MARROW TRANSPLANT THERAPY FOR RETROVIRUS INFECTIONS

逆转录病毒感染的骨髓移植治疗

基本信息

批准号：
3458579
负责人：
PETER W GASPER
金额：
$ 8.34万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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联合免疫治疗和/或抗病毒化疗最终可用于成功治疗患有逆转录病毒介导疾病的人。这是提议在一个国家进行骨髓移植（BMT）研究已建立的人类逆转录病毒感染动物模型；猫的猫白血病病毒（FeLV）感染。尝试治疗获得性免疫缺陷患者综合症（艾滋病）说明了摆脱持久性是多么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病毒介导的疾病逆转录病毒感染。只要病毒仍然存在，就有可能因为瘤形成或发育不全都会存在。治愈艾滋病和日益增长的逆转录病毒引起的疾病清单，有必要消除为病毒提供储存库的细胞。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生成细胞、巨核细胞和滤泡细胞淋巴组织中的淋巴母细胞。 BMT 的理由用于治疗逆转录病毒疾病的方法如下： 1) 如果可以消除受感染的血淋巴细胞，就可以消除大部分病毒负担来自个人； 2）如果有一个可以将未感染的血淋巴干细胞移植到其中个体，无逆转录病毒的血细胞、组织的来源巨噬细胞和免疫活性淋巴细胞提供 - 从而重建耗尽的免疫系统骨髓接受者并提供永久的潜力消除病毒。 3）最后，必须从药理学角度或通过免疫学方法去除或抑制残留的逆转录病毒消除先前存在的感染者之间的间隔血淋巴细胞和新的未感染细胞的植入血淋巴干细胞。我们最近消除了两名患者的持续 FeLV 感染使用 FeLV 免疫猫作为受体猫的捐赠者已经有明确的感染。基于这个初始成功后，已设计了具体目标以确认是否这项技术将被证明是一种可靠的治疗方法持续的逆转录病毒感染。首批移植手术将是在具有受控参数的猫中进行，即受者体内的非致病性病毒和捐赠猫的就业针对完全相同的病毒进行了免疫。下一步将是用更多的细胞病变病毒株进行移植，最终导致尝试治疗感染 FeLV 的宠物猫。其他研究包括白细胞介素 2 刺激和扩张免疫供体淋巴细胞和抗病毒化疗在将细胞移植到供体猫之前对其进行治疗持续感染的收件人。