Autologous hematopoietic stem cell transplantation in systemic sclerosis induces long-lasting changes in B cell homeostasis toward an anti-inflammatory B cell cytokine pattern

Gernert, Michael; Tony, Hans‐Peter; Schwaneck, Eva Christina; Gadeholt, Ottar; Schmalzing, Marc

doi:10.1186/s13075-019-1889-8

Cited by 42 publications

(39 citation statements)

References 43 publications

(50 reference statements)

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“…This notion is supported by the previous studies indicating that HSCT results in an active thymogenesis and increased production of naïve T-cells and restoration of immune repertoire after immune recovery approximately 2 years after transplant, resembling the activity level seen in young children 12 34. In a recent study, HSCT also led to a correction of dysfunctional B-cell homoeostasis in SSc by increasing naïve B-cells and decreasing memory, as well as CD27-/IgD double-negative B-cells 35…”

Section: Discussionsupporting

confidence: 63%

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures

et al. 2019

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ObjectiveIn the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) (NCT00114530), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study.MethodsGlobal transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples.ResultsAt the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score.ConclusionHSCT contrary to conventional treatment leads to a significant ‘correction’ in disease-related molecular signatures.

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Section: Discussionsupporting

confidence: 63%

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures

et al. 2019

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“…The immune reconstitution after aHSCT we present comprises increased B cell numbers, mainly due to increased naïve B cells (accompanied by decreased memory B cells) and decreased CD4 + T cells 1 year after aHSCT. This reconstitution pattern is comparable with previously reported SSc cohorts [ 22 , 23 ], even if different myeloablative protocols (without ATG) were used [ 23 ], and is in concordance with the reconstitution described in patients with systemic lupus erythematodes [ 24 ] and multiple sclerosis [ 25 ]. In contrast, patients with rheumatoid arthritis showed normalized levels of B cells 1 year after aHSCT, although a similar myeloablative protocol was performed [ 26 ].…”

Section: Discussionsupporting

confidence: 90%

Low B cell counts as risk factor for infectious complications in systemic sclerosis after autologous hematopoietic stem cell transplantation

et al. 2020

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Background: Autologous hematopoietic stem cell transplantation (aHSCT) is a treatment option for a selected group of systemic sclerosis (SSc) patients with good available evidence but can be associated with considerable morbidity and mortality. The aim of this study was to describe infectious complications and distinct immune reconstitution patterns after aHSCT and to detect risk factors in lymphocyte subsets, which are associated with an elevated rate of infections after aHSCT. Methods: Seventeen patients with SSc were included in this single-center retrospective cohort study. Clinical and laboratory data was collected before and for 12 months after aHSCT, including immunophenotyping of peripheral whole blood by fluorescence-activated cell sorting. Results: Cytomegalovirus (CMV) reactivations were common in CMV-IgG-positive patients (50%) and needed treatment. Mycotic infections occurred in 17.6%. One patient died (resulting in a mortality of 5.9%) due to pneumonia with consecutive sepsis. All patients showed decreased T helper cells (CD3 + /CD4 +) and within the B cell compartment decreased post-switched memory B cells (CD19 + /CD27 + /IgD −) and elevated naïve B cells (CD19 + / CD27 − /IgD +) until 12 months after aHSCT. Patients who developed infections had significantly lower B cells before aHSCT than patients who did not develop infections. Conclusion: After aHSCT, monitoring for infectious complications, especially for CMV reactivations, is crucial as the reconstitution of the immune system takes longer than 12 months. Low peripheral B cells might be a risk factor for an elevated infection rate.

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“…In patients with SSc that underwent autologous hematopoietic stem cell transplantation (aHSCT), a peak in the percentage of CD38++/CD10+/IgD+ transitional B cells and CD38++/CD27++/IgD−plasmablasts has been observed already one month after the procedure. These changes persisted for several months after aHSCT and were accompanied by an increased production of IL-10 [45]. As already mentioned for SLE, it has been also observed that SSc patients show altered number and function of IL-10 producing Breg cells [46][47][48].…”

Section: Systemic Sclerosissupporting

confidence: 57%

Is There a Future for Anti-CD38 Antibody Therapy in Systemic Autoimmune Diseases?

Benfaremo

Gabrielli

2019

Cells

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CD38 is a type II glycoprotein highly expressed on plasmablasts, short-lived and long-lived plasma cells, but weakly expressed on other lymphoid cells, myeloid cells and non-hematopoietic cells. This expression pattern makes CD38 an interesting target for a targeted therapy aiming to deplete antibody-producing plasma cells. We present data suggesting that anti-CD38 therapy may be effective for the prevention at the preclinical stage and for the treatment of established autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Given the high unmet need for efficacious disease-modifying treatment in these diseases, studies are warranted to determine if anti-CD38 antibody-based therapies may delay or prevent the disease progression of systemic autoimmune diseases.

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Autologous hematopoietic stem cell transplantation in systemic sclerosis induces long-lasting changes in B cell homeostasis toward an anti-inflammatory B cell cytokine pattern

Cited by 42 publications

References 43 publications

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures

Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures

Low B cell counts as risk factor for infectious complications in systemic sclerosis after autologous hematopoietic stem cell transplantation

Is There a Future for Anti-CD38 Antibody Therapy in Systemic Autoimmune Diseases?

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