Pellegrini J D, De A K, Kodys K, Puyana J C, Furse R K, Miller-Graziano C
University of Massachusetts Medical Center, Worcester, Massachusetts 01655, USA.
J Surg Res. 2000 Feb;88(2):200-6. doi: 10.1006/jsre.1999.5797.
Severely injured trauma patients experience T cell depletion. A subset of these patients also develop T cell unresponsiveness (anergy), as characterized by the failure of their T cells to proliferate or to produce T lymphokines in response to a direct stimulus through the T cell receptor. We hypothesized that T cell apoptosis plays a role in the development of posttrauma T cell depletion and/or T cell anergy by deleting an activated T cell population. We found that moderately increased T cell depletion posttrauma is not innately deleterious or immediately responsible for anergy, but may predispose to later development of T cell anergy, possibly due to a more stringent requirement for activation of the remaining naive T cells.
A total of 30 blunt trauma and burn patients were assessed twice weekly for the following parameters: (1) clinical outcome expressed as severity of organ dysfunction as measured by the multiple organ dysfunction syndrome score, (2) proliferative response of highly purified T cells to anti-CD3/anti-CD4, (3) level of apoptosis as determined by flow cytometric analysis of propidium iodide-stained monocyte reduced peripheral blood mononuclear cells, either unstimulated or in response to mitogenic challenge or Fas (CD95) stimulation.
A wide range of apoptosis levels are seen in the patients' T cells. Apoptosis is increased when all trauma patients' T cells are compared to T cells of normal volunteers. However, at the time a patients' T cells are anergic, there is no increased level of apoptosis. In fact, the point of maximum anergy (lowest proliferative response) correlates to diminished apoptotic response. Increased T cell apoptosis can be stimulated by anti-Fas antibody in trauma patients' responsive T cells but not in maximally anergic T cells. These data suggest that patients' T cell anergy is not an immediate result of apoptotic T cell depletion upon stimulation. However, patients who later develop T cell anergy have increased T cell apoptosis earlier in their clinical course than patients who never experience T cell anergy.
Increased levels of apoptosis are not directly associated with negative trauma patient outcome nor the immediate cause of T cell anergy. However, unusually high levels of apoptosis and development of severe T cell depletion occurring before complete activation and expansion of the posttrauma T cell response may presage anergy and subsequent organ failure.
严重受伤的创伤患者会出现T细胞耗竭。这些患者中的一部分还会出现T细胞无反应性（失能），其特征是T细胞无法通过T细胞受体对直接刺激做出增殖反应或产生T淋巴细胞因子。我们推测T细胞凋亡通过清除活化的T细胞群体，在创伤后T细胞耗竭和/或T细胞失能的发生中起作用。我们发现，创伤后T细胞耗竭适度增加本身并无有害影响，也不是失能的直接原因，但可能会使T细胞失能在后期更容易发生，这可能是由于对剩余幼稚T细胞的激活要求更为严格。
每周两次对30名钝性创伤和烧伤患者进行以下参数评估：（1）以多器官功能障碍综合征评分衡量的器官功能障碍严重程度表示的临床结局；（2）高度纯化的T细胞对抗CD3/抗CD4的增殖反应；（3）通过流式细胞术分析碘化丙啶染色的单核细胞减少的外周血单个核细胞（未刺激或对促有丝分裂刺激或Fas（CD95）刺激有反应）来确定凋亡水平。
在患者的T细胞中观察到广泛的凋亡水平。与正常志愿者的T细胞相比，所有创伤患者的T细胞凋亡均增加。然而，当患者的T细胞处于失能状态时，凋亡水平并未升高。事实上，最大失能点（最低增殖反应）与凋亡反应减弱相关。抗Fas抗体可刺激创伤患者反应性T细胞中的T细胞凋亡增加，但不能刺激最大失能的T细胞。这些数据表明，患者的T细胞失能不是刺激后凋亡性T细胞耗竭的直接结果。然而，后期出现T细胞失能的患者在临床过程中比从未经历过T细胞失能患者更早出现T细胞凋亡增加。
凋亡水平升高与创伤患者的不良结局无直接关联，也不是T细胞失能的直接原因。然而，在创伤后T细胞反应完全激活和扩增之前出现异常高水平的凋亡以及严重的T细胞耗竭，可能预示着失能和随后的器官衰竭。
