IMMUNOPATHOGENESIS OF LP-BM5 INFECTION-MURINE ACQUIRED IMMUNODEFICIENCY DISEASE

已经进行了研究来评估MAIDS的免疫发病机制， 一种鼠免疫缺陷病，由感染 LP-BM 5逆转录病毒。 具体而言，我们正在评估1）对以下问题的反应： 易感和耐药淋巴群体的感染，2） 同种异体反应对疾病产生的贡献，3） 对非淋巴宿主靶组织感染的贡献，以及4） 巨噬细胞在诱导和维持感染中的作用。 1)易感B6小鼠在感染后8周内发生MAIDS， 抗性129品系小鼠在超过8个月内不发生感染。 到 测试耐药细胞是否可以改变感染过程， 易感动物，我们感染了B6 <->129同种异体小鼠，其淋巴 隔室是嵌合的，因为它们含有B6细胞 （敏感）来源的细胞和129（抗性）来源的细胞，具有LP-BM 5。 令人惊讶的是，这些动物出现了加速的淋巴结病， 相对于对照B6小鼠脾肿大，表明存在 抗性细胞不足以抑制感染。 但这 发生在只有最多35%的淋巴细胞 隔室由抗性细胞组成。 实验正在进行 以评估感染是否可以被调制时， 抗性细胞更高。 2)逆转录病毒通过接种或作为无细胞接种来引发疾病。 提取物或以细胞相关的形式。在艾滋病毒感染的情况下， 细胞相关病毒的呈递在同种异体 组织相容性屏障 为了了解这种效应的作用，小鼠 接种细胞相关的LP-BM 5逆转录病毒， I或MHC II类组织相容性屏障，并评估感染。 初步结果显示，相对于同基因感染的对照， 在小鼠中，观察到加速的疾病跨越MHC II类屏障， 通过MHC I类屏障减弱疾病。 这不仅仅是 反映不同毒株对病毒的不同亲和性 感染表现为疾病发展的相同速率， 三个菌株接种无细胞病毒。 进一步的研究 正在做的工作，以确认这些意见，并探讨机制， 这种影响是由哪些因素引起的。 3)已经证明MAIDS感染的过程是 通过化学疗法显著减弱， 骨髓腔 然而，疾病复发后， 淋巴细胞的充盈表明其他组织可能含有LP- BM-85病毒并证明是再感染的来源。 先前的研究表明 皮肤细胞群可能携带LP-BM 5病毒，因为疾病可能是 通过受感染动物的皮肤移植传播。 我们已经发现证据 通过PCR分析感染者皮肤样本中的前病毒， 感染的老鼠 研究正在进行中，以具体确定哪种皮肤 细胞可能携带感染性病毒。 4)巨噬细胞在LP-BM 5产生MAIDS中的作用 感染尚不清楚。 为了评估巨噬细胞对 疾病的产生，我们专门通过注射消耗巨噬细胞 将毒性脂质体注射到接种LP-BM 5的小鼠中。

Studies have been undertaken to evaluate the immunopathogenesis of MAIDS, a murine immunodeficiency disease produced by infection with a mixture of LP-BM5 retroviruses. Specifically we are assessing 1) the response to infection by susceptible and resistant lymphoid populations, 2) the contribution of allospecific responses to generation of disease, 3) the contribution to infection of non-lymphoid host target tissues, and 4) the role of macrophages in induction and maintenance of infection. 1) Susceptible B6 mice develop MAIDS within 8 weeks of infection whereas resistant 129 strain mice do not develop infection in over 8 months. To test whether resistant cells could modify the course of infection in susceptible animals, we infected B6<->129 allophenic mice, whose lymphoid compartments were chimeric in that they contained cells of B6 (susceptible) origin and cells of 129 (resistant) origin, with LP-BM5. Surprisingly, these animals developed accelerated lymphadenopathy and splenomegaly relative to control B6 mice, indicating that the presence of resistant cells was not sufficient to suppress infection. However, this occurred in animals in which only a maximum of 35% of the lymphoid compartment was composed of resistant cells. Experiments are in progress to assess whether infection can be modulated when the percentage of resistant cells is higher. 2) Retroviruses initiate disease by inoculation either as a cell free extract or in a cell associated form. In the case of HIV infection, presentation of cell associated virus transpires across allogeneic histocompatibility barriers. To understand the role of such effects, mice were inoculated with cell associated LP-BM5 retroviruses across MHC class I or MHC class II histocompatibility barriers and assessed for infection. Preliminary results reveal that relative to control syngeneically infected mice, accelerated disease was observed across MHC class II barriers and attenuated disease across MHC class I barriers. That this did not merely reflect differential susceptibilities of different strains to viral infection was shown by an equivalent rate of disease development in the three strains on inoculation of cell free virus. Further studies are being done to confirm these observations and to explore the mechanisms by which such effects are mediated. 3) It has been demonstrated that the course of MAIDS infection is dramatically attenuated by chemotherapy that obliterates the lymphoid and bone marrow compartments. Nonetheless, disease recrudesces following repletion of lymphoid cells indicating that other tissues may harbor LP- BM-85 virus and prove a source of reinfection. Previous studies indicate that skin cell populations may harbor LP-BM5 virus because disease may be transmitted via skin grafts from infected animals. We have found evidence by PCR analysis of provirus in skin samples of infected but no non- infected mice. Studies are underway to specifically identify which skin cells may harbor infective virus. 4) The role of the macrophage in generation of MAIDS from LP-BM5 infection is not clear. To assess contributions of the macrophage to disease generation, we are specifically depleting macrophages by injection of toxic liposomes into mice inoculated with LP-BM5.