Immunologic Factors In Progressive Autoimmune Disease

进行性自身免疫性疾病的免疫因素

• 批准号: 6542633
• 负责人: Robert S Fujinami
• 金额: $ 24.94万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6542633
• 关键词: antibody; antibody formation; athymic mouse; autoantibody; cell migration; cytokine; disease /disorder model; environmental stressor; experimental allergic encephalomyelitis; flow cytometry; fluorescence microscopy; gender difference; genetic susceptibility; helper T lymphocyte; interferon gamma; interleukin 10; interleukin 4; leukocyte activation /transformation; multiple sclerosis; pathologic process; phenotype; radiotracer; tissue /cell culture

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) can be divided into four clinical forms: relapsing-remitting (RR), primary progressive (PP), secondary progressive (SP) and progressive relapsing (PR). The pathogenesis of the progressive forms of MS remains unclear, partly due to the lack of animal models that have these clinical patterns of disease. Using an encephalitogenic peptide from myelin oligodendrocyte glycoprotein (MOG)92-106, we have established animal models that mimic the different forms of MS in two strains of MHC identical H-2s mice, SJL/J and A.SW. We induce experimental allergic encephalomyelitis (EAE) with (MOG)92-106 in the presence or absence of supplemental Bordetella pertussis (BP). SJL/J mice develop RR-EAE whether BP was administered or not. Interestingly, A.SW mice develop PP-EAE without BP and SP-EAE with BP supplementation. Histologically, SJL/J mice develop a mild demyelinating disease with extensive T cell infiltration, while A.SW mice develop large plaque-like demyelinating lesions with immunoglobulin deposition and neutrophil infiltration, associated with very minimal T cell infiltration. In A.SW mice without BP, high titer serum anti-MOG antibody is detected and the anti-MOG IgG2a/IgG1 ratio correlated with survival times of the mice. We hypothesize that, in A.SW mice, a Th2 response favors the production of myelinotoxic antibodies, leading to progressive forms of EAE with early death, while a Th1 response in SJL mice favors a RR form with longer survival. To test this hypothesis, four specific aims are proposed. The first aim will study the role of NK1.1+ T cells in progressive disease. The second aim will determine whether IL-4 is responsible for the T helper (Th) 2 phenotype and progressive EAE seen in A.SW mice sensitized with (MOG)92-106. The third aim will be to investigate the role of anti-myelin antibodies in disease progression and contribution to lesion formation. The fourth and last aim will study other factors involved in progressive disease such as environmental and genetic contributions. These new models could help explain the transition from RR disease to progressive disease often observed in MS patients.

描述（由申请人提供）：多发性硬化症（MS）可以分为四种临床形式：复发缓解（RR），初级进行性（PP），次生进行性（SP）和进行性复发（PR）。 MS进行性形式的发病机理尚不清楚，部分原因是缺乏具有这些临床疾病模式的动物模型。使用髓磷脂少突胶质细胞糖蛋白（MOG）92-106中的脑生成肽，我们建立了动物模型，它们模仿了MS的两种MHC相同H-2S小鼠SJL/J和A.SW的MS不同形式的MS模型。我们在存在或不存在补充的百日咳（BP）的情况下，用（MOG）92-106诱导（MOG）92-106诱导实验性过敏性脑脊髓炎（EAE）。 SJL/J小鼠是否会开发RR-EAE，无论是否施用BP。有趣的是，A.SW小鼠在没有BP和SP-EAE并补充BP的情况下会开发PP-EAE。从组织学上讲，SJL/J小鼠会形成一种温和的脱髓鞘疾病，具有广泛的T细胞浸润，而A.SW小鼠则会形成大斑块样脱髓鞘病变，伴有免疫球蛋白沉积和中性粒细胞浸润，与非常微小的T细胞浸润有关。在没有BP的A.SW小鼠中，检测到高滴度血清抗MOG抗体，抗MOG IgG2A/IgG1比与小鼠的存活时间相关。我们假设，在A.SW小鼠中，Th2反应有利于骨髓毒性抗体的产生，从而导致EAE的渐进形式，而SJL小鼠的Th1反应则偏爱具有更长生存的RR形式。为了检验这一假设，提出了四个具体目标。第一个目标将研究NK1.1+ T细胞在进行性疾病中的作用。第二个目的将确定IL-4是否负责T助手（Th）2表型和A.SW小鼠中看到的（MOG）92-106的A.SW小鼠。第三个目的是研究抗膜蛋白抗体在疾病进展中的作用和对病变形成的贡献。第四和最后一个目标将研究涉及进行性疾病的其他因素，例如环境和遗传贡献。这些新模型可以帮助解释MS患者经常观察到的从RR疾病到进行性疾病的过渡。