Grave effects of a specific immune therapy

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Science Translational Medicine  30 Nov 2016:
Vol. 8, Issue 367, pp. 367ec192
DOI: 10.1126/scitranslmed.aal2801

Autoimmune diseases typically result from the actions of only a few immune cells. Approaches to treat these diseases have generally been unable to specifically target only the harmful immune cells and instead have relied on treatments that broadly suppress immune function. An approach to alter immunity against only specific, targeted antigens that are seen by disease-causing cells would be preferred and could be expected to have fewer side effects; however, most autoimmune diseases involve multiple antigens that drive pathology, making it difficult to develop and assess a single target. Using a model of Graves’ disease, in which targeting of the thyroid stimulating hormone receptor (TSH-R) by autoantibodies is the sole pathogenic interaction, Rapoport and colleagues have explored the potential of an antigen specific immune therapy.

To advance their studies, the group developed a spontaneous model of Graves’ disease in which the disease-susceptible murine stain NOD.Hb4 transgenically expressed the human TSH-R; this spontaneous model is more similar to the disease process in humans than previously studied “induced” models. The A-subunit of the hTSH-R was used as the antigen-specific treatment in a fashion similar to an allergy shot. In nontransgenic animals, antigen injection induced antibodies, but these antibodies were not pathogenic. This deviation of the immune response to nonpathogenic specificities is thought to be one mechanism of disease protection. However, injection of transgenic animals substantially increased the production of pathogenic antibodies, which stimulated thyroid activity in an ex vivo assay. The authors suggest that the transgenic expression of the hTSH-R may influence B lymphocyte development to produce more reactive precursors that respond pathologically to the antigen injection.

This study points to the significant risks of antigen exposure during autoimmune disease progression. This same antigen injection had some capacity to prevent Graves’ disease when given before immune activation in an induced model, suggesting that antigen-specific immune therapy may become harmful as the immune response progresses. In addition, the authors found expression of significant levels of the hTSH-R in the transgenic thymus. How thymic hTSH-R alters the development of regulatory and effector T cells that modulate the B cell response is an important area for further investigation. Understanding the roles played by lymphocyte responders and their interactions may enable improved, safer design of antigen-specific therapy to realize the goal of tolerance induction.

B. Rapoport et al., Critical differences between induced and spontaneous mouse models of Graves’ disease with implications for antigen-specific immunotherapy in humans. J. Immunol. 10.4049/jimmunol.1601393 (2016). [Abstract]

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