S MANSONI HEPATOSPLENISM AND HLA AND T CELL RESPONSES

肝脾疾病可能是危及生命的并发症 血吸虫病。在这方面，我们最近表现出了强大的 人类白细胞抗原II类等位基因DQbeta*0201与银屑病发病的关系 巴西患者中的肝脾疾病。此等位基因与 与免疫调节缺陷的其他疾病、乳糜泻和 胰岛素依赖型糖尿病。我们假设这个MHC 2类等位基因 影响T细胞的启动，导致不同于 具有其他DQ单倍型的个体。此外，对人类白细胞抗原2类的分析 等位基因和患者免疫反应显示出很强的相关性 等位基因DQbeta1*0501、DQalpha1*0101和DR1对 可溶性卵子抗原与患者总人数的比较。我们 建议比较外周血体外启动反应 血吸虫携带者的单个核细胞(PBMC)抗血吸虫抗原 这些等位基因对携带DQ和DR等位基因的个体没有 统计学上显示与疾病有关联。对以下问题的回应 然后将血吸虫抗原与来自相同来源的 个人对第三方抗原，如PPD。 我们将测量体外启动(IVP)细胞因子谱/增殖 原始PBMC与血吸虫抗原的关系，然后将这些结果关联起来 具有人类白细胞抗原II类单倍型。然后我们将确定这些回应是否 是人类白细胞抗原II类相合的外周血单核细胞体外反应的代表 患者在发展为肝脾疾病之前或之后。我们会 探讨人类白细胞抗原II类单倍型与MHC II类基因表达的相关性 与血吸虫抗原IVP后PBMC上的共刺激分子。 我们将确定IVP对血吸虫抗原的反应是否可以 通过外源性细胞因子或抗细胞因子抗体的治疗而改变， 以及这种改变的能力是否与人类白细胞抗原II类相关 单倍型。 这些研究应该为人类白细胞抗原的影响提供重要的新数据。 第二类等位基因与细胞免疫反应的发生和调控 血吸虫抗原，并导致预测标志物 抵抗力/敏感度或发生疾病的可能性。

Hepatosplenic disease can be a life threatening complication of schistosomiasis. In this regard, we have recently demonstrated the strong association of HLA class II allele DQbeta*0201 with the development of hepatosplenic disease in Brazilian patients. This allele is associated with other diseases with defects in immune regulation, celiac disease and insulin dependent diabetes. We hypothesize that this MHC Class 2 allele influences the priming of T cells leading to a response distinct from individuals with other DQ haplotypcs. Further, analysis of HLA Class 2 alleles and patients immune responses showed a strong association of alleles DQbeta1*0501, DQalpha1*0101 and DR1 with lowered or no response to soluble egg antigens as compared to the total patient population. We propose to compare the in vitro priming response of peripheral blood mononuclear cells (PBMC) to schistosome antigens of individuals carrying these alleles to individuals carrying DQ and DR alleles where no statistical association was shown with disease. The response to schistosome antigens would then be compared to the response from the same individuals to third party antigen such as PPD. We will measure the in vitro priming (IVP) cytokine profiles/proliferation of naive PBMC to schistosome antigens, and then correlate these results with HLA Class II haplotype. Then we will determine if these responses are representative of in vitro responses of HLA Class II matched PBMC from patients prior to, or after development of hepatosplenic disease. We will see if HLA Class II haplotype correlate with expression of MHC class II and co-stimulatory molecules on PBMC after IVP with Schistosome antigens. We will determine whether the IVP response to schistosome antigens can be altered by treatment with exogenous cytokines or anti-cytokine antibodies, and whether the ability to be altered correlates with HLA Class II haplotype. These studies should provide significant new data on the influence of HLA Class II alleles on development and control of cellular immune responses to schistosome antigens and lead to predictive markers for resistance/susceptibility or the likelihood of developing disease.