Artikel
Reset of tolerance by ablation of a pathogenic memory in chronic autoimmune diseases
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Autoren
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Tobias Alexander
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Andreas Thiel
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin
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Lars Templin
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Gerd-Rüdiger Burmester
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
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Andreas Radbruch
- Deutsches Rheuma-Forschungszentrum (DRFZ), Berlin
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Renate Arnold
- Charité - Universitätsmedzin Berlin, Hämatologie und Onkologie, Berlin
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Falk Hiepe
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und klinische Immunologie, Berlin
| Veröffentlicht: | 4. September 2017 |
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Gliederung
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Background: Chronic immunosuppression and novel biologic therapies can suppress or attenuate the inflammatory process in autoimmune disease (ADs) as long as they are applied, but cannot switch off the underlying mechanisms to induce therapy-free remission, i.e., cure. In contrast, high-dose immunosuppression followed by autologous hematopoietic stem cell transplantation (ASCT) has been demonstrated to induce long-term treatment-free remissions in ADs.
Methods: Since 1998, 22 patients with different ADs received a CD34+-selected ASCT after immunoablation with ATG and cyclophosphamide at the Charité – University Medicine Berlin. Multiparametric flow cytometry was applied to characterize peripheral blood lymphocytes subsets including analysis of the TCR-Vbeta repertoire on CD4+ T cells, CD31 expression as marker for thymic output and Siglec-1 on monocytes as surrogate for interferon activity in SLE. Autoantibodies were investigated with ELISA.
Results: With a median follow-up of 132 months, 67.1% of patients achieved a progression-free survival despite discontinuation of chronic immunosuppression. Immunoablation was associated with significant reduction or even normalization of autoantibody levels and a profound reconfiguration of the adaptive immune system. Such immune reset was characterized by a reemergence of thymic-naïve CD31+ CD45RA+ T cells with absolute counts exceeding those of age-matched controls, recurrence of Helios+ natural regulatory T cells with renewed TCR repertoire as well as regeneration of naïve B-cells. In SLE patients, Siglec-1 expression on monocytes completely normalized.
Conclusion: Our data provide the „proof-of-concept“ that a pathogenic immunologic memory is an essential driver of chronic inflammation in ADs, which needs to be ablated for curative therapeutic approaches in autoimmunity. Re-indcution of self-tolerance depends on recurrence of naïve B cells and a stable thymic reactivation, providing a pool of naïve T cells, including Foxp3+ Helios+ regulatory T cells with new antigen receptors, i.e. immune reset.
