Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE). Vitamin D is known to reduce responsiveness of healthy donor DCs to the ...stimulatory effects of Type I IFN. As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFNalpha amplification loop in SLE. Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFNalpha-regulated genes in vitro.
In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients. Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml. The degree of vitamin D deficiency correlated inversely with disease activity; R = -.234, p = .002. In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype. Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D. Additionally, vitamin D conditioning reduced expression of IFNalpha-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma.
We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity. Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation. We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFNalpha activity in vivo and, most importantly, improves clinical outcome.
Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies and systemic inflammation that results in part from dendritic cell activation by nucleic acid containing immune ...complexes. There are many mouse models of lupus, some spontaneous and some induced. We have been interested in an induced model in which estrogen is the trigger for development of a lupus-like serology. The R4A transgenic mouse expresses a transgene-encoded H chain of an anti-DNA Ab. This mouse maintains normal B cell tolerance with deletion of high-affinity DNA-reactive B cells and maturation to immunocompetence of B cells making nonglomerulotropic, low-affinity DNA-reactive Abs. When this mouse is given estradiol, normal tolerance mechanisms are altered; high-affinity DNA-reactive B cells mature to a marginal zone phenotype, and the mice are induced to make high titers of anti-DNA Abs. We now show that estradiol administration also leads to systemic inflammation with increased B cell-activating factor and IFN levels and induction of an IFN signature. DNA must be accessible to B cells for both the production of high-affinity anti-DNA Abs and the generation of the proinflammatory milieu. When DNase is delivered to the mice at the same time as estradiol, there is no evidence for an abrogation of tolerance, no increased B cell-activating factor and IFN, and no IFN signature. Thus, the presence of autoantigen is required for positive selection of autoreactive B cells and for the subsequent positive feedback loop that occurs secondary to dendritic cell activation by DNA-containing immune complexes.
Summary Large body of clinical and scientific data has been generated since the first cord blood transplantation (CBT) was performed in 1989. Superior immune plasticity of CB grafts, that allows for ...less stringent HLA matching, is especially valuable in the face of a persistently growing need for unrelated donor (UD) transplants. Limited cell dose remains the main setback of CBT, particularly in adult population. New strategies, such as transplantation with two cord blood units or using non-myeloablative conditioning, have remarkably expanded the availability of CB transplants in adults with hematological malignancies. Clinical trials with in vitro expanded CB-derived stem cells are under way. Currently cord blood is considered a second best choice after matched bone marrow. However, results of recent international studies indicate that in particular clinical settings, such as in children with leukemia, CB may become a frontline hematopoietic stem cell (HSC) source for transplantation. Recent advances in understanding the unique biology of cord blood will further expand indications for its use in different settings, including those beyond hematopoietic stem cells transplantation (HSCT).
Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma (MM) but is associated with an increased risk of venous thromboembolism (VTE). This prospective, open-label, ...randomized substudy of a phase 3 trial compared the efficacy and safety of thromboprophylaxis with low-dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in patients with newly diagnosed MM, treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation. Overall, 342 patients who did not have clinical indications or contraindications to antiplatelet or anticoagulant therapy were randomly assigned to receive ASA 100 mg/d (n = 176) or LMWH enoxaparin 40 mg/d (n = 166). The incidence of VTE was 2.27% in the ASA group and 1.20% in the LMWH group. Compared with LMWH, the absolute difference in the proportion of VTE was 1.07% (95% confidence interval, −1.69-3.83; P = .452) in the ASA group. Pulmonary embolism was observed in 1.70% of patients in the ASA group and none in the LMWH group. No arterial thrombosis, acute cardiovascular events, or sudden deaths were reported. No major hemorrhagic complications were reported. In previously untreated patients with MM receiving lenalidomide with a low thromboembolic risk, ASA could be an effective and less-expensive alternative to LMWH thromboprophylaxis. This study was registered at www.clinicaltrials.gov as #NCT00551928.
The inappropriate expansion and activation of autoreactive memory B cells and plasmablasts contributes to loss of self-tolerance in systemic lupus erythematosus (SLE). Defects in the inhibitory Fc ...receptor, FcγRIIB, have been shown to contribute to B cell activation and autoimmunity in several mouse models of SLE. In this paper, we demonstrate that expression of FcγRIIB is routinely up-regulated on memory B cells in the peripheral blood of healthy controls, whereas up-regulation of FcγRIIB is considerably decreased in memory B cells of SLE patients. This directly correlates with decreased FcγRIIB-mediated suppression of B cell receptor–induced calcium (Ca2+) response in those B cells. We also found substantial overrepresentation of African-American patients among those who failed to up-regulate FcγRIIB. These results suggest that the inhibitory receptor, FcγRIIB, may be impaired at a critical checkpoint in SLE in the regulation of memory B cells; thus, FcγRIIB represents a novel target for therapeutic interventions in this disease.
