IGG SUBCLASS & FUNCTION OF ANTIPOLYSACCHARIDE ANTIBODY
IGG亚类
基本信息
- 批准号:2067505
- 负责人:
- 金额:$ 21.37万
- 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:1993-01-01 至 1996-12-31
- 项目状态:已结题
- 来源:
- 关键词:Pseudomonas aeruginosa antibacterial antibody bacterial disease bacterial polysaccharides bactericidal immunity chimeric proteins complement pathway disease /disorder model fusion gene gene mutation gene rearrangement human genetic material tag human tissue humoral immunity immunodeficiency immunoglobulin G immunoglobulin genes laboratory mouse laboratory rat molecular cloning monoclonal antibody opsonin tissue /cell culture transfection
项目摘要
Polysaccharide (PS)-encapsulated bacteria are a major cause of infections
in humans. Anti-PS IgG antibodies (Ab) are critical to host defense
against infection with these bacteria. The function of anti-PS Ab
includes complement fixation and opsonization of bacteria for uptake and
killing by phagocytes. The mammalian IgG anti-PS Ab response, however
is restricted to only one or two subclasses (IgG3 in mice, IgG1 and IgG2
in man). Defining the relative function of anti-PS Ab of different IgG
subclasses is crucial to better understanding of immunity to PS-coated
bacteria as well as the pathogenesis of several human disease states such
as IgG subclass deficiency, and chronic pneumonia in Cystic Fibrosis
where inappropriate IgG subclass of anti-P. aeruginosa (PA) Ab may
contribute to inability to clear PA from the lung. The relative function
of anti-PS Ab of different IgG subclass remains unclear due to previous
studies primarily using polyclonal affinity purified Ab exposed to
chaotropic agents that alter Fc function, or to the use of monoclonal Ab
with different antigenic specificities. In this proposal, we will
precisely define the role of IgG subclass in anti-PS Ab effector
function. First, we will make murine monoclonal Ab (MAb) directed to O-
PS-side chain of PA LPS and to mucoid exopolysaccharide of PA. Next,
using sequential sublining, we will make switch variants of these MAb
that have identical variable regions but are of different IgG subclasses.
The variable region genes will be cloned and ligated to the gamma
constant region human genes to make human/murine chimeric transfectomas
producing Ab of all four human IgG subclasses that have identical
variable regions. The functional characteristics of the murine and
chimeric anti-PS Ab will be compared in terms of: 1) ability to fix
complement, 2) ability to opsonize PA for uptake by phagocytes, and 3)
protective efficacy in animal models of PA infection. Finally, to
determine the in vivo importance of the predominant anti-PS IgG subclass,
IgG3 deficient mice will be mae by targeting the murine gamma 3 gene for
mutation and homologous recombination in embryonic stem cells. These
mice will be evaluated for their ability to immunologically respond to
PS, PS-protein conjugates, and bacterial infection. These studies will
determine which anti-PS IgG subclass functions most efficiently against
PS-coated bacteria, better define the mechanism of functional differences
between IgG subclasses and explore the immunologic relevance of these
differences in vivo. This information will allow more rational
strategies of active and passive immunization against PS-coated bacteria
and improved treatment of IgG subclass deficiencies.
