Artikel
Resetting the immune system with immunoablation followed by autologous stem cell transplantation is associated with long-term remissions in SLE
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Veröffentlicht: | 8. Oktober 2019 |
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Gliederung
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Background: Our previous studies provided the proof-of-concept that depletion of the autoreactive immunologic memory by immunoablation followed by transplantation of autologous hematopoietic stem cells (ASCT) is associated with a “reset” of the immune system in systemic autoimmune diseases. Here, we aimed to analyze the long-term immune reconstitution in 10 SLE patients receiving ASCT in our institution.
Methods: Autoantibody titers were evaluated with ELISA, peripheral blood lymphocyte subsets immunophenotyped using multicolor flow cytometry, including Siglec-1 expression on CD14+ monocytes (as IFN surrogate) and assessment of TCR Vβ repertoire. Serum levels of IFN2a were investigated with the DELFIA assay (Miltenyi Biotec). In addition, the gene expression profile was analyzed with Microarray (Affymetrix) in FACS-sorted CD14+ monocytes from SLE patients after ASCT, compared with SLE patients with active disease and healthy controls.
Results: Clinical remission (clinical SLEDAI=0) could be achieved in all patients, despite immunosuppressive drug withdrawal, associated with disappearance of anti-dsDNA antibodies and marked reduction of protective antibodies in serum. Transplant-related mortality (TRM) occurred in 2 cases. From the remaining eight patients, five patients are in long-term clinical remission for up to 20 years after HSCT, while three patients suffered a relapse of SLE at 18, 36 and 80 months post-transplantation, respectively. Immune reconstitution was characterized by stable thymic reactivation with recurrence and persistence of CD31+ recent thymic emigrants with absolute numbers exceeding those in age-matched healthy controls, including Helios+ natural Tregs. Initially disturbed T cell repertoire normalized on conventional and regulatory T cells. Serum IFN2a levels significantly decreased from a median 43.1pg/ml at baseline to 3.01 pg/ml at 2 years after HSCT (p<0.001) and Siglec-1 expression on monocytes completely normalized. Compared to patients with active SLE, the IFN signature (cut-off of fold change ≥2 or ≤2) in monocytes from ASCT-treated patients decreased down to 24% (77/320) and clustered with healthy controls, suggesting a normalization of type I IFN signature.
Conclusion: Resetting the immune system with ASCT is associated with a vast immunodepletion and a profound reconfiguration of the adaptive immune system and complete normalization of the IFN signature in SLE providing long-term clinical remissions despite discontinuation or chronic immunosuppression.