The defective bone marrow-derived mesenchymal stem cells in patients with chronic immune thrombocytopenia

Zhang, Donglei; Li, Huiyuan; Ma, Li; Zhang, Xian; Xue, Feng; Zhou, Zeping; Cheng, Ying; Liu, Xiaofan; Huang, Yueting; Yang, Yanhui; Yang, Renchi

doi:10.3109/08916934.2014.938320

Cited by 30 publications

(38 citation statements)

References 54 publications

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“…Our previous study (Zhang et al , ) showed that MSCs from ITP patients displayed enhanced senescence and apoptosis and showed a lower capacity for inhibiting the proliferation of activated T cells, inducing regulatory T cells (Tregs) and suppressing the synthesis of anti‐glycoprotein (GP)IIb‐IIIa antibodies. Thus, it was confirmed that BM‐MSCs were defective in chronic ITP patients (Zhang et al , ).…”

mentioning

confidence: 76%

Mesenchymal stem cell deficiency influences megakaryocytopoiesis through the TNFAIP3/NF‐κB/SMAD pathway in patients with immune thrombocytopenia

Feng

et al. 2018

Br J Haematol

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Immune thrombocytopenia (ITP) is an autoimmune disease. Mesenchymal stem cells (MSCs) play important roles in the physiology and homeostasis of the haematopoietic system, including supporting megakaryocytic differentiation from CD34 haematopoietic progenitor cells. Tumour necrosis factor alpha-induced protein 3 (TNFAIP3, also termed A20) plays a key role in terminating NF-κB signalling. Human genetic studies showed that the polymorphisms of the TNFAIP3 gene may contribute to ITP susceptibility. In this study, we showed a significant decrease in TNFAIP3 and increase in NF-κB/SMAD7 in ITP-MSCs. In co-cultures with CD34 cells, NF-κB was overexpressed in MSCs from healthy controls (HC-MSCs) after transfection with NFKBIA (IκB)-specific short hairpin (sh)RNAs, resulting in MSC deficiency and a reduction in megakaryocytic differentiation and thrombopoiesis. Knockdown of TNFAIP3 expression using TNFAIP3-specific shRNAs in HC-MSCs affected megakaryocytopoiesis. However, IKBKB knockdown corrected megakaryocytopoiesis inhibition in the ITP-MSCs by decreasing NF-κB expression. Amplified TNFAIP3 expression in ITP-MSCs by TNFAIP3 cDNA can facilitate megakaryocyte differentiation. shRNA-mediated knockdown of SMAD7 expression rescued the impaired MSC function in ITP patients. Therefore, we demonstrate that a pathological reduction in TNFAIP3 levels induced NF-κB/SMAD7 pathway activation, causing a deficiency in MSCs in ITP patients. The ability of ITP-MSCs to support megakaryocytic differentiation and thrombopoiesis of CD34 cells was impaired.

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mentioning

confidence: 76%

Mesenchymal stem cell deficiency influences megakaryocytopoiesis through the TNFAIP3/NF‐κB/SMAD pathway in patients with immune thrombocytopenia

Feng

et al. 2018

Br J Haematol

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“…The reason for the decreased number of Ts cells is currently unknown. We speculated that decreased plasma IL10 and TGFB1 concentrations and the impaired immune regulated ability of bone marrow‐derived mesenchymal stem cells could, at least, partly explain the reasons (Andersson et al , ; Zhang et al , ). Consistent with the literature, we also found a positive correlation between age and the percentage of CD8 + CD28 − Ts cells in controls but not in ITP patients (Bandres et al , ; Vallejo, ).…”

Section: Discussionmentioning

confidence: 99%

Numerical and functional defects in CD8⁺CD28⁻ T‐suppressor lymphocytes from patients with primary immune thrombocytopenia

Hao

Zhang

et al. 2017

Br J Haematol

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Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, and loss of immune tolerance has been implicated in ITP pathogenesis. CD8 CD28 suppressor (Ts) cells have an immunosuppression function and are involved in several autoimmune disorders. However, the role of Ts cells in ITP is currently not clear. Here, flow cytometry was used to detect the CD8 CD28 CD127 proportion, which was decreased in active ITP patients compared with that of controls. Function analysis showed that immunosuppression of CD8 CD28 Ts cells in ITP patients was impaired. Mechanistic studies have shown that CD8 CD28 Ts cells from controls can downregulate CD80 and upregulate LILRB4 (ITL3) and LILRB2 (ILT4) expression on CD14 monocytes, whereas these abilities were not found in Ts cells from ITP patients. Furthermore, Inducible T-cell costimulatory (ICOS) expression on the Ts cell surface after activation was decreased whereas programmed death 1 and interleukin 10 expression was not changed in ITP patients compared with those of controls. In summary, the down-regulated quantity and function of Ts cells in active patients indicated that a Ts defect was involved in ITP. Moreover, decreased ICOS expression and the loss of the ability to regulate co-stimulator expression on antigen-presenting cells partly explained the defective Ts-mediated suppression.

