Article
Normalization of type I interferon (IFN) signature after “immune reset” with immunoablation and autologous stem cell transplantation in systemic lupus erythematosus (SLE)
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Published: | September 12, 2014 |
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Objective: Our previous research provided the evidence that an autoreactive immune system can be “reset” into a healthy, tolerant state by immunoablative treatment to eradicate pathogenic effector cells, followed by transplantation of hematopoietic progenitor. Recently, gene expression profiling in peripheral blood revealed an up-regulation of type I interferon (IFN) related genes in systemic lupus erythematosus and their first-degree relatives. Here, we aimed to analyze the IFN signature in SLE patients after receiving HSCT to evaluate whether IFN signature is normalized after “immune reset” or is permanently present, resembling a heritable trait.
Methods: Since 1998, ten patients with treatment-refractory SLE received a CD34+-selected autologous stem cell transplantation after immunoablation with antithymocyte-globulin (ATG-Fresenius, 90mg/kg) and cyclophosphamide (200mg/kg) as part of a monocentric phase I/II clinical trial. Siglec-1 expression on CD14+ monocytes (as IFN surrogate) was analyzed longitudinally using flow cytometry. In addition, gene expression profile was analyzed with Microarray (Affymetrix) from purified CD14+ monocytes (FACSAria cell sorter) and compared to active SLE and healthy donors.
Results: Clinical remission (SLEDAI ≤3) was achieved in all patients despite immunosuppressive drug withdrawal, associated with disappearance of anti-dsDNA antibodies. Two patients died from transplant-related infections; from the remaining eight patients, five are in long-term clinical remission for up to 15 years after HSCT, while three patients suffered a relapse of SLE. Siglec-1 expression on monocytes, which is increased in active SLE, completely normalized in responding patients after HSCT and was only elevated during viral infections. Based on gene expression profiling, the number of IFN signature probe-sets with a cut-off of fold change ≥2 or ≤2 was decreased down to 24% (77/320) in patients after HSCT compared to active SLE and completely clustered with healthy controls suggesting a normalization of type I IFN signature.
Conclusion: The normalization of type I IFN signature observed in responding patients after HSCT suggests that up-regulation of IFN-related genes is not a predisposition but rather the consequence of chronic autoimmunity in SLE. Apparently, immunoablation resets the innate immune system into a self-tolerant state where even up-regulation of IFN during viral infections is not associated with reactivation of SLE.