Alexander Tobias

MD, Dr. med., Senior physician,
Head of the rheumatology specialized outpatient clinic, Department of Rheumatology and Clinical Immunology,
Charité – Universitätsmedizin Berlin, Germany.
Alexander Tobias
Berlin where he is heading the outpatient clinic. The focus of his clinical practice is connective tissue diseases and systemic vasculitis. His research is focused on the investigation of autoreactive immunologic memory in rheumatic diseases, biomarkers in inflammatory rheumatic diseases, new targeted therapeutic approaches for inflammatory and auto-immune diseases, regulatory T-cells and autoimmunity.
Immunological Reconstitution after
Autologous Stem Cell Transplantation
in Autoimmune Diseases
Sharing the Experience at International Conference in Moscow, Russia, November 2019
Over the past 20 years, immunoablation followed by transplantation of autologous hematopoietic stem cells (ASCT) has emerged as a promising treatment option for patients with severe forms of autoimmune diseases (ADs) that insufficiently respond to standard immunosuppressive or novel biologic treatment.

ASCT is performed with the premise to reconstitute, and ideally re-condition, the immune system towards a self-tolerant state by depleting the autoreactive immunologic memory with high- dose chemotherapy followed by a profound regeneration of a renewed and diverse immune system, i.e. 'immune reset'. In MS, a range of mechanistic studies post-transplant have shown that the T-cell repertoire, particularly of CD4+ T cells, may be almost completely renewed, its diversity increased and that new thymic output of T cells is achieved following ASCT. The analysis of TCR repertoires by deep sequencing confirms that ASCT induces the regeneration of circulating T-cell clones, more profoundly in the CD4+ T helper cell compartment. Early post-transplant T-cell repertoire diversity is associated with complete clinical responses during the 5- year follow-up. Other studies examined proinflammatory T-cell effector responses specifically, including Thl 7 cell frequency, the mRNA expression of their master regulator ROR[gamma]t and the production of the inflammatory cytokine IL-17A all decreased post-HSCT. Several additional immune mechanisms that may contribute to the efficacy of ASCT in MS have include depletion of peripheral blood mucosal-associated invariant T (MAIT) cells, decrease of MS- associated inflammatory micro RNAs (miR-155, miR142-3p, miR-16), along with increased immune T and NK regulatory cells and increased expression of immune checkpoint receptors and regulatory molecules such as PD1, CTLA-4, GITR and TGF-bl. Other neuroinflammatory diseases have not been studied to any significant extent in the context of immune reconstitution and further research is warranted. The collection of cellular, serum, plasma and CSF samples at baseline, during the immunosuppression-free remission and at relapse/progression for mechanistic and pathogenetic studies in accordance with regulatory requirements for tissue banking and ADWP guidelines is recommended.

Meanwhile, mechanistic studies have provided the proof-of-concept that the long-term, treatment-free remissions achieved by ASCT are associated with the eradication of the autoreactive immunologic memory and a fundamental reconfiguration of the immune system. The latter comprises regeneration of naive В cells and a stable thymic reactivation with re- emergence of thymic-derived naive T cells, including Foxp3+ regulatory T cells, with new antigen receptors, i.e. immune reset. In this presentation, mechanistic studies that investigated how such immune renewal after ASCT may rewire a faulty immune system in ADs into a self- tolerant state, to induce long-term remissions will be discussed.
Alexander Lila, Lidiya Ananieva, Evgeniy Nasonov
Scientific Research Institute of Rheumatology named after V.A. Nasonova of the Ministry of Healthcare of Russian Federation, Moscow, Russian Federation