MECHANISM OF ANTIBODY PROTECTION TO C NEOFORMANS

性状（改编自申请人摘要）：隐球菌 新生儿是一种真菌，可导致致命的脑膜脑脊髓炎， 免疫抑制个体。因为单独的抗真菌药物 清除感染，小鼠单克隆抗体（mabs）已被 产生真菌的荚膜多糖。过程中 研究这些单克隆抗体库的保护潜力 在免疫活性小鼠和免疫缺陷小鼠体内， 鉴定保护性、非保护性和增强性抗体。我们有 表明抗体调节感染的能力 取决于效应子的同种型、表位特异性和状态 细胞特别是，IgG 3单克隆抗体不能延长动物的寿命， 在某些情况下可以增强感染，而IGGI，IgG 2b 这些单抗的IgG 2a同种型转换变体可以延长 那个禽兽 这表明效应细胞上的FcR也起作用。 以确定这些抗体在体内的功效。此外，委员会认为， CD 4+和CD 8 + T细胞和干扰素-γ在免疫应答的能力中发挥作用。 被动施用抗体以调节感染。初步 实验表明，IgG 3和IGGI的不同作用也可以 在体外用原代巨噬细胞观察到。我们在此提议， 用遗传缺陷小鼠进行体外和体内实验， 为什么不同同种型的抗体调节小鼠感染 C.以不同的方式。希望这些研究将 为抗体的作用机制提供了新的见解， 预防和治疗新型隐球菌感染， 被包裹的有机体

DESCRIPTION (Adapted from the applicant's abstract): Cryptococcus neoformans is a fungus that causes a lethal meningoencephalomyelitis in immunosuppressed individuals. Since anti-fungal agents alone do not clear the infection, mouse monoclonal antibodies (mabs) have been generated to the capsular polysaccharide of the fungus. In the course of studying the protective potential of a large library of these mabs in vivo in both immunocompetent and immunoincompetent mice, we have identified protective, non-protective and enhancing antibodies. We have shown that the ability of the antibodies to modulate the infection depends upon the isotype, epitope specificity and state of the effector cells. In particular, IgG3 mabs do not prolong the life of the animals, and in certain situations can enhance the infection, while IGGI, IgG2b and IgG2a isotype switch variants of these mab can prolong the life of the animal. This suggests that the FcRs on effector cells are also playing a role. In determining the efficacy of these antibodies in vivo. Furthermore, CD4+ and CD8+ T cells and interferon-y play a role in the ability of the passively administered antibodies to modulate infection. Preliminary experiments reveal that the different effects of IgG3 and IGGI can also be observed in vitro with primary macrophages. We propose here to do in vitro and in vivo experiments with genetically defective mice to learn why antibodies of different isotypes modulate the infection of mice with C neoformans in different ways. It is hoped that these studies will provide new insights into the mechanism of action of antibodies in preventing and treating infection with C neoformans, and perhaps other encapsulated organisms.