Barry S M, Johnson M A, Janossy G
Department of Immunology, Royal Free and University College Hospital Medical School, London, UK.
Bone Marrow Transplant. 2000 Sep;26(6):591-7. doi: 10.1038/sj.bmt.1702562.
Various hypotheses have been proposed to explain why cytomegalovirus pneumonitis (CMV-P) is frequent and severe in bone marrow transplant patients while remaining rare and mild in HIV infected patients. One hypothesis suggests that CMV-P is an immunopathological condition that is common in bone marrow transplantation (BMT) under the effects of an abnormally regenerating immune system that reacts against CMV infected lung tissue. Such a hypothesis implicates CD4 T lymphocytes as one of the critical cell populations involved in immunopathology and also suggests that this process would be aborted by CD4 T cell deficiency in HIV infection. However, studies correlating the onset of CMV-P with lymphocyte reconstitution following BMT have revealed that CD4 cells are present at very low frequencies in the blood during the early period after transplantation when most cases of CMV-P occur. Furthermore, studies directly investigating bronchoalveolar lavage cell types during episodes of CMV-P in BMT patients have also failed to demonstrate significant CD4 involvement and, instead, have emphasized a predominance of natural killer (NK) cells and CD8 cells. These findings serve as the basis for questioning the validity of a CD4-driven immunopathological model of CMV-P in BMT. On the other hand, a variety of experimental and clinical observations support the protective role of CMV-specific CD3+ CD8 T lymphocytes against CMV in both immunocompetent individuals and BMT patients. In a murine BMT model, adoptive transfer of syngeneic BM cells was associated with massive increases in lung CD8 cells which resulted in the resolution rather than the exacerbation of existing CMV-P. In the light of these findings a more plausible hypothesis for CMV-P in BMT is that during the early period after transplantation adequate protective CD8 responses are absent and an uncontrolled CMV proliferation is allowed to develop. Once a critical viral load is reached a cytokine 'storm' may be triggered in the lung tissue that aggravates direct CMV-associated cytopathic effects. Likely candidates for this process would include the release of tumour necrosis factor-alpha (TNF-alpha) from alveolar macrophages stimulated by interferon-gamma (IFN-gamma) released from NK cells that are reconstituted early after BMT.
人们提出了各种假说，以解释为何巨细胞病毒性肺炎（CMV-P）在骨髓移植患者中频繁且严重，而在HIV感染患者中却罕见且症状轻微。一种假说认为，CMV-P是一种免疫病理状态，在骨髓移植（BMT）中很常见，这是由于异常再生的免疫系统对感染CMV的肺组织产生反应所致。这种假说认为CD4 T淋巴细胞是参与免疫病理的关键细胞群体之一，并且还表明，HIV感染导致的CD4 T细胞缺乏会使这一过程终止。然而，将CMV-P的发病与BMT后淋巴细胞重建相关联的研究表明，在移植后的早期，即大多数CMV-P病例发生时，血液中CD4细胞的频率非常低。此外，直接研究BMT患者CMV-P发作期间支气管肺泡灌洗细胞类型的研究也未能证明CD4有显著参与，相反，这些研究强调自然杀伤（NK）细胞和CD8细胞占主导地位。这些发现对BMT中CD4驱动的CMV-P免疫病理模型的有效性提出了质疑。另一方面，各种实验和临床观察结果支持CMV特异性CD3+ CD8 T淋巴细胞在免疫功能正常个体和BMT患者中对CMV的保护作用。在小鼠BMT模型中，同基因骨髓细胞的过继转移与肺中CD8细胞的大量增加相关，这导致现有CMV-P的缓解而非加重。鉴于这些发现，对于BMT中CMV-P更合理的假说是，在移植后的早期，缺乏足够的保护性CD8反应，从而允许CMV不受控制地增殖。一旦达到临界病毒载量，可能会在肺组织中引发细胞因子“风暴”，加剧直接的CMV相关细胞病变效应。这一过程可能的候选因素包括，BMT后早期重建的NK细胞释放的干扰素-γ（IFN-γ）刺激肺泡巨噬细胞释放肿瘤坏死因子-α（TNF-α）。