Background: Structural mitochondrial abnormalities as well as alterations in gene expression of key mitochondrial proteins are well recognized in myelodysplastic syndrome (MDS), suggesting that ...mitochondrial dysfunction is important in the pathogenesis of this disease. Both Coenzyme Q10 and L- carnitine play an essential role in efficient cellular energy production. Clinical and cytogenetic response to high dose of Coenzyme Q10 in patients with MDS was demonstrated previously. The combination of L- carnitine and Coenzyme Q10 has shown a beneficial effect in other mitochondrial disorders. Aim: To assess the effect of combination of food supplements on the clinical course and mitochondrial function of peripheral blood cells obtained from patients with in low/intermediate- 1 risk MDS.Materials and Methods: Ultra-coenzyme Q10 (180 mg/day), L-carnitine (2000 mg/day) and a vitamin mineral complex were administered for 6 months; patients were allowed to continue treatment for an additional 6 months, if it was beneficial. Inclusion criteria were Hb<10.5g/dL or PLT<100x109/L or ANC<0.8X109/L. As of May 2017, 33 pts. have been enrolled in the study. Peripheral blood cells were assessed by the Seahorse XF analyzer which is a state- of- the- art tool for assessment of real time cellular respiration, by continuous measurement of Oxygen Consumption Rate (OCR) under different conditions in-vitro . Mitochondrial function assessment was performed at baseline and at six-month point. Results: The median age of the entire cohort was 75 years (range: 56-93), 20(61%) of pts. were male. Pts. were classified per IPSS-R: very low risk 7 (21%), low risk 21(64%),int. 5 (15%). Median Hb was 9.5 g/dL (6.4-12.2); 17 (52%) were transfusions dependent and 16(48%) failed treatment with erythropoietin stimulating agents (ESA). 28 patients completed treatment protocol. Six pts. (21.4%) showed a hematological Improvement according to IWG 2006 criteria (out of which 4 were transfusions dependent). Median time to the initial response was 9 weeks (5-24). At 3 months' time point 14 of 18 patients had an increased in their integral Quality of life (QOL) score per FACT questionnaire; mean improvement was 14.3 points per patient (p=0.011). The pre-treatment mitochondrial basal respiration and especially spare respiratory capacity tested on cells of 11 MDS cases were uniformly lower in comparison with healthy controls (p=0.04 and p=0.007,respectively). There was significant improvement of basal, as well as spare respiration in peripheral blood cells obtained from MDS patients after six months food supplements (p=0.0027 and p=0.02, respectively). Conclusions: We demonstrated for the first time that mitochondrial energy production in peripheral blood is impaired in patients with MDS. Furthermore, we showed that this is at least partially reversible with food supplementations known to augment mitochondrial function. Combination of Ultra coenzyme Q10 with L-carnitine and vitamin mineral complex leads to moderate clinical response in low/intermediate-1 risk MDS patients and improve QOL
No relevant conflicts of interest to declare.
Structural mitochondrial abnormalities and genetic aberrations in mitochondrial proteins have been known in Myelodysplastic syndrome (MDS), yet there is currently little data regarding MDS's ...metabolic properties and energy production cells. In the current study, we used state-of-the-art methods to assess OXPHOS in peripheral blood cells obtained from MDS patients and healthy controls. We then assessed the effect of food supplements-Coenzyme Q10 and carnitine on mitochondrial function and hematological response. We show here for the first time that there is a significant impairment of mitochondrial respiration in peripheral blood cells in low-risk MDS, which can be improved with food supplements. We also show that these supplements may improve the cytopenia and quality of life.
Cord blood transplant (CBT) is characterized by the limited amount of hematopoietic stem cells (HSCs), and exhibits higher incidence of engraftment failure. Transplant using two (double) CB units ...(DCBT) is the most promising strategy to date to augment the total transplanted HSC dose. DCBT increases the availability of transplant to adults, for whom there is only a small chance of finding a matched CB suitable for a single unit transplant. Better selection of CB units, optimization of conditioning regimen, and GVHD prophylaxis are important to further improve DCBT outcomes. In this review we attempt to summarize recent progress in the field of DCBT, to present the strategies applied, and to point out directions for the future.
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