MOLECULAR BASIS OF MALT-INDUCED MUCOSAL IMMUNITY TO SIV

粘膜免疫系统对抗传染病的重要性 包括艾滋病在内的疾病现在得到了广泛的认可，因为粘膜疫苗可以 粘膜和全身的抗原特异性免疫反应 车厢。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疫苗研究进展 豁免权是最重要的。我们研究的主要目标仍然是 一种分子佐剂鼻用疫苗的研制 将引发对猿猴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，有必要阐明细胞和分子 鼻腔相关免疫应答的诱导基础 淋巴网状组织(NALT)，并确定扁桃体、腺样体和 恒河猴鼻腔相关淋巴组织为NALT。至 为了促进这些研究，我们将使用霍乱毒素的新突变体 (MCT)保留佐剂特性，但缺乏ADP-核糖 转移酶活性和相关毒性。为了实现我们的全面目标 在目标方面，这笔赠款分为五个具体目标。具体来说，我们 将：1)用含SIV gp130的鼻疫苗免疫恒河猴 和CT(MCTs)的无毒性保持佐剂作用的突变体 用于诱导最适的粘膜和系统抗体(Ab) 回答；2)阐明CD4阳性(CD4+)T辅助细胞(Th)的性质 鼻腔免疫后诱导的1型(Th1)或Th2型反应 以SIV疫苗和MCTs为佐剂；3)检验恒河猴 猕猴扁桃体或腺样体代表以下黏膜诱导部位 鼻腔免疫。这项分析将涉及到手术切除猕猴 扁桃体、腺样体和其他鼻部相关组织以评估SIV- 鼻腔免疫后特异性T和B细胞亚群。在其他 研究将在血管疫苗接种之前移除NALT以确定是否 它们确实是鼻腔免疫反应的诱导部位。 疫苗；4)完全鉴定NALT CD8+细胞毒性T淋巴细胞(CTL) 它们被诱导成以MCT为佐剂的SIV疫苗 NALT中趋化因子的表达增强；以及5)确定鼻部SIV 以NCTs为粘膜佐剂的疫苗可诱导粘膜免疫 为了保护雌性恒河猴免受挑战， 生殖道。这些对恒河猴的拟议研究将提供 关于细胞和分子机制的新信息 猪瘟病毒鼻腔免疫诱导特异性保护性免疫 含SIV抗原和MCTs的黏膜疫苗。

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.