Antibody Mediated Immune Regulation

项目摘要 抗体是获得性免疫的重要组成部分，提供免受微生物感染的保护。 然而，在自身抗体和同种异体抗体的情况下，抗体也可以导致疾病。 尽管经常被认为是体液免疫的终点，但长期以来一直认识到抗体可以 还以抗原特异性方式调节适应性免疫应答的发展 它们所识别的抗原。这种普遍现象被称为抗体介导的免疫 抑制（AMIS），并已观察到在各种各样的设置，包括免疫微生物 病原体、疫苗接种、移植和输血。也许非盟驻苏特派团最著名的案例是， 在人类中施用抗RhD作为治疗剂，以对抗同种免疫， 妊娠和/或分娩，这是一个广泛成功的方法，以减少溶血性疾病的 胎儿和新生儿。事实上，抗RhD仍然是仅有的抗原特异性免疫疗法之一， 预防对特定目标的免疫，而不进行一般免疫抑制。因此，实际 利用AMIS治疗人类疾病的潜力已得到充分确认。但尽管 尽管抗RhD的治疗取得了成功，但免疫抑制的机制仍然知之甚少。此外，若干 有研究报道，在某些情况下，抗RhD抗体反而增强同种免疫， 我们对抗RhD作用机制的理解不足。缺乏对机械的理解也 阻碍了制备单克隆抗RhD的尝试，一些单克隆抗体抑制了免疫力， 其他人增强。本申请利用了一种创新的临床前小鼠模型， 红细胞的同种免疫，以测试一系列不同的机制假设，关于AMIS的影响，根据 中心假设，即抗体的IgG亚型是其调节免疫能力的关键因素。的确， 初步数据表明，IgG亚型决定了抗体是免疫抑制还是免疫抑制， 增强。该提案使用了新工具和小鼠品系的组合，以及人性化的步骤 小鼠模型。在这方面，提出了三个具体目标。具体目标1：IgG 2a 抗RBC抗体增强对RBC的同种免疫。具体目标2：IgG 1抗- RBC抗体抑制RBC的体液同种免疫。具体目标3：测试效果和 在人源化小鼠模型中抗RBC抗体对同种免疫的机制。的长期目标 这个项目是为了产生新的机械理解，将提供未来的概念基础， 人体试验，以完善单克隆抗RhD，为如何将AMIS样作用应用于其他疾病提供基础。 新疗法在不同领域，并产生抗体如何调节体液免疫的基本理解， 一般的豁免权。这些知识与理解体液免疫过程有关，因为它涉及 适应性抗微生物免疫、体液自身免疫的发病机制和免疫介导的疾病。

Project Summary Antibodies are an essential component of adaptive immunity, providing protection from microbial infection. However, antibodies can also contribute to disease in the context of autoantibodies and alloantibodies. Although often considered an endpoint of humoral immunity, it has long been appreciated that antibodies can also modulate the development of adaptive immune responses in an antigen specific fashion and as a function of the antigens they recognize. This general phenomenon has been named antibody mediated immune suppression (AMIS), and has been observed in a wide variety of settings, including immunity to microbial pathogens, vaccination, transplantation and transfusion. Perhaps the most well known case of AMIS in humans is the administration of anti-RhD as a therapeutic to prophylax against alloimmunization during pregnancy and/or delivery, which has been a widely successful approach to decrease hemolytic disease of the fetus and newborn. Indeed, anti-RhD remains one of the only antigen specific immune therapies, allowing prevention of immunization to a specific target without general immunosuppression. Thus, the practical potential of harnessing AMIS for the treatment of human disease is well established. However, despite the success of anti-RhD, the mechanism of immune suppression remains poorly understood. Moreover, several studies have reported that anti-RhD paradoxically enhances alloimmunization in some settings, underscoring our poor understanding of anti-RhD mechanisms of action. Lack of mechanistic understanding has also hampered attempts to make monoclonal anti-RhD, with some monoclonals suppressing immunity whereas others enhance. The current application makes use of an innovative preclinical mouse model of alloimmunization to RBCs to test a series of distinct mechanistic hypotheses regarding AMIS effects, under the central hypothesis that the IgG subtype of an antibody is a key factor in its ability to regulate immunity. Indeed, preliminary data demonstrates that IgG subtype determines if an antibody is immune suppressing or immune enhancing. The proposal uses a combination of novel tools and murine strains, as well as steps to humanize the murine model. In this context, 3 specific aims are proposed. Specific aim 1: Mechanisms by which IgG2a anti-RBC antibodies enhance alloimmunization to RBCs. Specific aim 2: Mechanisms by which IgG1 anti- RBC antibodies suppresses humoral alloimmunization to RBCs. Specific Aim 3: Testing effects and mechanisms of anti-RBC antibodies on alloimmunization in a humanized mouse model. The long-term goals of this project are to generate novel mechanistic understanding that will provide the conceptual basis for future human trials to refine monoclonal anti-RhD, to provide a basis for how AMIS like effects can be applied to other new therapeutics in different areas, and to generate a basic understanding of how antibodies regulate humoral immunity in general. Such knowledge is relevant to understanding processes of humoral immunity as it relates to adaptive anti-microbial immunity, pathogenesis of humoral autoimmunity, and immune-mediated diseases.