MODELING CELLULAR IMMUNITY DURING HIV AND TB INFECTIONS

这项建议的目的是解释TH1型和TH2-型的作用。 类型细胞因子在人类病原体疾病进展中的作用 免疫缺陷病毒1型(HIV-1)和结核分枝杆菌。 我们研究了以下假设：(1)疾病的进展 在发病过程中，HIV感染是长期依赖的 TH1和TH2型细胞因子在细胞周期中表达的变化 疾病的演变。这一范式将预测一个占主导地位的 以TH2型细胞因子为特征的表型出现在终末期 疾病。(2)感染潜伏期的建立和维持 根据细胞因子可以预测结核分枝杆菌感染 配置文件，平衡组织破坏反应与分辨率。这个 三个具体目标是根据 复杂的细胞因子网络在疾病的细胞免疫反应中： (1)确定TH1/TH2细胞因子平衡的预测作用 分枝杆菌感染的疾病结局的鉴别 肺结核。具体地说，我们将调查为什么大多数个人 发展为潜在的结核病感染，但其他人通过以下两种方式之一进展为疾病 快速或缓慢的进展。(2)探讨长期TH1/TH2的作用 在HIV-1疾病进展过程中表达的细胞因子转移 确定TH1/TH2细胞因子失衡在其中的预测作用 进步。(3)研究细胞因子的治疗作用 作为免疫治疗药物的策略，无论是单独还是联合 对于潜伏性和进展性疾病，都需要化疗 耐药和敏感的艾滋病毒-1和结核分枝杆菌。这些 预计结果还将使人们更好地了解联合 感染艾滋病毒-1和结核病。将开发数学模型 它们反映了不同疾病的动态以及疾病 各州。这些模型包括实验数据，并将进行分析 用数学方法刻画非线性动力学 系统。控制、激活或控制的多种因素的相互作用 促进对病原体的细胞免疫反应将是 已定义。将确定管理这些交互的关键参数 通过数学灵敏度分析。这些结果将 结合已知的临床和实验数据并进行测试 数据。

The goal of this proposal is to explain the role of TH1-type and TH2- type cytokine profiles in disease progression for the pathogens human immunodeficiency virus type 1 (HIV-1) and Mycobacterium tuberculosis. We investigate the following hypotheses: (1) The progression of disease during the pathogenesis of HIV infection is dependent upon a long-term shift of TH1- and TH2-type cytokines that are expressed during the evolution of the disease. This paradigm would predict that a dominant phenotype characterized by TH2-type cytokines is present in end-stage disease. (2) The establishment and maintenance of latency in infection with Mycobacterium tuberculosis may be predicted based on the cytokine profiles, balancing the tissue damaging response with resolution. The three specific aims are to formulate mathematical models based on the complex cytokine network in the cellular immune response to disease to: (1) Determine the predictive role of a TH1/TH2 cytokine balance in differentiating the disease outcomes in infection with Mycobacterium tuberculosis. Specifically, we will investigate why most individuals develop latent TB infection, yet others progress to disease, via either a fast or slow progression. (2) Explore the role of a long-term TH1/TH2 cytokine shift expressed during HIV-1 disease progression and to determine the predictive role of a TH1/TH2 cytokine imbalance in that progression. (3) Investigate the use of cytokines as therapeutic strategies as agents of immunotherapy, either alone or in conjunction with chemotherapy, for both latent and progressive disease for both drug-resistant and drug-sensitive HIV-1 and M. tuberculosis. These results are also expected to lead to a greater understanding of co- infections with HIV-1 and TB. Mathematical models will be developed that reflect the dynamics of the different diseases as well as disease states. These models include experimental data and will be analyzed using mathematical approaches for characterizing nonlinear dynamical systems. The interaction of multiple factors that control, activate or facilitate the cellular-immune response to the pathogens will be defined. Key parameters governing these interactions will be identified through mathematical sensitivity analyses. These results will incorporate, and be tested against, known clinical and experimental data.