RECTAL IMMUNIZATION AGAINST SIV INFECTION
针对 SIV 感染的直肠免疫接种
基本信息
- 批准号:2071297
- 负责人:
- 金额:$ 9.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1993
- 资助国家:美国
- 起止时间:1993-11-01 至 1997-10-31
- 项目状态:已结题
- 来源:
- 关键词:Macaca mulatta active immunization antibody receptor antiviral antibody cellular immunity disease /disorder model drug delivery systems enzyme linked immunosorbent assay gut associated lymphoid tissue helper T lymphocyte immunoglobulin A immunoglobulin G intestinal mucosa lymph nodes lymphocyte proliferation neutralizing antibody polymerase chain reaction postmortem receptor binding rectum /anus secretory immune system serology /serodiagnosis simian immunodeficiency virus viral vaccines
项目摘要
Rectal transmission of HIV is the most common route of infection during
homosexual intercourse in developed countries, and anal sex increases the
risk of male to female transmission in developing countries. The
mechanism of protective immunity induced by rectal vaccination differs
from that induced by systemic immunization. The objectives of this
proposal are to develop an immunization strategy in non-human primates
that will elicit 3 levels of immunity which match 3 phases of HIV
infection (a) To induce rectal secretory IgA antibodies and cytotoxic T
cells to prevent rectal infection by SIV. (b) To elicit regional lymph
node proliferative and cytotoxic T cells and specific B cells to prevent
the development of a reservoir of latency of the virus in these lymph
nodes. (c) To induce specific serum neutralizing antibodies and
circulating cytotoxic T cells, in order to prevent dissemination of the
virus. The project has been designed to overcome a low degree of rectal
immunity. This might be achieved (i) by increasing the binding affinity
of the vaccine to two mucosal receptors; GM1 ganglioside and Fcgamma
receptors. Recombinant envelope gp160, core p27 and reverse
transcriptase will be used to link to cholera toxin subunit B (CT-B) and
to IgG class of antibodies. (ii) The rectal associated lymphoid tissue
will be augmented by gut, nasal or bronchial associated lymphoid tissue,
through oral or nasal administration of the vaccine.
The immunological changes involving antibodies and T cell functions will
be assayed sequentially. IgA and IgG antibodies will be assayed by
ELISA, using rectal washings, urine, serum and saliva. To overcome the
unpredictable dilution factor inherent in collecting rectal washings, the
IgA antibodies will be quantitated in terms of affinity purified
antibody, and expressed as a percentage of total IgA concentration in
rectal washings. T cell proliferative and cytotoxicity assays will be
carried out with PBMC before and after each immunization, and at autopsy
with iliac, mesenteric, and other lymph nodes, and spleen. T cell
epitopes will be mapped by stimulating short term cell lines with
overlapping peptides of the sequenced antigens and the resulting peptides
will be applied to T cell cytotoxicity assays. Antibody forming B cells
and cytotoxic T cells will be assayed directly by separating lymphocytes
from the rectal tissue. The triple level of immunity to SIV in the
rectal mucosa, regional lymph nodes and blood will then be tested by
rectal challenge of macaques with live SIV. Pre-titrated stocks of well
characterized SIVmac 32H and molecular clones will be used to challenge
vaccinates by the rectal route. The macaques will be monitored for
infection by virus isolation, PCR and seroconversion. Alternative
vaccines will be tried in the SIV model, using cholera and salmonella
vectors, in order to develop the most effective rectal immunity of SIV
infection. These experiments should pave the way in the development of
an effective strategy of rectal immunization, in preventing human
transmission of HIV infection by the anal route.
直肠传播艾滋病毒是最常见的感染途径
发达国家的同性性行为和肛交增加了
发展中国家男性向女性传播的风险。这个
直肠接种诱导保护性免疫的机制不同
而不是由系统免疫引起的。这样做的目的是
建议在非人类灵长类动物中开发免疫策略
这将引发3个免疫水平,与艾滋病毒的3个阶段相匹配
感染(A)诱导直肠分泌型IgA抗体和细胞毒性T细胞
细胞,以防止SIV直肠感染。(B)激发区域淋巴
结节增殖性和细胞毒性T细胞和特异性B细胞预防
这些淋巴中病毒潜伏的蓄水池的形成
节点。(C)诱导特定的血清中和抗体和
循环中的细胞毒性T细胞,以防止传播
病毒。该项目旨在克服直肠功能低下的问题。
豁免权。这可以通过(I)增加结合亲和力来实现
针对两种粘膜受体的疫苗;GM1神经节苷脂和FcGamma
感受器。重组包膜蛋白gp160、核心蛋白p27及其反转
转录酶将用于连接霍乱毒素B亚单位(CT-B)和
转至Ig G类抗体。(Ii)直肠相关淋巴组织
将由肠道、鼻腔或支气管相关淋巴组织增强,
通过口服或鼻腔注射疫苗。
涉及抗体和T细胞功能的免疫学变化将
按顺序进行化验。将通过以下方法检测IgA和Ig G抗体
酶联免疫吸附试验,采用直肠冲洗、尿液、血清和唾液。要克服这个问题
收集直肠冲洗液固有的不可预测的稀释系数,
免疫球蛋白抗体将根据纯化的亲和力进行定量
抗体,并以占总IgA浓度的百分比表示
直肠洗涤。T细胞增殖和细胞毒性检测将是
在每次免疫前后和尸检时进行PBMC检查
有髂骨、肠系膜等淋巴结和脾。T细胞
将通过刺激短期细胞系来绘制表位图
测序抗原的重叠多肽和所得的多肽
将应用于T细胞杀伤活性检测。形成B细胞的抗体
而细胞毒性T细胞将通过分离淋巴细胞直接进行检测
从直肠组织中提取。中国人对SIV的三重免疫水平
然后对直肠粘膜、区域淋巴结和血液进行检测
SIV活体对猕猴直肠的挑战。油井的预滴定库存
特征化的SIVmac 32H和分子克隆将用于挑战
通过直肠途径接种疫苗。将对猕猴进行监测
通过病毒分离、聚合酶链式反应和血清转换感染。备择
疫苗将在SIV模型中进行试验,使用霍乱和沙门氏菌
载体,以发展最有效的SIV直肠免疫
感染。这些实验应该为发展
一种有效的直肠免疫策略,预防人类
通过肛门途径传播艾滋病毒感染。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Thomas Lehner其他文献
Thomas Lehner的其他文献
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{{ truncateString('Thomas Lehner', 18)}}的其他基金
Mucosal SIV-CCR5 receptor vaccine in SIV infection
粘膜 SIV-CCR5 受体疫苗治疗 SIV 感染
- 批准号:
6695196 - 财政年份:2003
- 资助金额:
$ 9.16万 - 项目类别:
Mucosal SIV-CCR5 receptor vaccine in SIV infection
粘膜 SIV-CCR5 受体疫苗治疗 SIV 感染
- 批准号:
6799189 - 财政年份:2003
- 资助金额:
$ 9.16万 - 项目类别:
CHEMOKINES AND CYTOKINES IN MUCOSAL SIV PROTECTION
粘膜 SIV 保护中的趋化因子和细胞因子
- 批准号:
2864007 - 财政年份:1998
- 资助金额:
$ 9.16万 - 项目类别:
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