Bottazzo G F, Bonifacio E, Wagner R, al-Sakkaf L, Dean B M, Mirakian R
Department of Immunology, University College, London.
Klin Wochenschr. 1990;68 Suppl 21:26-37.
The observations emerged from the pancreatic transplant experiments in identical twins indicate that Type I diabetic patients maintain memory cytotoxic T cells for several years and these can be "re-awakened" when Class I identical beta cells are re-introduced into the diabetic melieu. In addition, these data have shown that these lymphocytes can (in a matter of a few weeks) cause rapid irreversible decompensation of beta cell function. From this, an important lesson is learnt: cytotoxic T cells, when generated in sufficient number against beta cells do not leave much "breathing space" for these cells. This has important implications for explaining the long latency period preceding the acute onset of Type I diabetes. ICA, when produced, seem unable to cause gross damage to beta cells. They persist for several years in the blood, but beta cell function remains apparently unaltered. It is only when cytotoxic T cells, with fine specificity for beta cells are generated that the 'killing cycle' is completed. Whether these cells are present all the time, and kept under tight control by active suppressor mechanisms or whether they appear only after an environmental trigger (e.g., retroviruses) is unknown. If the former is the case, this would give strong support to the suggested important role of suppressor T cells in the pathogenetic circuit. Some evidence for this has been produced (rev. in [116]) but, obviously, it requires confirmation (see debate which followed [116]). If, on the other hand, the latter is experimentally confirmed, one can return to the theory that cytotoxic T cells acquire the characteristics of autoreactivity by expressing receptors on their surface in a configuration which enables combination with self-autoantigens (rev. in [45]). In summary, the study of the etiopathogenesis of Type I diabetes and human autoimmunity in general has attracted a great deal of interest among immunologists. It is only by further dissecting the various limbs of the undesirable immune response against beta cells and, by trying to formulate novel hypotheses, sometimes against accepted dogmas [32], that the complete picture will be finally disclosed. At this stage it will be possible to design effective therapy trials, so that Type I diabetes and other related autoimmune disorders ultimately may be prevented.
在同卵双胞胎胰腺移植实验中得出的观察结果表明，I型糖尿病患者体内的记忆性细胞毒性T细胞可维持数年，当I类相同的β细胞重新引入糖尿病环境时，这些细胞可被“重新唤醒”。此外，这些数据表明，这些淋巴细胞可（在几周内）导致β细胞功能迅速发生不可逆的失代偿。由此得到一个重要教训：针对β细胞产生足够数量的细胞毒性T细胞时，不会给这些细胞留下太多“喘息空间”。这对于解释I型糖尿病急性发作前的长时间潜伏期具有重要意义。ICA产生时，似乎无法对β细胞造成严重损害。它们在血液中持续数年，但β细胞功能显然仍未改变。只有当对β细胞具有精细特异性的细胞毒性T细胞产生时，“杀伤循环”才会完成。这些细胞是否一直存在，并受到活跃抑制机制的严格控制，或者它们是否仅在环境触发因素（如逆转录病毒）出现后才出现，目前尚不清楚。如果是前一种情况，这将有力支持抑制性T细胞在发病机制中所起重要作用的观点。对此已有一些证据（见[116]中的综述），但显然还需要证实（见[116]之后的讨论）。另一方面，如果后一种情况得到实验证实，人们可以回归到这样一种理论，即细胞毒性T细胞通过在其表面表达能够与自身自身抗原结合的构型的受体而获得自身反应性特征（见[45]中的综述）。总之，I型糖尿病和一般人类自身免疫性疾病的病因发病机制研究引起了免疫学家的极大兴趣。只有通过进一步剖析针对β细胞的不良免疫反应的各个环节，并尝试提出新的假设，有时甚至与公认的教条相悖[32]，最终才能揭示全貌。到那时，才有可能设计有效的治疗试验，从而最终预防I型糖尿病和其他相关自身免疫性疾病。