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“…This will increase patient willingness to get free of steroids when possible, helping physician to limit the continuum damage accrual of SLE patients. References: [1] …”

Section: Disclosure Of Interestmentioning

confidence: 99%

“…The use of corticosteroids (CS) increases the risk of osteoporosis induced by corticosteroid (GIOP) and FF [1]. Denosumab is monoclonal antibody that binds to RANKL, inhibiting osteoclast formation and activation, used for both male and women OP to prevent FFx [2,3].…”

Section: Introductionmentioning

confidence: 99%

AB0449 Off label of biolologics in connective tissue diseases. a single center experience

Orsolini

Crowson

Viapiana

et al. 2017

Abstracts Accepted for Publication

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BackgroundConnective tissue diseases (CTDs) are a broad spectrum of autoimmune conditions including different entities such as systemic sclerosis (SSc), Sjogren syndrome (SSj), systemic lupus erythematosus (SLE) and autoimmune myositis. There are many patients that do not meet the classification or diagnostic criteria and they fall under the diagnosis of Undifferentiated connective tissue disease (UCTD). Treatment of refractory forms of these could be challenging and clinicians sometimes are forced to try off label drugs such as biologics on the basis of scarce literature support and the experience on different rheumatic disease.ObjectivesTo evaluate duration of biologic drug administered off label for the treatment of CTD and investigate variables possibly associated to drug suspension.MethodsWe used ACE program to search among Mayo Clinic clinical records all the patients that had in their records the words “undifferentiated connective tissue disease” or “lupus” or “myositis” or “Sjogren” or “systemic sclerosis” or “scleroderma”(and acronyms) AND “infliximab” or “etanercept” or “golimumab” or “certolizumab” or “tocilizumab” or “abatacept” or “adalimumab” (and their brand names).All records were checked for definite diagnosis and patients with uncertain ones where excluded. Also medications were checked, patients without any information about treatments where excluded. All the records of the selected patients were used to collect information about the off label biologic treatment but also clinical, serological and demographic variables.ResultsWe collected data on 122 patients with connective tissue diseases, some of them had other concomitant autoimmune diseases with indication for biologic treatment (e.g. rheumatoid arthritis, etc). We analyze the group with some CTD alone (n=72) considering SLE (n=18 – 25%), inflammatory myositis (n=22 – 31%) and UCTD (n=32 – 44%). In this group the first biologic was etanercept in 55%, adalimumab in 18%, infliximab in 17%, golimumab in 1% and abatacept in 8%. The 22% tried also a second biologic and 4% a third. We consider for analysis the first treatment.Mean treatment duration was 0.8 (±1.1)years. In our population 12,5% experienced a flare of CTD, 12,5% had infections, 18% had allergic reactions (of any type). The 44% experienced primary failure, 11% loss of efficacy, 31% had minor adverse events, 14% major ones (possible more than one reason for interruption).Analysis showed no definite factors correlated with treatment duration or failure or adverse events, No difference due to type of CTD.ConclusionsThe study is retrospective and this limits the conclusions to be taken from it, however is one of largest population of off label treatments in CTDs so far. Due to retrospective data we choose as outcome only treatment duration and adverse events, direct outcomes of efficacy were impossible to evaluate. Our results indicates a poor treatment duration of biologics given off label in CTDs with a relevant prevalence of adverse events and failures. It has to be underlined that ou...

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The defective bone marrow-derived mesenchymal stem cells in patients with chronic immune thrombocytopenia

Cited by 30 publications

References 54 publications

Mesenchymal stem cell deficiency influences megakaryocytopoiesis through the TNFAIP3/NF‐κB/SMAD pathway in patients with immune thrombocytopenia

Mesenchymal stem cell deficiency influences megakaryocytopoiesis through the TNFAIP3/NF‐κB/SMAD pathway in patients with immune thrombocytopenia

Numerical and functional defects in CD8⁺CD28⁻ T‐suppressor lymphocytes from patients with primary immune thrombocytopenia

AB0449 Off label of biolologics in connective tissue diseases. a single center experience

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The defective bone marrow-derived mesenchymal stem cells in patients with chronic immune thrombocytopenia

Cited by 30 publications

References 54 publications

Mesenchymal stem cell deficiency influences megakaryocytopoiesis through the TNFAIP3/NF‐κB/SMAD pathway in patients with immune thrombocytopenia

Mesenchymal stem cell deficiency influences megakaryocytopoiesis through the TNFAIP3/NF‐κB/SMAD pathway in patients with immune thrombocytopenia

Numerical and functional defects in CD8+CD28− T‐suppressor lymphocytes from patients with primary immune thrombocytopenia

AB0449 Off label of biolologics in connective tissue diseases. a single center experience

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Numerical and functional defects in CD8⁺CD28⁻ T‐suppressor lymphocytes from patients with primary immune thrombocytopenia