Nonobese diabetic (NOD) mice spontaneously develop autoimmune diabetes, bearing close resemblance to the human condition. The disease is mediated by auto-specific T cells, which infiltrate the pancreatic islets and destroy insulin-producing β cells. A hallmark of the disease is the de novo generation of lymph-node-like structures in the pancreas, which are essential for progression of the disease. A large body of evidence implicates lymphotoxin (LT) in the formation of these lymphoid structures and the production of follicular dendritic cells. In support of this notion, the ectopic expression of LT can result in the in situ generation of lymph-node-like organs in the periphery. Hence, it was supposed that the formation of organized lymphoid structures in the pancreas of NOD mice might be regulated by LT.The paper by Wu et al. 1xReversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. Wu, Q. et al. J. Exp. Med. 2001; 193: 1327–1332Crossref | PubMed | Scopus (88)See all References1 addresses the role of LT in autoimmune diabetes in NOD mice. Using a LTβ-receptor Ig fusion molecule, they blocked the function of LTβ at various time points during the life of NOD mice. Perhaps not surprisingly, they found that blocking LTβ in 3–4-week-old mice for approximately six weeks prevented the induction of diabetes. However unexpectedly, they were also able to prevent the induction of diabetes in older mice that already exhibited insulitis at the onset of therapy. Moreover, treatment for only three weeks was sufficient to reduce the severity of diabetes dramatically and essentially, reverse the insulitis. Thus, blocking LTβ was able to prevent diabetes even if therapy was started after the onset of autoimmunity.These observations indicate that in NOD mice, LT functions as a ‘master’ cytokine essential for the de novo formation of lymph-node-like structures in the pancreas during the disease process. The results make two important points. First, the presence of auto-specific T cells seems insufficient to induce autoimmunity. Target organs might need to be chronically inflamed and it seems that the generation of lymphoid follicles is necessary for overt disease. Thus, although priming of self-specific T cells might occur in the lymph nodes, the stimulation of T cells in the peripheral lymph-node-like structures appears to be essential for progression of the disease. Second, the results might be relevant to the therapy of type I diabetes in humans. Although it was not possible to reverse disease in mice with pre-existing diabetes, short-term therapy was able to cure mice exhibiting severe insulitis. Thus, the close monitoring of people at risk of developing type I diabetes might allow therapy to commence early enough to prevent or, at least, delay the onset of disease. Moreover, blocking LTβ might be a promising treatment for other autoimmune diseases, including Hashimoto's thyroiditis and arthritis.