A Balancing Act

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Science  07 Jul 2006:
Vol. 313, Issue 5783, pp. 19
DOI: 10.1126/science.313.5783.19c

The intention of the recent TeGenero monoclonal antibody trial was to test the down-modulation of the chronic T cell activation underlying many inflammatory disorders. Crucially, the trial was based on preclinical data showing that a superagonist for the T cell costimulatory molecule CD28 would preferentially tilt the immunological balance in favor of suppressive T cell responses. However, the devastating outcome of the trial was wholesale acute T cell activation, serving to underscore how widely the activity of such reagents can vary under different conditions. Similarly, the clinically approved monoclonal antibody OKT3 can block T cell activity in certain settings, although scope for its therapeutic application is constrained by long-term effects associated with T cell activation.

By administering a CD3-specific antibody orally rather than systemically, Ochi et al. were able to inhibit the onset and to treat therapeutically experimental autoimmune encephalitis in mice. These effects corresponded with uptake of the antibody by gut-associated lymphoid tissue, leading to the activation of mucosal regulatory T cells, which expressed latency-associated peptide and inhibited the T cell-mediated pathology via the cytokine transforming growth factor-β. This mechanism is distinct from the recognized depletion of T cells observed with systemic intravenous administration of a CD3-specific antibody. Thus, the results further highlight the profound divergence between the immune environments of the periphery and the mucosa. — SJS

Nature Med. 12, 627 (2006).

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