MOLECULAR BASIS OF MALT-INDUCED MUCOSAL IMMUNITY TO SIV

粘膜免疫系统对感染性疾病的重要性 包括艾滋病，现在已经得到了充分的认识，因为粘膜疫苗可以诱导 粘膜和全身的抗原特异性免疫应答 隔间由于艾滋病毒主要通过性接触传播， 以泌尿生殖道粘膜为靶点的HIV疫苗的研制 豁免权是最高优先事项我们研究的主要目标仍然是 用分子佐剂给药的鼻疫苗的开发， 会引发针对猿免疫缺陷病毒的保护性免疫反应 (SIV)以防止SIV在恒河猴中的性传播。 要做到这一点，将有必要阐明细胞和分子 诱导鼻相关免疫应答的基础 淋巴网状组织（NALT），并确定是否扁桃体，腺样体和 相关的鼻淋巴组织是恒河猴的NALT。到 为了促进这些研究，我们将使用霍乱毒素的新突变体， 保留佐剂性质但缺乏ADP-核糖基的mCT 转移酶活性和相关毒性。为了实现我们的整体 这项补助金分为五个具体目标。我们特别 目的：1）用含SIV gp130的鼻用疫苗免疫恒河猴 以及CT的突变体（mCT），其缺乏毒性，通过其保留佐剂性 用于诱导最佳粘膜和系统性抗体（Ab） 2）阐明CD4阳性（CD4+）辅助性T细胞（Th）的性质。 鼻免疫后诱导的1型（Th1）或Th2型应答 用SIV疫苗和mCTs作为佐剂; 3）检验恒河猴 猕猴扁桃体或腺样体代表粘膜诱导位点， 鼻腔免疫这项分析将涉及手术切除猕猴 扁桃体、腺样体和其他鼻相关组织，以评估SIV- 鼻免疫后特异性T和B细胞亚群。换句 研究将在血管疫苗接种之前去除NALT，以确定是否 它们确实代表了鼻粘膜免疫应答的诱导位点， 4）充分表征NALT CD8+细胞毒性T淋巴细胞（CTL） 将其诱导为以mCT为佐剂的SIV疫苗， NALT中趋化因子的表达增强;和5）确定鼻SIV 以NCT作为粘膜佐剂的疫苗将诱导粘膜免疫 保护雌性恒河猴免受攻击， 生殖道这些拟议的恒河猴研究将提供 关于细胞和分子机制的新信息， 鼻内免疫诱导特异性保护性免疫 含有SIV抗原和mCT的粘膜疫苗。

The importance of the mucosal immune system against infectious diseases including AIDS is now well recognized since mucosal vaccine can induce antigen-specific immune responses in both mucosal and systemic compartments. Since HIV is primarily transmitted through sexual contact, the development of HIV vaccines which target genitourinary mucosal immunity is a high priority. The major goal of our studies continues to be the development of a nasal vaccine given with a molecular adjuvant which will elicit protective immune responses to simian immunodeficiency virus (SIV) in order to prevent sexual transmission of SIV in rhesus macaques. To do this, it will be necessary to elucidate the cellular and molecular basis for induction of immune responses to nasal-associated lymphoreticular tissues (NALT) and to determine if tonsils, adenoids and associated nasal lymphoid tissues are NALT in rhesus macaques. To facilitate these studies, we will use novel mutants of cholera toxin (mCTs) which retain adjuvant properties, but which lack ADP-ribosyl transferase activity and associated toxicity. To accomplish our overall goal, this grant is divided into five specific aims. Specifically, we will: 1) Immunize rhesus macaques with nasal vaccine containing SIV gp130 and mutants of CT (mCTs) which lack toxicity by which retain adjuvanticity for the induction of optimal mucosal and systematic antibody (Ab) responses; 2) Elucidate the nature of CD4- positive (CD4+) T helper (Th)- TYPE 1 (Th1) or Th2-type responses induced following nasal immunization with SIV vaccine and mCTs as adjuvant; 3) Test the hypothesis that rhesus macaque tonsils or adenoids represent mucosal inductive sites following nasal immunization. This analysis will involve surgical removal of macaque tonsils, adenoids and other nasal-associated tissues to assess SIV- specific T and B cell subsets following nasal immunization. In other studies removal of NALT will precede vasal vaccination to determine if they indeed represent inductive sites for immune responses to nasal vaccines; 4) Fully characterize NALT CD8+ cytotoxic T lymphocytes (CTLs) which are induced to SIV vaccine which mCT is used as adjuvant and for enhanced expression of chemokines in NALT; and 5) Determine if a nasal SIV vaccine given with NCTs as mucosal adjuvants will induce mucosal immunity for protection of female rhesus macaques from challenge via the reproductive tract. These proposed studies in rhesus macaques will provide new information regarding the cellular and molecular mechanisms for the induction of specific protective immunity by nasal immunization with mucosal vaccines containing SIV antigen and mCTs.