Green K A, Noelle R J, Green W R
Department of Microbiology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Virology. 1998 Feb 15;241(2):260-8. doi: 10.1006/viro.1997.8970.
In genetically susceptible C57BL/6 mice the LP-BM5 isolate of murine retroviruses causes profound splenomegaly, lymphadenopathy, hypergammaglobulinemia, and an immunodeficiency syndrome bearing many similarities to the pathologies seen in AIDS. Because of these similarities, which also include terminal B cell lymphoma formation, this syndrome has been called murine AIDS or MAIDS. Prompted by previous reports showing that the onset of MAIDS is dependent on the presence of both CD4+ T and B cells, we have previously shown that anti-gp39/CD40 ligand mAb (anti-CD40L mAb) treatment of LP-BM5-infected mice is effective in inhibiting the induction of MAIDS when a short course of anti-CD40L mAb treatment was started on the same day as LP-BM5 administration. The success of anti-CD40L mAb therapy, as indicated by a much reduced degree of splenomegaly, hypergammaglobulinemia, and mitogen and allogeneic CTL unresponsiveness, demonstrated that CD40L/CD40 interactions were critical to the establishment of MAIDS. Here we extend these findings through the use of delayed anti-CD40L mAb treatment of mice, beginning 3-4 weeks after LP-BM5 infection, by showing that interruption of CD40L/CD40 interactions also interferes with the progression of MAIDS. About 60% of LP-BM5-preinfected mice were affected by delayed anti-CD40L mAb treatment, with substantially reduced spleen weights and serum hypergammaglobulinemia and normal or greatly restored proliferative responses to Con A stimulation and CTL responses to allogeneic stimulation. The other LP-BM5-infected mice that did not respond to anti-CD40L therapy were found to have made antibodies to the anti-CD40L mAb. Thus, in a majority of mice anti-CD40L mAb therapy was very effective in interfering with MAIDS pathogenesis well after the establishment of the virus infection and MAIDS symptomatology, indicating that CD40L/CD40 interactions are crucial to the maintenance and progression of the disease, as well as its initiation.
在具有遗传易感性的C57BL/6小鼠中，鼠逆转录病毒的LP - BM5分离株可引起严重的脾肿大、淋巴结病、高球蛋白血症以及一种免疫缺陷综合征，该综合征与艾滋病中所见的病理状况有许多相似之处。由于这些相似性，其中还包括终末期B细胞淋巴瘤的形成，这种综合征被称为鼠艾滋病或MAIDS。受先前报道（显示MAIDS的发病依赖于CD4 + T细胞和B细胞的同时存在）的启发，我们先前已表明，当在LP - BM5给药当天开始短期抗CD40L单克隆抗体（抗CD40L mAb）治疗时，用抗gp39/CD40配体单克隆抗体（抗CD40L mAb）治疗LP - BM5感染的小鼠可有效抑制MAIDS的诱导。抗CD40L mAb治疗的成功表现为脾肿大、高球蛋白血症程度大幅降低，以及对有丝分裂原和同种异体CTL无反应性，这表明CD40L/CD40相互作用对MAIDS的发生至关重要。在此，我们通过在LP - BM5感染后3 - 4周开始对小鼠进行延迟抗CD40L mAb治疗来扩展这些发现，结果表明CD40L/CD40相互作用的中断也会干扰MAIDS的进展。约60%的预先感染LP - BM5的小鼠受到延迟抗CD40L mAb治疗的影响，脾脏重量大幅减轻，血清高球蛋白血症减轻，对Con A刺激的增殖反应以及对同种异体刺激的CTL反应恢复正常或大幅恢复。发现其他对抗CD40L治疗无反应的LP - BM5感染小鼠已产生针对抗CD40L mAb的抗体。因此，在大多数小鼠中，抗CD40L mAb治疗在病毒感染和MAIDS症状出现后很长时间仍能非常有效地干扰MAIDS发病机制，这表明CD40L/CD40相互作用对于疾病的维持、进展以及起始都至关重要。
