CONSTRUCTION OF FUSION MOLECULES FOR REDIRECTING IMMUNE RESPONSES

表达A基因的杀伤细胞治疗HIV感染者的研究 靶向和杀伤HIV感染细胞的新型融合分子(CD4-Zeta) 正在进行中。虽然没有小动物模型可以评估艾滋病毒 这种细胞的安全性和有效性，即负责移植的T细胞 排斥反应和自身免疫可能是杀伤细胞的类似靶标。 表达由胞外部分组成的融合分子 MHC和TCR的信号分子Zeta。我们已经建造了 MHC-Zeta融合分子，并开发了一种动物模型进行测试 他们。我们发现，信号分子与MHC的融合是可能的 增强T细胞功能的表达，包括辅助和杀伤功能 细胞识别或抗体连接。然而，这样的能力 细胞消除识别这些分子的同种异体特异性淋巴细胞 目前尚不清楚，正在追查中。我们进一步发现，输注 在正常小鼠中表达这种结构的淋巴细胞不仅是好的 耐受，但也延长了表达 与构造中相同的MHC，这一发现不一定 与否决活动有关，但与转基因基因的缺乏表达有关 “专业的”抗原提呈细胞。 CD4-Zeta融合分子正在进行积极的临床研究。 该计划为中心提供了评估关键问题的专业知识 与这种构造的制造、安全和功效有关的。 因此，在通过交叉链接进行选择的过程中的激活问题 配基与单抗的相互作用及其对患者输液的后续影响 可以被评估。此外，淋巴瘤的发展在一个相对 表达这种结构的小鼠中有很大比例提醒我们注意一些 以前未知的安全问题。该计划还预计将使用 一类有潜力的新型生物制剂治疗慢性粒细胞白血病 移植排斥和自身免疫。

Treatment of HIV infected patients with killer cells expressing a novel fusion molecule (CD4-Zeta) to target and kill HIV infected cells is underway. Although there are no small animal models of HIV to assess the safety and efficacy of such cells, the T cells responsible for graft rejection and autoimmunity may be similarly targeted by killer cells expressing fusion molecules consisting of the extracellular portion of MHC and the signaling molecule zeta of the TcR. We have constructed MHC-zeta fusion molecules and developed an animal model in which to test them. We found that fusion of a signaling molecule to MHC allowed enhanced expression of T cell functions, both helper and killer following cellular recognition or antibody ligation. However, the ability of such cells to eliminate allospecific lymphocytes that recognize such molecules is unclear and being pursued. We further found that infusion of lymphocytes expressing such constructs into normal mice not only is well tolerated, but also prolongs survival of allografts expressing the identical MHC as in the construct, a finding which does not necessarily pertain to veto activity but to the lack of expression of the transgeneon "professional" antigen presenting cells. The CD4-zeta fusion molecule is under active clinical investigation. This program gives the Center the expertise to assess critical issues relating to the manufacture, safety,and efficacy of such constructs. Thus, issues of activation during the selection process by cross linking of ligand with mAb and the subsequent effects on infusion into patients can be assessed. Further, the development of lymphoma in a relatively large percentage of mice expressing this construct has alerted us to some previously unknown safety issues. This program also anticipates the use of a potential new class of biological agents for treatment of transplantation rejection and autoimmunity.