Immune modulating therapies to treat complex regional pain syndrome

免疫调节疗法治疗复杂的区域疼痛综合征

• 批准号: 10583271
• 负责人: Seena Ajit
• 金额: $ 201.82万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583271
• 关键词: Acute; Affect; Aftercare; Autoimmune; Autoimmune Diseases; Autoimmune Process; Binding; Biological Markers; Biopsy; Blood; Blood Circulation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell surface; Cells; Chronic; Chronic Phase; Chronic disabling pain; Clinical; Complex Regional Pain Syndromes; Coupled; Data; Development; Disease; Disease Progression; Dose; Etiology; Flow Cytometry; Fracture; Functional disorder; Future; GTP-Binding Proteins; Genes; Homeostasis; Hyperalgesia; Hypersensitivity; IL2RB gene; Immune; Immunotherapy; Impairment; Infiltration; Interleukin 2 Receptor; Interleukin-15; Interleukin-2; Intervention; Lectin; Limb structure; Mediating; Membrane; Memory; MicroRNAs; Modeling; Molecular; Monoclonal Antibodies; Mus; Nerve Fibers; Organ; Outcome; Pain; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Pharmacology; Population; Reporting; Research; Residencies; Resolution; Rodent; Role; STAT protein; Sampling; Signal Transduction; Skin; Sphingosine-1-Phosphate Receptor; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Treatment outcome; abuse liability; allodynia; antagonist; autoinflammatory; base; cellular transduction; chronic painful condition; circulating microRNA; cytokine; cytotoxic; immune function; immune system function; immunomodulatory therapies; interleukin-15 receptor; keratinocyte; monocyte; mouse model; multiple omics; novel; novel therapeutic intervention; receptor; response; response biomarker; sensor; sensory stimulus; sex; single-cell RNA sequencing; stem; targeted treatment; tibia

Abstract Complex regional pain syndrome (CRPS) is a chronic pain disorder of unknown etiology that can affect one or more extremities. Difficulty in treating CRPS stems from incomplete understanding of the underlying mechanisms. Despite different clinical presentations, clear evidence for altered processing of sensory stimuli leading to allodynia, hyperalgesia, and hyperaesthesia has been demonstrated in CRPS. Aberrant immune function is reported to contribute to CRPS pathology. Autoinflammatory and autoimmune mechanisms in the skin of the affected limb, and systemically in circulation, reportedly contribute to increased pain hypersensitivity. Systemically, CRPS patients have increased proinflammatory monocytes, and altered circulating memory T cells (Tcircm). An expansion of long-lived central memory CD8+ and CD4+ T cells with increased proinflammatory signaling is reported in CRPS patients. However, current studies on Tcircm do not account for local tissue-resident memory T cells (Trm) which have been implicated in several autoimmune disorders. Cluster of differentiation 69 (CD69) is a type II C-lectin membrane receptor that is rapidly induced upon T cell activation, enabling their accumulation in nonlymphoid tissues like skin. CD69 antagonizes the cell-surface expression of G-protein– coupled sphingosine-1-phosphate receptor-1 and 5 (S1PR1/5). By inhibiting the expression of S1PR1/5, CD69 impairs egress and promotes T cell residency. We have identified dysregulation of circulating miRNA signatures common to both CRPS patients and mouse tibia fracture model (TFM) of CRPS that can regulate Tcircm. Interestingly several miRNAs, including a miRNA directly associated with positive outcomes for CRPS patients, can target genes critical to Trm development. This led us to evaluate Tcircm and Trm dysfunction in TFM mice, where preliminary data demonstrate formation of pathological Trm in TFM mice. We hypothesize that dysregulation of T cells in CRPS converges on targets crucial for both Tcircm homeostasis and Trm formation. We will test whether pathological Tcircm and Trm contribute to CRPS pathology, and if therapies that cooperatively target both populations can serve as a novel therapeutic strategy. By following Tcircm and Trm, we will elucidate mechanisms of T cell dysfunction and investigate novel immune modulating therapies for treating CRPS.

摘要 复杂局部疼痛综合征（CRPS）是一种病因不明的慢性疼痛疾病，可影响一个或多个患者。 更多的四肢。治疗CRPS的困难源于对基础疾病的不完全理解。 机制等尽管临床表现不同，但有明显证据表明感官刺激的处理发生了改变 导致异常性疼痛、痛觉过敏和感觉过敏已经在CRPS中得到证实。异常免疫 据报道，该功能有助于CRPS病理。皮肤中的自身炎症和自身免疫机制 据报道，受影响肢体的局部和全身循环中的局部疼痛会导致疼痛超敏反应增加。 全身而言，CRPS患者的促炎单核细胞增加，循环记忆T细胞改变 （Tcircm）。长寿命的中枢记忆性CD 8+和CD 4 + T细胞的扩增， 在CRPS患者中报道了信号传导。然而，目前关于Tcircm的研究没有考虑局部组织驻留 记忆T细胞（Trm），其与几种自身免疫性疾病有关。分化群69 （CD 69）是一种II型C-凝集素膜受体，其在T细胞活化后迅速诱导，使其能够在T细胞中表达。 积聚在皮肤等非淋巴组织中。CD 69拮抗G蛋白的细胞表面表达， 偶联鞘氨醇-1-磷酸受体-1和5（S1 PR 1/5）。通过抑制S1 PR 1/5、CD 69 损害出口并促进T细胞驻留。我们已经发现了循环miRNA特征的调节异常 CRPS患者和CRPS的小鼠胫骨骨折模型（TFM）共同的可以调节Tcircm。 有趣的是，几种miRNA，包括与CRPS患者的阳性结果直接相关的miRNA， 可以靶向对Trm发育至关重要的基因。这导致我们评估TFM小鼠中的Tcircm和Trm功能障碍，其中 初步数据表明在TFM小鼠中形成了病理性Trm。我们假设T细胞的失调 CRPS中的细胞聚集在对Tcircm稳态和Trm形成都至关重要的靶标上。我们将测试 病理性Tcircm和Trm有助于CRPS病理，并且如果协同靶向这两者的治疗， 人群可以作为一种新的治疗策略。通过遵循Tcircm和Trm，我们将阐明其机制 的T细胞功能障碍和研究新的免疫调节疗法治疗CRPS。