Studies in the Pathogenesis of Systemic Capillary Leak Syndrome

全身毛细血管渗漏综合征发病机制的研究

• 批准号: 8555992
• 负责人: Kirk m Druey
• 金额: $ 44.25万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8555992
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Actins; Acute; Address; Anaphylaxis; Angioneurotic Edema; Angiopoietin-2; Antibodies; Antigen Targeting; Apoptosis; Binding; Biocompatible Materials; Biological Assay; Biological Markers; Blood; Blood Cells; Blood Vessels; Blood capillaries; CD8-Positive T-Lymphocytes; Capillary Leak Syndrome; Case Series; Clinical; Clinical Protocols; Development; Disease; Disease remission; Edema; Endothelial Cells; Etiology; Event; Extravasation; Gene Expression Profile; Genetic; Goals; Growth and Development function; Hematopoietic; High Prevalence; Human; Hypotension; Hypovolemia; IL2RA gene; Immune; Immunoglobulin G; Immunoglobulins; In Vitro; Infiltration; Intravenous Immunoglobulins; Link; Liquid substance; Mediator of activation protein; Molecular; Monoclonal gammopathy of uncertain significance; Morbidity - disease rate; Multiple Myeloma; Nature; Nomenclature; Oliguria; Paraproteins; Pathogenesis; Pathology; Patients; Permeability; Plasma; Plasma Cells; Plasmacytic Leukemia; Population; Premalignant; Process; Property; Proteins; Proteome; Protocols documentation; RNA; Reporting; Research; Sepsis; Serum; Shock; Signs and Symptoms; Skin; Source; Stress Fibers; Symptoms; Syndrome; T-Lymphocyte; Testing; Tissues; Toxic effect; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vascular Permeabilities; Withdrawal; angiogenesis; base; bevacizumab; cadherin 5; capillary; cell type; chemotherapy; experience; genome sequencing; macromolecule; mortality; novel therapeutic intervention; research study

Several lines of evidence suggest that immune dysregulation may contribute to the pathophysiologic findings seen in SCLS. First, a monoclonal gammopathy of unknown significance (MGUS) is present in a majority of SCLS cases. MGUS is a premalignant precursor to multiple myeloma (MM), in which a clonal plasma cell population secretes large amounts of monoclonal immunoglobulin (Ig, also referred to as a paraprotein) detectable in patient sera. Additionally, increased numbers of circulating CD25+ T cells and peri-capillary infiltration of CD8+ lymphocytes in skin have been noted during acute SCLS attacks in a few patients. Finally, several patients with SCLS in whom MGUS evolved into frank myeloma or plasma cell leukemia experienced fewer capillary leak episodes after chemotherapy for the hematopoietic disorder. Considered together, these findings suggest that the monoclonal paraprotein from the dysregulated plasma cell population may be the direct or indirect source of the pathophysiologic findings observed, possibly through activation of T lymphocytes. We are exploring the molecular mechanisms of SCLS by examining the function of the monoclonal Ig in the development of vascular pathology in vitro. Using monoclonal Ig from SCLS patients, we will determine whether it binds to a specific cell type, target antigen (if any), and resulting effect (direct or indirect) on endothelial cells. We are also characterizing the transcriptome of blood cell RNA and the proteome of SCLS serum/plasma, both pre- and post-attack, to determine whether specific biomarkers of acute symptoms can be identified. We have now evaluated 32 patients at the NIH clinical center in association with this protocol in the last 3 years. We are the primary worldwide referral center for research on SCLS. Although the nomenclature of this disorder implies a pathogenic increase in vascular permeability, this hypothesis has not been formally tested, in part due to the rarity of the condition. While the high prevalence of MGUS in SCLS suggests a pathogenic contribution of endogenous Igs, the mechanisms of vascular hyperpermeability remain obscure. We compiled clinical parameters and studied biomaterial from 23 subjects, the largest SCLS case series to date. Application of episodic SCLS sera, but neither the purified Ig fraction nor sera obtained from subjects during remission, to human microvascular endothelial cells caused vascular endothelial cadherin (VE-cadherin) internalization, disruption of inter-endothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. IVIG, one promising therapy for SCLS, mitigated the permeability effects of episodic sera directly. Consistent with the presence of endogenous, non-Ig, circulating permeability factor(s) constrained to SCLS episodes, we found that two such proteins, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Antibody-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Comparable experiments with anti-VEGF antibody (bevacizumab) yielded less interpretable results, likely due to endothelial toxicity of VEGF withdrawal.

多项证据表明，免疫失调可能导致 SCLS 的病理生理学结果。首先，大多数 SCLS 病例中都存在意义不明的单克隆丙种球蛋白病 (MGUS)。 MGUS 是多发性骨髓瘤 (MM) 的癌前前兆，其中克隆浆细胞群分泌大量可在患者血清中检测到的单克隆免疫球蛋白（Ig，也称为副蛋白）。 此外，在少数患者急性 SCLS 发作期间，注意到皮肤中循环 CD25+ T 细胞数量增加和 CD8+ 淋巴细胞毛细血管周围浸润。最后，几位 MGUS 演变为骨髓瘤或浆细胞白血病的 SCLS 患者在接受造血障碍化疗后毛细血管渗漏事件减少。 综合考虑，这些发现表明，来自失调的浆细胞群的单克隆副蛋白可能是所观察到的病理生理学结果的直接或间接来源，可能是通过 T 淋巴细胞的激活。我们正在通过体外检查单克隆 Ig 在血管病理发展中的功能来探索 SCLS 的分子机制。使用来自 SCLS 患者的单克隆 Ig，我们将确定它是否与特定细胞类型、靶抗原（如果有）结合，以及对内皮细胞产生的影响（直接或间接）。我们还对攻击前和攻击后的血细胞 RNA 转录组和 SCLS 血清/血浆的蛋白质组进行了表征，以确定是否可以识别急性症状的特定生物标志物。在过去 3 年里，我们已经根据该方案对 NIH 临床中心的 32 名患者进行了评估。我们是全球主要的 SCLS 研究转诊中心。 尽管这种疾病的命名意味着血管通透性的致病性增加，但这一假设尚未得到正式检验，部分原因是这种情况很罕见。虽然 SCLS 中 MGUS 的高患病率表明内源性 Igs 的致病作用，但血管通透性过高的机制仍不清楚。我们编制了临床参数并研究了 23 名受试者的生物材料，这是迄今为止最大的 SCLS 病例系列。将间歇性 SCLS 血清（但不是纯化的 Ig 级分或从缓解期受试者获得的血清）应用于人微血管内皮细胞，会导致血管内皮钙粘蛋白 (VE-cadherin) 内化、内皮间连接破坏、肌动蛋白应力纤维形成和增加。补充功能测定中的通透性，而不诱导内皮细胞凋亡。 IVIG 是一种有前途的 SCLS 疗法，可直接减轻偶发性血清的渗透性影响。与 SCLS 发作受限的内源性非 Ig 循环渗透因子的存在相一致，我们发现两种这样的蛋白质，即血管内皮生长因子 (VEGF) 和血管生成素 2 (Ang2) 在发作性 SCLS 血清中升高，但不在缓解血清中。 基于抗体的 Ang2 抑制抵消了偶发性 SCLS 血清诱导的通透性。 使用抗 VEGF 抗体（贝伐珠单抗）进行的可比实验产生了难以解释的结果，可能是由于 VEGF 撤药的内皮毒性所致。