking translational study

项目摘要

PROJECT SUMMARY Limb trauma can lead to the development of complex regional pain syndrome (CRPS), a potentially debilitating chronic state. Currently there is no consensus on either the pathogenesis or treatment for CRPS, and translational and CRPS tissue studies are clearly needed to identify therapeutic targets and effective treatments. Recent observations suggest that some CRPS patients express autoantibodies and respond profoundly to intravenous immunoglobulin treatment. Additional reports suggest that: 1) Langerhans antigen presenting cells proliferate in CRPS affected limbs, 2) that antinuclear autoantibodies are present in some CRPS patients, and 3) that genetic associations with specific HLA loci can be identified in some CRPS patients. Our own studies indicate that CRPS-like changes in the fracture mouse model are reliant upon antibody production, and that passive transfer autoimmunity occurs after transfusing serum from either fracture mice or CRPS patients into antibody deficient fracture mice. Moreover, after fracture in mice, exaggerated substance P signaling stimulates antibody accumulating in the skin, nerves, and spinal cord innervating the injured hindlimb and triggers Langerhans cell proliferation in the hindpaw skin. Furthermore, IgM serum antibodies obtained from fracture mice bind to dermal cell nuclear antigens in fracture limb skin, but not in contralateral intact hindlimb skin. These observations are potentially paradigm shifting. The central hypothesis guiding our work is that limb trauma causes the neural activation of the innate and adaptive systems of immunity, with the regional expression of neo-antigens ultimately supporting nociceptive sensitization. The primary objective of this proposal is to identify specific pharmacologic targets for the successful treatment of CRPS. The specific aims are: 1) to map post-fracture changes in dendritic cell antigen recruitment, maturation, trafficking and adaptive immune responses in skin, lymph nodes, sciatic nerve, and spinal cord, 2) to determine whether passive-transfer autoimmunity occurs when immunoglobulin obtained from the fracture mice or from CRPS patients is injected into other mice, potentially rekindling CRPS-like sequelae in post-fracture mice with resolving CRPS symptoms, and in addition, to use mouse and CRPS patient antibodies to identify regionally restricted autoantigens fracture mouse skin, nerve, cord, and fracture callus, and in CRPS patient skin, and 3) to determine whether sensory neuropeptide or sympathetic adrenergic signaling is required for the development of post-traumatic autoimmune responses. These experiments will establish a rigorous foundation for exploring the mechanisms of post-traumatic autoimmunity, greatly improve our understanding of CRPS, identify specific molecular targets for future CRPS trials, and potentially suggest novel mechanisms supporting other enigmatic chronic pain syndromes.

项目总结