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Antigen-specific therapeutic approaches for autoimmunity

Abstract

The main function of the immune system in health is to protect the host from infection by microbes and parasites. Because immune responses to nonself bear the risk of unleashing accidental immunity against self, evolution has endowed the immune system with central and peripheral mechanisms of tolerance, including regulatory T and B cells. Although the past two decades have witnessed the successful clinical translation of a whole host of novel therapies for the treatment of chronic inflammation, the development of antigen-based approaches capable of selectively blunting autoimmune inflammation without impairing normal immunity has remained elusive. Earlier autoantigen-specific approaches employing peptides or whole antigens have evolved into strategies that seek to preferentially deliver these molecules to autoreactive T cells either indirectly, via antigen-presenting cells, or directly, via major histocompatibility complex molecules, in ways intended to promote clonal deletion and/or immunoregulation. The disease specificity, mechanistic underpinnings, developability and translational potential of many of these strategies remain unclear.

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Fig. 1: Transfer of unmodified or antigen-specific Treg cells, peptides, autoantigens or autoantigen-encoding DNA, or autoantigen-loaded vehicles.
Fig. 2: Immunological consequences of therapy as a function of antigenic specificity and site of antigen uptake.
Fig. 3: pMHC-based nanomedicines.

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Acknowledgements

We thank the members of our laboratories for their contributions and insights. The authors’ work summarized here was funded by the Canadian Institutes of Health Research (CIHR), Diabetes Canada, the Crohn’s and Colitis Foundation of Canada, the Multiple Sclerosis Society of Canada (MSSC), ISCIII and FEDER (PIE14/00027, PI15/0797), NEURON-ERANET (European Research Projects on Neuroinflammation; NEURON7-FP-715-018), the Ministerio de Economia y Competitividad of Spain (MINECO) and Generalitat de Catalunya (SGR and CERCA Programmes). P. Serra was an investigator of the Ramon y Cajal Re-integration Program and is supported by a JDRF Career Development Award. P. Santamaria was a Scientist of the Alberta-Innovates – Health Solutions (AI–HS) and a scholar of the Instituto de Investigaciones Sanitarias Carlos III. The JMDRC was supported by the Diabetes Association (Foothills) and currently by Diabetes Canada.

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Correspondence to Pau Serra or Pere Santamaria.

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P. Santamaria is scientific founder of Parvus Therapeutics Inc. and has a financial interest in the company.

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Serra, P., Santamaria, P. Antigen-specific therapeutic approaches for autoimmunity. Nat Biotechnol 37, 238–251 (2019). https://doi.org/10.1038/s41587-019-0015-4

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