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  • Perspective
  • Published:

Defining immune reset: achieving sustained remission in autoimmune diseases

Nature Reviews Immunology (2025)Cite this article

Abstract

Personalized cell therapies for autoimmune diseases — such as autologous haematopoietic stem cell transplantation and chimeric antigen receptor-expressing T cells — have the potential to achieve sustained remission in patients with certain autoimmune diseases. The effective elimination of pathogenic lymphocytes and their subsequent repopulation with naive cells has been termed ‘immune reset’. In this Perspective, we trace the origins of the immune reset concept and its clinical, cellular and molecular definitions, and we review current attempts to identify biomarkers for long-term clinical remission in autoimmune diseases. Emerging data from clinical trials support the concept that higher probabilities of long-term remission can be achieved with therapies that can more deeply and broadly deplete B cells than the anti-CD20 antibody rituximab. A better understanding of the cellular and molecular basis for immune reset and the biomarkers associated with this state should accelerate progress towards the goal of restoring a non-autoimmune state and sustaining remission, while reducing the need for chronic immunosuppression.

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Fig. 1: Working model of immune activation and immune reset.
Fig. 2: Marker expression and differentiation of B cells.
Fig. 3: Evolution of CAR constructs and therapeutic approaches for CAR T cell therapy.
Fig. 4: Positioning of immune reset and B cell depletion therapies.

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Acknowledgements

The authors thank J. Brogdon, D. Bu, B. Cenni, T. Chapuis, S. De Vita, S. Diehl, L. Gabryšová, I. Isnardi, J. Rohr and G. Wieczorek for the discussion.

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Authors and Affiliations

  1. BioMedical Research, Novartis Pharma AG, Basel, Switzerland

    Tobias Junt, Thomas Calzascia, Elisabetta Traggiai, André Nogueira da Costa, Peter Gergely & Richard M. Siegel

  2. Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

  3. Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

  4. Department of Rheumatology and Clinical Immunology, Charite Universitätsmedizin Berlin and Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany

    Thomas Dörner

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T.J., T.C., P.G. and R.M.S. conceived the article. T.J., T.C., E.T., A.N.d.C., P.G., G.S., T.D. and R.M.S. wrote the manuscript. T.J. and T.D. prepared display items with constructive input from T.C., E.T., A.N.d.C. and R.M.S. All authors contributed to editing and finalization of the content and approved the submitted version of the article.

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Competing interests

T.J., T.C., E.T., A.N.d.C., P.G. and R.M.S. are employees of Novartis Pharma AG and hold stock of the company. T.D. received honorary from Novartis, Sanofi, Roche/Genentech, AbelZeta, Amgen/Horizon and J&J for scientific advice. T.D. also received support for clinical studies (all paid to the university) from Novartis, Roche, BMS, J&J and Sanofi. G.S. has received speaker’s fees from Cabaletta, Janssen, Kyverna and Novartis.

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Junt, T., Calzascia, T., Traggiai, E. et al. Defining immune reset: achieving sustained remission in autoimmune diseases. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01141-w

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