Search

Regulatory T cells are crucial for preventing autoimmunity, but how their function is restrained to allow optimal effector T cells responses in appropriate contexts is unclear. In a recent paper in the Journal of Experimental Medicine, Campbell and colleagues demonstrate that virus-induced type I interferon acts directly on Treg cells to allow for functional antiviral T cell responses.

Several studies have suggested that some viruses use superantigens to modulate immune responses in humans. However, the identification and characterization of putative viral superantigens has proven to be very difficult. Two recent papers confirm the presence of an endogenous retroviral superantigen in humans, and show that its expression can be induced by secondary viral infections. The up-regulation of expression of endogenous retroviral superantigens has substantial implications for understanding the pathology of virus infections and human disease.

1998 marked the bicentennial for the publication of Edward Jenner's first manuscript on successful immunization against smallpox – a manuscript that changed modern medicine forever and the course of human history. It is amazing to think that more than two hundred years had to pass until the potential of the concept of immunization would begin to be realized for non-infectious diseases. Alzheimer's disease (AD), the most widespread and one of the most devastating neurological disorders, remains without effective cure. The culprit of AD is β-amyloid (Aβ), a fibrillar 40–42 amino-acid peptide accumulating in the brains of AD patients and eliciting neuronal cell death. The past two years has witnessed a flood of papers, following the pioneering work of Dale Schenk and his colleagues from Elan Pharmaceuticals (Dublin, Ireland), and addressing the potential of immunization with Aβ itself for slowing amyloid deposition in animal AD models. The logic behind this scheme is that immunization will stimulate the immune system to fight the abnormal pathologies associated with Aβ and thereby accelerate removal of the amyloid plaques. However, concern has been raised that immunization of AD patients with Aβ might initially accelerate the brain's amyloid deposition process, as the peptide crosses the blood–brain barrier and could seed further fibril formation and further neuronal death. Even without this extra risk, the notion of immunization with a toxic peptide does not sound very attractive.A new study by Sigurdsson et al. 1xImmunization with a nontoxic/nonfibrillar amyloid-β homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Sigurdsson, E.M. et al. Am. J. Pathol. 2001; 159: 1–9Abstract | Full Text | Full Text PDFSee all References1 presents new hopes that this concern will soon be resolved. The study employed immunization with an alternative peptide K6Aβ1-30-NH2 that is similar to Aβ, highly soluble in water (unlike natural Aβ), includes the immunogenic Aβ1–11 and Aβ22–28 regions yet is entirely nontoxic and nonfibrillar. Repeated immunization with this Aβ-like peptide reduced amyloid deposition in brains of transgenic Tg2576 APP mice–animals frequently used as an AD model because of their similar brain pathology. After 7 months from the beginning of the protocol, the immunized mice demonstrated a reduced burden of Aβ plaques in both the cortical and hippocampal regions of the brain.It remains to be seen whether this immunization method will also diminish the AD-like memory impairment observed in similar AD animal models. Hopefully, this new approach will open the door for safer human trials in AD patients. Jenner's legacy seems to have been awakened and is thriving – this could trumpet the dawn of a new exciting chapter in modern medicine, where non-infectious diseases, possibly including stroke and nerve trauma 2xProtective autoimmunity: regulation and prospects for vaccination after brain and spinal cord injuries. Schwartz, M. and Kipnis, J. Trends Mol. Med. 2001; 7: 252–258Abstract | Full Text | Full Text PDF | PubMed | Scopus (118)See all References2, will become treatable by vaccination.

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.