Roep Bart O
Department of Immunohaematology and Blood Transfusion, E3-Q, Leiden University Medical Center, PO Box 9600, NL-2300 RC Leiden, The Netherlands.
Novartis Found Symp. 2008;292:159-71; discussion 171-3, 202-3. doi: 10.1002/9780470697405.ch15.
Type 1 diabetes results from a T cell-mediated autoimmune destruction of the insulin-producing pancreatic beta cells in subjects with a genetic predisposition to this disease. Therapies directed against T cells have been shown to halt the disease process and prevent recurrent beta cell destruction after islet transplantation. Less is known about the mechanisms by which T cell-targeted therapies modify disease, how the immune system may suppress autoreactivity, and whether (or which) autoantigen(s) are critically involved in disease modulation. Autoreactive T cells have proven to be valuable tools to study pathogenic or diabetes-related processes. Measuring T cell autoreactivity has also provided critical information to determine the fate of islet allografts transplanted to type 1 diabetic patients. Unfortunately, cellular autoimmunity is a difficult study subject, and most activities were aiming at defining disease-associated T cell responses. A perhaps even more important goal will be to define and measure changes in T cell autoimmunity that are associated with disease intervention following immunotherapy, as autoantibodies do not qualify for this purpose. Recently, we have identified immune markers that associate with remission after initiation of insulin therapy ('honeymoon'), and disease suppression with antibody therapy (ATG, daclizumab, anti-CD3) or islet autoantigen. The challenge for the future is to determine which immune factors associate with tolerance to beta cell antigens, and to define what measures T cells can provide to suppress autoreactivity.
1型糖尿病是由T细胞介导的自身免疫性破坏所致，这些自身免疫性破坏发生在对该疾病具有遗传易感性的个体的胰岛素分泌胰腺β细胞中。针对T细胞的疗法已被证明可阻止疾病进程，并防止胰岛移植后β细胞的反复破坏。对于以T细胞为靶点的疗法改变疾病的机制、免疫系统如何抑制自身反应性以及自身抗原是否（或哪些）在疾病调节中起关键作用，人们了解较少。事实证明，自身反应性T细胞是研究致病或糖尿病相关过程的宝贵工具。测量T细胞自身反应性也为确定移植到1型糖尿病患者体内的胰岛同种异体移植物的命运提供了关键信息。不幸的是，细胞自身免疫是一个难以研究的课题，大多数研究活动旨在确定与疾病相关的T细胞反应。一个可能更重要的目标将是确定和测量与免疫治疗后疾病干预相关的T细胞自身免疫变化，因为自身抗体不适合用于此目的。最近，我们已经确定了与胰岛素治疗开始后的缓解（“蜜月期”）以及抗体治疗（抗胸腺细胞球蛋白、达利珠单抗、抗CD3）或胰岛自身抗原导致的疾病抑制相关的免疫标志物。未来的挑战是确定哪些免疫因素与对β细胞抗原的耐受性相关，并确定T细胞可以采取哪些措施来抑制自身反应性。
