HUMAN FC RECEPTOR--ENHANCED ANTIGEN PRESENTATION DEFINED

该建议的指导假设是， (Ag)通过Ag、抗体（Ab）和Fc的相互作用呈递 受体（FcR）：1）将刺激对免疫原的主动免疫，和2） 将根据所涉及的FcR或人Ab同位素的类型而变化。 FcR介导的Ag-Ab复合物的摄取可以通过以下方式增强Ag呈递： 单核细胞至少100倍。 此外，最近的研究表明， 在体内将Ag导向FcR可能会导致 疫苗的有效性。 具体目标1将是确定哪种FcR 型在增强单核细胞的Ag呈递方面最有效。 这 将通过将Ag连接至（Fab '）2或Fab单克隆抗体（mAb） 特异于人Fc γ RI、Fc γ RII、Fc γ RIII（IgG的FcR） 或FcalphaR（伊加的FcR）。 试验将包括不同数量的 Ag呈递细胞、Ag特异性T细胞、单独Ag、单独Ab或Ag-Ab 共轭 T细胞增殖和T细胞产生的淋巴因子 将用于测量Ag呈递。 根据所涉及的传染原或免疫原， 产生的人Ab会有所不同。 具体目标2将确定 所有人IgG同位素和伊加参与增强的免疫应答的能力， 银介绍。 半抗原NP将与Ag连接。 人Fc小鼠 Fab抗NP嵌合Ab将用于产生Ag-Ab复合物。 嵌合 由每种人IgG同位素组成的Ab是可用的， 将改变NP与Ag的比率以改变复合物的大小。 FcR类型- 特异性mAb将用作阻断剂，以确认哪些FcR 在FcR增强的Ag呈现期间使用。 人单核细胞、巨噬细胞和B细胞都表达一种或多种形式 的FcR。 此外，B细胞具有表面免疫球蛋白（IG），其 结合Ag，从而也增强Ag摄取和随后的呈递。 树突状细胞被认为是一种重要的抗原呈递细胞， 尽管它们表面并不表达Fc γ R。 具体目标3将是比较受体增强和 非增强的Ag呈递在这些细胞类型中。 这些研究不仅会提高我们对正常的理解， 免疫反应，但也将提供新的方法来增强免疫反应， 疫苗的有效性。

The guiding hypotheses for this proposal are that enhancement of antigen (Ag) presentation through the interaction of Ag, antibody (Ab) and Fc receptors (FcR): 1) will stimulate active immunity to immunogens, and 2) will vary dependent on the type of FcR or the human Ab isotope involved. FcR-mediated uptake of Ag-Ab complexes can enhance Ag presentation by monocytes at least 100-fold. In addition, recent studies suggest that directing Ag to FcR in vivo may bring out substantial increases in the effectiveness of vaccines. Specific Aim 1 will be to determine which FcR types are most effective at enhancing Ag presentation by monocytes. This will be done by attaching Ag to (Fab')2 or Fab monoclonal Ab (mAb) specific for human FcgammaRI, FCgammaRII, FcgammaRIII (the FcR for IgG) or FcalphaR (the FcR for IgA). Assays will consist of varying numbers of Ag presenting cells, Ag-specific T cells, Ag alone, Ab alone or Ag-Ab conjugates. T cell proliferation and lymphokine production by T cells will be used to measure Ag presentation. Depending on the infectious agent or immunogen involved, the isotope of human Ab produced will vary. Specific Aim 2 will be to define the ability of all human IgG isotopes, and IgA, to participate in enhanced Ag presentation. The hapten NP will be linked to the Ag. Human Fc mouse Fab anti-NP chimeric Ab will be used to create Ag-Ab complexes. Chimeric Ab composed of each of the human IgG isotopes is available and the ratio of NP to Ag will be varied to vary the size of the complex. FcR type- specific mAb will be used as blocking agents to confirm which FcR are being utilized during FcR-enhanced Ag presentation. Human monocytes, macrophages and B cells all express one or more forms of FcR. In addition, B cells have surface immunoglobulin (Ig) which binds Ag and thereby also enhances Ag uptake and subsequent presentation. Dendritic cells are considered to be an important Ag presenting cell as well, although they do not appear to express FcgammaR on their surface. Specific Aim 3 will be to compare the efficiency of receptor-enhanced and non-enhanced Ag presentation among these cell types. These studies will not only improve our understanding of the normal immune response, but will also provide novel approaches for enhancing the effectiveness of vaccines.