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IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H).
J Clin Invest. 2009 Jul; 119(7):2052-61.JCI

Abstract

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.

Authors+Show Affiliations

Department of Clinical Neuroscience, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. jls53@medschl.cam.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19546505

Citation

Jones, Joanne L., et al. "IL-21 Drives Secondary Autoimmunity in Patients With Multiple Sclerosis, Following Therapeutic Lymphocyte Depletion With Alemtuzumab (Campath-1H)." The Journal of Clinical Investigation, vol. 119, no. 7, 2009, pp. 2052-61.
Jones JL, Phuah CL, Cox AL, et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009;119(7):2052-61.
Jones, J. L., Phuah, C. L., Cox, A. L., Thompson, S. A., Ban, M., Shawcross, J., Walton, A., Sawcer, S. J., Compston, A., & Coles, A. J. (2009). IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). The Journal of Clinical Investigation, 119(7), 2052-61. https://doi.org/10.1172/JCI37878
Jones JL, et al. IL-21 Drives Secondary Autoimmunity in Patients With Multiple Sclerosis, Following Therapeutic Lymphocyte Depletion With Alemtuzumab (Campath-1H). J Clin Invest. 2009;119(7):2052-61. PubMed PMID: 19546505.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). AU - Jones,Joanne L, AU - Phuah,Chia-Ling, AU - Cox,Amanda L, AU - Thompson,Sara A, AU - Ban,Maria, AU - Shawcross,Jacqueline, AU - Walton,Amie, AU - Sawcer,Stephen J, AU - Compston,Alastair, AU - Coles,Alasdair J, Y1 - 2009/06/22/ PY - 2008/10/27/received PY - 2009/04/15/accepted PY - 2009/6/24/entrez PY - 2009/6/24/pubmed PY - 2009/7/31/medline SP - 2052 EP - 61 JF - The Journal of clinical investigation JO - J. Clin. Invest. VL - 119 IS - 7 N2 - Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity. SN - 1558-8238 UR - https://www.unboundmedicine.com/medline/citation/19546505/IL_21_drives_secondary_autoimmunity_in_patients_with_multiple_sclerosis_following_therapeutic_lymphocyte_depletion_with_alemtuzumab__Campath_1H__ L2 - https://doi.org/10.1172/JCI37878 DB - PRIME DP - Unbound Medicine ER -