Altered Th17/Treg ratio in recurrent miscarriage after treatment with paternal lymphocytes and vitamin D3: a double-blind placebo-controlled study

Background: Recurrent miscarriage [RM] affects 2-5% of pregnant women. Paternal lymphocyte immunotherapy is a common treatment for RM patients but the outcome has not been consistent. Therefore, combined therapy with other immunosuppressive drugs such as 1a, 25-dihydroxy-vitamin-D3 [vitamin D3] may improve the outcome

Objectives: To investigate the effect of vitamin D3 on the balance of two essential T cells subsets, T helper [Th] 17 and T regulatory [Treg] cells, which regulate tolerance

Methods: The expression levels of CD4 and forkhead box protein 3 [FOXP3] in Treg cells, and the expression levels of CD4 and IL-17 in Th17 cells, were evaluated pre- and 3 months post-immunotherapy in RM patients treated with a combination of paternal lymphocytes and vitamin D3 compared with RM patients receiving lymphocyte immunotherapy alone

Results: Vitamin D3 therapy decreased the frequency of Th17 cells in addition to reducing the Th17/Treg ratio in peripheral blood of RM patients compared with the control group [p<0.05]

Conclusion: Considering that RM patients have a higher Th17/Treg ratio in peripheral blood, vitamin D3 may be a candidate therapeutic approach in this disease

Co-administration of silymarin and deferoxamine against kidney, liver and heart iron deposition in male iron overload rat model

Tissue iron deposition may disturb functions of the organs. In many diseases like thalassemia, the patients suffer from iron deposition in kidney and heart tissues. Deferoxamine [DF] is a synthetic iron chelator and silymarin [SM] is an antioxidant and also a candidate for iron chelating. This study was designed to investigate the effect of DF and SM combination against kidney and heart iron deposition in an iron overload rat model. Male Wistar rats were randomly assigned to 5 groups. The iron overloading was performed by iron dextran 100 mg/kg/day every other day during 2 weeks and in the 3[rd] week, iron dextran was discontinued and the animals were treated daily with combination of SM [200 mg/kg/day, i.p.] and DF [50 mg/kg/day, i.p.] [group 1], SM [group 2], DF [group 3] and saline [group 4]. Group 5 received saline during the experiment. Finally, blood samples were obtained and kidney, heart and liver were immediately removed and prepared for histopathological procedures. The results indicated no significant difference in kidney function and endothelial function biomarkers between the groups. However, combination of SM and DF did not attenuate the iron deposition in the kidney, liver and heart. DF alone, rather than DF and SM combination, significantly reduced the serum level of malondialdehyde [P < 0.05]. Co-administration of SM and DF significantly increased the serum level of ferritin [P <0.05]. DF and SM may be potentially considered as iron chelators. However, combination of these two agents did not provide a protective effect against kidney, liver and heart iron deposition

Variations in T-helper 17 and regulatory T cells during the menstrual cycle in peripheral blood of women with recurrent spontaneous abortion

Disorders in immune system regulation may result in pregnancy abnormalities such as recurrent spontaneous abortion [RSA]. This study aims to determine the ratio of regulatory T [Treg] and T helper [Th] 17 cells in unexplained RSA [URSA] women during proliferative and secretory phases of their menstrual cycles compared to healthy non-pregnant women. In this case control study, 25 women with URSA and 35 healthy, non-pregnant women were enrolled. The percentage of Th17 and Treg cells in participants peripheral blood were determined by flow cytometry. The percentage of Th17 cells and their related cytokines in serum [IL-17A] were higher in the proliferative and secretory phases of the menstrual cycles of URSA women compared to the control women. However, a lower percentage of Treg cells and their related cytokines in serum, transforming growth factor [TGF] beta1 and interleukin [IL]-10 were detected in the proliferative but not the secretory phase of the URSA group. The ratio of Th17/CD4+ Treg was higher in the URSA group than the control group. We observed an increased ratio of Th17/CD4+ Treg during the proliferative and secretory phases in URSA women. The imbalance between Th17 and Treg cells during the proliferative phase of menstrual cycles in the URSA group may be considered a cause for spontaneous abortion

Protective role of silymarin and deferoxamine against iron dextran-induced renal iron deposition in male rats

