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    • 4. 发明申请
    • USE OF ALLOGENEIC CELL LINES TO LOAD ANTIGEN-PRESENTING CELLS TO ELICIT OR ELIMINATE IMMUNE RESPONSES
    • 使用同种异体细胞系负载抗原呈递细胞以免疫或免疫免疫应答
    • WO0129192A3
    • 2002-01-17
    • PCT/US0028670
    • 2000-10-16
    • BAYLOR RES INSTBANCHEREAU JACQUES FBERARD FREDERICBLANCO PATRICKNEIDHART BERARD EVE MARIENOURI SHIRAZI MAHYARPALUCKA ANNA KAROLINA
    • BANCHEREAU JACQUES FBERARD FREDERICBLANCO PATRICKNEIDHART-BERARD EVE-MARIENOURI-SHIRAZI MAHYARPALUCKA ANNA KAROLINA
    • A61K35/12A61K39/00A61P35/00C12N5/0784C12N5/08
    • C12N5/0639A61K39/0008A61K39/001A61K39/0011A61K2035/122A61K2039/5152A61K2039/5154A61K2039/5158A61K2039/57C12N5/064
    • Novel antigen-presenting cells, including but not limited to dendritic cells (DC), that are loaded with antigens from dead or dying cells including allogenic cell lines, and the methods for making such antigen-presenting cells are described. These loaded antigen-presenting cells are useful to induce both prophylactic immune responses and therapeutic immune responses in humans. In particular, such loaded antigen-presenting cells are useful in the management of cancer and infectious diseases. Alternatively, the loaded antigen-presenting cells can be used to eliminate undesired immune responses such as autoimmune responses and graft versus host disease or host versus graft reaction, i.e., graft rejection in organ and bone marrow transplantation. Antigen-presenting cells useful in the present invention include but are not limited to dendritic cells at various differentiation stages (precursors, immature dendritic cells and mature dendritic cells), dendritic cells derived from blood precursors including but not limited to monocytes, dendritic cells derived from CD34-hematopoetic progenitor cells, subsets of dentritic cells such as Langerhans cells, interstitial DCs and lymphoid DCs. The antigen-presenting cells and the precursors of cytotoxic cells are derived from healthy volunteers or from tumor-bearing patients. Antigen-loaded dendritic cells prepared as described here can also prime naïve T cells to differentiate into effector cells able to recognize multiple and/or shared tumor antigens that are expressed either on the tumor cells that are used to load the dentritic cells and/or on other tumor cells. The cytotoxic T cells generated by exposure to antigen-loaded dendritic cells prepared as described here can also be used in adoptive therapy. This induction of responses against multiple antigens shared between different cells, for instance tumor cells, as described here is important as it leads to broad immune responses. In the present invention, the T cells that are exposed to dendritic cells loaded with killed cells can be tolerized against the antigen(s) expressed on the killed cells. That can be achieved by manipulation of loaded dentritic cells that allows presentation of the antigen but inhibits the expression of co-stimulatory molecules.
    • 描述了载有来自死亡或死亡细胞(包括同种异体细胞系)的抗原的新型抗原呈递细胞,包括但不限于树突细胞(DC),以及制备这种抗原呈递细胞的方法。 这些负载的抗原呈递细胞可用于诱导人类的预防性免疫应答和治疗性免疫应答。 特别地,这种负载的抗原呈递细胞可用于治疗癌症和感染性疾病。 或者,加载的抗原呈递细胞可用于消除不期望的免疫应答,例如自身免疫应答和移植物抗宿主病或宿主与移植物反应,即在器官和骨髓移植中的移植排斥反应。 可用于本发明的抗原呈递细胞包括但不限于在各种分化阶段的树突状细胞(前体,未成熟树突细胞和成熟树突状细胞),衍生自血液前体的树突状细胞,包括但不限于单核细胞,衍生自 CD34-造血祖细胞,诸如朗格汉斯细胞,间质性DCs和淋巴样DCs的树突状细胞亚群。 抗原呈递细胞和细胞毒性细胞的前体衍生自健康志愿者或来自肿瘤的患者。 如本文所述制备的抗原负载的树突状细胞也可以使初始的T细胞分化成能够识别多次和/或共享肿瘤抗原的效应细胞,所述多个和/或共有的肿瘤抗原在用于装载树突细胞的肿瘤细胞上表达和/或在 其他肿瘤细胞。 通过暴露于如本文所述制备的抗原负载的树突状细胞产生的细胞毒性T细胞也可用于过继疗法。 如本文所述,这种对不同细胞(例如肿瘤细胞)共有的多种抗原的反应诱导是重要的,因为它导致广泛的免疫应答。 在本发明中,暴露于负载有杀死细胞的树突细胞的T细胞可以耐受在杀死的细胞上表达的抗原。 这可以通过操作允许呈递抗原但抑制共刺激分子的表达的负载的树突状细胞来实现。