ATTENUATION OF INDUCIBLE TH2 IMMUNITY WITH AUTOIMMUNE-DISEASE PROGRESSION

Autoantigen-based immunotherapeutics have been shown to activate regul atory responses capable of inhibiting T cell-mediated autoimmune disea se in animal models. However, their efficacy generally declines, as tr eatment occurs later in the disease process, and their mechanism of ac tion is a matter of intense debate. Here, me report that the early adm inistration of beta cell autoantigens (beta CAAs) to nonobese diabetic (NOD) mice broadly diverts the natural development of potentially pat hogenic Th1-biased autoimmune responses toward the Th2 phenotype throu gh Th2 spreading. With disease progression, there was a steady decline in the ability of beta CAA treatment to promote Th2-type cellular and humoral autoimmunity. Late in the disease process, some beta CAAs wer e still able to induce Th2 responses and Th2 spreading (although to a much lesser extent), while other autoantigens were not. This attenuati on of inducible Th2 immunity with disease progression is likely to ref lect a reduction in the availability of uncommitted autoantigen-reacti ve precursor T cells. These findings suggest that there are inherent d ifferences in the frequency of beta CAA-reactive T cells and that, in advanced stages of autoimmune disease, regulatory responses may be bes t elicited with target tissue Ags against which large uncommitted T ce ll pools are still available, Since individuals presenting the first s igns of autoimmune disease are likely to already have an advanced dise ase process, these findings may be useful for the rational design of A g-based immunotherapeutics.