多糖(PS)包裹的细菌是感染的主要原因
在人类身上。抗PS免疫球蛋白抗体(Ab)对宿主防御至关重要
抵抗这些细菌的感染。抗PS抗体的功能
包括补体结合和细菌调理以摄取和
吞噬细胞的杀戮。然而,哺乳动物的免疫球蛋白抗体抗PS抗体
仅限于一个或两个亚类(小鼠中的IgG3,IgG1和IgG2
在人类中)。确定不同免疫球蛋白的抗PS抗体的相对功能
亚类是更好地理解PS涂层免疫的关键
细菌以及几种人类疾病的发病机制
作为免疫球蛋白亚类缺陷与囊性纤维化的慢性肺炎
其中,不适当的抗P-G亚类。铜绿假单抗(PA)可
导致无法将PA从肺中清除。相关函数
由于先前的研究,不同免疫球蛋白亚类的抗PS抗体的性质尚不清楚
应用多克隆亲和纯化抗体初步研究
改变Fc功能的杂交剂,或使用单抗
具有不同的抗原性。在这项提案中,我们将
准确定位免疫球蛋白亚类在抗PS抗体效应器中的作用
功能。首先,我们将制备针对O-1的鼠源单抗。
PA内毒素的PS侧链和PA的粘液性胞外多糖。下一首,
使用顺序子链接,我们将制作这些单抗的开关变体
它们具有相同的可变区,但属于不同的免疫球蛋白亚类。
可变区基因将被克隆并连接到伽马
恒定区人类基因制作人/鼠嵌合转染瘤
产生具有相同的四个人类免疫球蛋白亚类的抗体
可变区。小鼠和小鼠的功能特征
嵌合的抗PS抗体将在以下方面进行比较:1)修复能力
补体,2)调理PA供吞噬细胞摄取的能力,以及3)
PA感染动物模型的保护作用。最后,为了
确定主要抗PS免疫球蛋白亚类在体内的重要性,
IgG3缺陷小鼠将通过靶向小鼠Gamma 3基因进行MAE
胚胎干细胞中的突变和同源重组。这些
将对小鼠进行免疫反应能力的评估
PS、PS-蛋白结合物与细菌感染。这些研究将
确定哪个抗PS免疫球蛋白亚类最有效地对抗
包被PS的细菌,更好地定义了功能差异的机制
免疫球蛋白亚类之间的关系,并探讨这些亚类之间的免疫学相关性
活体内的差异。这一信息将使更多的理性
PS包被细菌的主动免疫和被动免疫策略
并改进了对免疫球蛋白亚类缺陷的治疗。
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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JOHN R SCHREIBER其他文献
JOHN R SCHREIBER的其他文献
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{{ truncateString('JOHN R SCHREIBER', 18)}}的其他基金
HUMAN T CELL RESPONSE TO PNEUMOCOCCAL CONJUGATE VACCINES
人类 T 细胞对肺炎球菌结合疫苗的反应
- 批准号:
6511181 - 财政年份:2000
- 资助金额:
$ 21.37万 - 项目类别:
HUMAN T CELL RESPONSE TO PNEUMOCOCCAL CONJUGATE VACCINES
人类 T 细胞对肺炎球菌结合疫苗的反应
- 批准号:
6374389 - 财政年份:2000
- 资助金额:
$ 21.37万 - 项目类别:
HUMAN T CELL RESPONSE TO PNEUMOCOCCAL CONJUGATE VACCINES
人类 T 细胞对肺炎球菌结合疫苗的反应
- 批准号:
6632203 - 财政年份:2000
- 资助金额:
$ 21.37万 - 项目类别:
HUMAN T CELL RESPONSE TO PNEUMOCOCCAL CONJUGATE VACCINES
人类 T 细胞对肺炎球菌结合疫苗的反应
- 批准号:
6756507 - 财政年份:2000
- 资助金额:
$ 21.37万 - 项目类别:
HUMAN T CELL RESPONSE TO PNEUMOCOCCAL CONJUGATE VACCINES
人类 T 细胞对肺炎球菌结合疫苗的反应
- 批准号:
6195663 - 财政年份:2000
- 资助金额:
$ 21.37万 - 项目类别:
Teaching Biology Through Immunology Fellowships
通过免疫学奖学金教授生物学
- 批准号:
6666522 - 财政年份:1998
- 资助金额:
$ 21.37万 - 项目类别:
TEACHING BIOLOGY THROUGH IMMUNOLOGY FELLOWSHIPS
通过免疫学奖学金教授生物学
- 批准号:
6532756 - 财政年份:1998
- 资助金额:
$ 21.37万 - 项目类别:
TEACHING BIOLOGY THROUGH IMMUNOLOGY FELLOWSHIPS
通过免疫学奖学金教授生物学
- 批准号:
6373965 - 财政年份:1998
- 资助金额:
$ 21.37万 - 项目类别: