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Antigen receptor genes exist in the germline in a “split” configuration and are assembled in developing B and T lymphocytes by V(D)J recombination. This site-specific recombination reaction is initiated by a complex containing the RAG1 and RAG2 proteins and completed by general DNA repair factors. RAG1 and RAG2, like the adaptive immune system itself, are found exclusively in jawed vertebrates, and are thought to have entered the vertebrate genome by horizontal transmission as components of a transposable element. This review discusses the structure of antigen receptor genes and the mechanisms by which they are assembled and diversified, and then goes on to consider the evolutionary implications of the arrival of the hypothetical “RAG transposon”. [Copyright &y& Elsevier]

Experimental autoimmune encephalomyelitis (EAE) is mediated by CD4+ T cells which preferentially use the Vβ8.2 TCR in response to myelin basic protein (MBP). Two strains of Tg mice (Vα2.3/Vβ8.2 and Vα4/Vβ8.2) have T cell receptors that recognize the NAc1-11 immunodominant epitope of MBP. We previously reported that oral administration of MBP protects both Vα2.3/Vβ8.2 and Vα4/Vβ8.2 mice from EAE; however, tolerance induction differs between strains and is dependent on the timing of oral antigen. Here we analyze the peripheral and gut-associated lymphoid tissue (GALT) environments of the two strains of Tg mice. Tg cells in the Peyer''s patch (PP) but not the spleen of Vα2.3/Vβ8.2 mice demonstrate increased CD69 and decreased CD45RB relative to Vα4/Vβ8.2 mice. High levels of Th1 and Th2 cytokines, proliferative activity and CC chemokines (MCP-1) are observed in the periphery and GALT of Vα2.3/Vβ8.2 Tg mice. In contrast, more non-Tg CD4+ cells are seen in the PP of Vα4/Vβ8.2 mice. These studies suggest that activated Tg T cells and fewer potential regulatory cells in the PP of Vα2.3/Vβ8.2 Tg mice may influence oral tolerance. [Copyright &y& Elsevier]

Interleukin 2 (IL-2) and interleukin 12 (IL-12) have potent anti-tumour activity as single agent therapy against several different murine and human tumours. Combining these cytokines may result in improved therapeutic effectiveness, however, the toxicity associated with simultaneous administration is prohibitive. This study was designed to determine the specific histopathologic changes associated with combination therapy. Mice were treated with 5 days of interleukin-2, interleukin-12, or both using standard doses and schedules. Histologic specimens were prepared from all internal organs on a daily basis to identify specific pathologic abnormalities. Treatment with interleukin-2, interleukin-12, or both resulted in pathologic insult to the liver and gastrointestinal tract. Mild lymphoplasmacytic infiltrates were seen in the liver. The most significant pathology was seen in the large bowel and consisted of apoptosis of colonic epithelial cells. While recovery of injured gastrointestinal mucosa occurred in mice treated with interleukin-2 or interleukin-12 alone, combination therapy resulted in death before recovery was possible. Combination interleukin-2 and interleukin-12 therapy results in irreversible injury of the colon as manifested by increased epithelial cell apoptosis and death in mice. Understanding the pathologic changes associated with combination cytokine therapy may lead to strategies that prevent toxicity while maintaining therapeutic effects. [Copyright &y& Elsevier]