Kidney iron deposition [KID] is caused by iron overload that is observed in kidney diseases and anemia. The protective effects of deferoxamine [DF] and silymarin [SM] were studied against iron overload-induced KID in rat model. Rats received iron dextran [200 mg/kg] for a period of 4 weeks every other day, but at the beginning of week 3, they also were subjected to a 2-week [every other day] treatment with vehicle [group 2, positive control], SM [200 mg/kg; group 3], DF [50 mg/kg; group 4], SM [400 mg/kg; group 5], and combination of SM and DF [200 and 50 mg/kg, respectively; group 6]. Group 1, as the negative control, received saline alone during the study. The levels of serum creatinine [Cr], blood urea nitrogen [BUN], iron, ferritin, and nitrite were determined, and the kidney was removed for histopathological investigations. Before treatment, the serum levels of iron and ferritin in all iron dextran receiver groups were significantly higher than those of the negative control group [P < 0.05]. However, the serum levels of BUN, Cr, and nitrite were not different between the groups. No statistical differences were detected in kidney weight and the serum levels of BUN, Cr, iron, ferritin, and nitrite after 2 weeks of treatment with SM, DF, or combination of both. The SM and DF treatments reduced the intensity of the KID, but only in the SM [200 mg/kg] group, a significant reduction in KID was observed [P < 0.05]. It seems that SM is a nephroprotectant agent against KID in acute iron overload animal models

Antibodies to Interferon beta in Patients with Multiple Sclerosis Receiving CinnoVex, Rebif, and Betaferon

Treatment with interferon beta (IFN-beta) induces the production of binding antibodies (BAbs) and neutralizing antibodies (NAbs) in patients with multiple sclerosis (MS). NAbs against IFN-beta are associated with a loss of IFN-beta bioactivity and decreased clinical efficacy of the drug. The objective of this study was to evaluate the incidence and the prevalence of binding antibodies (BAbs) and neutralizing antibodies (NAbs) to IFN-beta in MS patients receiving CinnoVex, Rebif, or Betaferon. The presence of BAbs was studied in serum samples from 124 MS patients using one of these IFN-beta medications by ELISA. The NAbs against IFN-beta were measured in BAb-positive MS patients receiving IFN-beta using an MxA gene expression assay (real-time RT-PCR). Of the 124 patients, 36 (29.03%) had BAbs after at least 12 months of IFN-beta treatment. The proportion of BAb+ was 38.1% for Betaferon, 21.9% for Rebif, and 26.8% for CinnoVex. Five BAb-positive MS patients were lost to follow-up; thus 31 BAb-positive MS patients were studied for NAbs. NAbs were present in 25 (80.6%) of BAb-positive MS patients receiving IFN-beta. In conclusion, the three IFN-beta preparations have different degrees of immunogenicity.

influence of iron loading and iron chelation on the proliferation and telomerase activity of human peripheral blood mononuclear cells

Iron is an essential trace element in cell proliferation. Several investigations demonstrate that iron deprivation inhibits cell proliferation. However, the impact of iron on telomerase activity of activated lymphocytes remains unexplained to date. In this study, the effect of iron on the proliferation and telomerase activity of lymphocytes stimulated by phytohemagglutinin [PHA] were investigated. Iron loading was performed by incubating peripheral blood mononuclear cells in 500 micro M FeSO[4].7H[2]O for 24 h and iron chelation was done by exposing cells to desferrioxamine, a potent iron chelator. The effects of silymarin, a flavonoid with both antioxidant and iron chelating activities, on the proliferation and telomerase activity of PHA-activated lymphocytes were also compared with desferrioxamine. Proliferation and telomerase activity were assessed using BrdU incorporation assay and Telomeric Repeat Amplification Protocol [TRAP], respectively. The proliferations of lymphocytes were significantly inhibited by 10 and 20 micro g/ml desferrioxamine in a dose dependent manner, while iron loading recovered suppressed cell proliferation to the normal level. Silymarin at 20 micro g/ml significantly increased the proliferation of lymphocytes in both normal and iron-treated conditions. Telomerase activity of lymphocytes was markedly increased by iron treatment and suppressed by desferrioxamine. Conversely, iron treatment had no effect on the telomerase activity of lymphocytes incubated with silymarin. Iron plays a significant role in the proliferation and telomerase activity of lymphocytes. The effects of silymarin on the proliferation and telomerase activity of lymphocytes were completely different from those of desferrioxamine, suggesting that the immunomodulatory effect of silymarin is probably not associated with its iron chelating activity