MARROW TRANSPLANT THERAPY FOR RETROVIRUS INFECTIONS

逆转录病毒感染的骨髓移植治疗

• 批准号: 3458580
• 负责人: PETER W GASPER
• 金额: $ 8.43万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1993-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3458580
• 关键词: AIDS; AIDS therapy; Retroviridae disease; antiAIDS agent; antiviral agents; antiviral antibody; bone marrow transplantation; cats; cellular immunity; density gradient ultracentrifugation; disease /disorder model; enzyme linked immunosorbent assay; feline leukemia /sarcoma virus; hematopoiesis; histopathology; immunofluorescence technique; immunomodulators; immunopharmacology; immunotherapy; interleukin 2; monoclonal antibody; nonhuman therapy evaluation; tissue /cell culture; virus antigen; virus replication; zidovudine

The overall goal of this investigation is to determine whether marrow transplantation therapy combined with immunotherapy and/or antiviral chemotherapy can ultimately be used to successfully treat people with retrovirus-mediated diseases. It is proposed to perform bone marrow transplant (BMT) studies in a well established animal model of human retrovirus infection; feline leukemia virus (FeLV) infection of cats. Attempts to treat patients with acquired immune deficiency syndrome (AIDS) illustrate how difficult it is to unseat persistent retrovirus infections. History suggests that inactivation of cellular replication of virus will not eliminate disease mediated by retrovirus infection. As long as the viurs remains, the potential for neoplasia or aplasia will exist. To cure AIDS and the growing list of retrovirus-induced diseases it will be necessary to eliminate the cells which are providing a reservoir for the virus. In cats, as in people, retrovirus infections are hemolymphatic cell infections--FeLV replication occurs primarily in mitotically active myelopoietic cells, megakaryocytes and follicular lymphoblasts in lymphatic tissues. Our rationale for how BMT can be used to treat retroviral diseases is as follows: 1) If one could eliminate infected hemolymphatic cells, on would be eliminating the majority of the virus burden from the individual; 2) If one could transplant non-infected hemolymphatic stem cells into that individual, a source of retrovirus-free blood cells, tissue macrophages, and immunocompetent lymphocytes would be provided - thereby reconstituting the depleted immune system of the marrow recipient and providing the potential for permanent elimination of the virus. 3) Finally, one must pharmacologically or immunologically remove or inhibit residual retrovirus during the interval between elimination of pre-existing infected hemolymphatic cells and engraftment of new noninfected hemolymphatic stem cells. We have recently eliminated persistent FeLV infection from two cats by using FeLV immunized cats as donor for recipient cats which had well established infections. Based on this initial success, the Specific Aims have been design to confirm whether this technique will prove to be a dependable means to cure persistent retrovirus infections. The first transplants will be performed in cats with controlled parameters, namely an apathogenic virus in the recipients and employment of donor cats immunized against the exact same virus. The next step will be to perform transplants with more cytopathic strains of the virus, ultimately leading to attempting to treat FeLV-infected pet cats. Additional studies include interleukin 2 stimulation and expansion of immune donor lymphocytes and antiviral chemotherapeutic treatment of donor cats prior to transplanting their cell into persistently infected recipients.

这项调查的总体目标是确定是否 骨髓移植疗法与免疫疗法结合 和/或抗病毒化疗最终可用于 成功治疗逆转录病毒介导的疾病的人。 这是 提议在A中进行骨髓移植（BMT）研究 人类逆转录病毒感染的良好动物模型； 猫的猫白血病病毒（FELV）猫的感染。 试图治疗获得性免疫缺陷的患者 综合征（AIDS）说明了持久持续的困难 逆转录病毒感染。 历史表明失活 病毒的细胞复制不会消除由 逆转录病毒感染。 只要Viurs仍然存在，潜力 对于肿瘤或呼吸症，将存在。 治愈艾滋病和成长 逆转录病毒引起的疾病清单必须 消除为病毒提供储层的细胞。 在猫中，就像在人中一样，逆转录病毒感染是血淋巴细胞 感染 - FELV复制主要发生在有丝分裂中 活跃的骨髓细胞，巨核细胞和卵泡 淋巴组织中的淋巴细胞。 我们关于BMT的理由 用于治疗逆转录病毒疾病如下：1）如果可以 消除感染的血淋巴细胞，将消除 大多数病毒负担来自个人； 2）如果一个 可以将未感染的血淋巴干细胞移植到 个人，无逆转录病毒的血细胞的来源，组织 巨噬细胞和免疫能力的淋巴细胞将是 提供 - 从而重构耗尽的免疫系统 骨髓接收者并提供了永久性的潜力 消除病毒。 3）最后，必须在药理学上 或在免疫学上去除或抑制残留逆转录病毒 消除现有感染的间隔 新未感染的血淋巴细胞和植入 血淋巴干细胞。 我们最近从两种中消除了持续的FELV感染 通过使用FELV免疫猫作为接收者猫的供体 已经建立了良好的感染。 基于这个初始 成功，具体的目标是确认是否 该技术将被证明是治愈的一种可靠手段 持续的逆转录病毒感染。 第一个移植将是 在具有受控参数的猫中进行，即 供体猫的接受者和就业 针对完全相同的病毒免疫。 下一步将是 用更多的细胞质菌株进行病毒的移植， 最终导致尝试治疗FELV感染的宠物猫。 其他研究包括白介素2刺激和扩张 免疫供体淋巴细胞和抗病毒化学治疗的 将其细胞移植到 持续感染的接收者。