• Asian Pacific Journal of Cancer Prevention
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• v.17 no.10
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• pp.4699-4711
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• 2016

Background: In the last decade, it has become clear that change of gene expression may alter the hematopoietic cell quiescent state and consequently play a major role in leukemogenesis. WT1 is known to be a player in acute myeloid leukemia (AML) and FOXP3 has a crucial role in regulating the immune response. Objectives: To evaluate the impact of overexpression of WT1and FOXP3 genes on clinical course in adult and pediatric AML patients in Egypt. Patients and methods: Bone marrow and peripheral blood samples were obtained from 97 de novo non M3 AML patients (63 adult and 34 pediatric). Real-time quantitative PCR was used to detect overexpression WT1 and FOXP3 genes. Patient follow up ranged from 0.2 to 39.0 months with a median of 5 months. Results: In the pediatric group; WT1 was significantly expressed with a high total leukocyte count median 50X109/L (p=0.018). In the adult group, WT1 had an adverse impact on complete remission induction, disease-free survival and overall survival (p=0.02, p=0.035, p=0.019 respectively). FOXP3 overexpression was associated with FAB subtypes AML M0 +M1 vs. M2, M4+M5 (p =0.039) and the presence of hepatomegaly (p=0.005). Conclusions: WT1 and FOXP3 overexpression has an adverse impact on clinical presentation, treatment response and survival of pediatric and adult Egyptian AML patients.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.6
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• pp.2613-2618
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• 2014

Aims: Dysfunction of the host immune system in cancer patients can be due to a number of factors, including lymphocyte apoptosis. Several studies showed that $Foxp3^+T$ cells take part in inducing this process by expressing FasL in tumor patients. However, the relationship between apoptosis, $CD8^+T$ cells and $Foxp3^+T$ cells in HCC patients is still unclear. The present study was designed to investigate the correlation between apoptosis levels and Fas/FasL expression in $CD8^+T$ lymphocytes and $Foxp3^+T$ cells in patients with HCC. Methods: $CD8^+T$ cells and $CD3^+Foxp3^+T$ cells were tested from peripheral blood of HCC patients and normal controls and subjected to multicolor flow cytometry. The expression of an apoptosis marker (annexin V) and the death receptor Fas in $CD8^+T$ cells and FasL in $CD3^+Foxp3^+T$ cells were evaluated. Serum TGF-${\beta}1$ levels in patients with HCC were measured by enzyme-linked immunosorbent assay. The relationship between apoptosis and Fas expression, as well as FasL expression in $CD3^+Foxp3^+T$ cells was then evaluated. Results: The frequency of $CD8^+T$ cells binding annexin V and Fas expression in $CD8^+T$ cells, were all higher in HCC patients than normal controls and the proportion of apoptotic $CD8^+T$ cells correlated with their Fas expression. Serum TGF-${\beta}1$ levels correlated inversely with $CD3^+Foxp3^+T$ cells. Conclusions: Fas/FasL interactions might lead to excessive turnover of $CD8^+T$ cells and reduce anti-tumor immune responses in patients with HCC. Further investigations of apoptosis induction in $Fas^+CD8^+T$ cells in vitro are required.

• BLOOD RESEARCH
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• v.53 no.4
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• pp.294-298
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• 2018

Background Production of immunosuppressive enzymes such as indoleamine 2,3-dioxygenase (IDO) is one of the strategies employed by hematologic malignancies, including acute myeloid leukemia (AML), to circumvent immune surveillance. Moreover, IDO has the ability to convert $CD4^+CD25^-$ conventional T cells into regulatory T cells (Tregs). In this study, we evaluated the expression of IDO in cytogenetically normal acute myeloid leukemia (CN-AML) patients and its correlation with the Treg marker, FOXP3, as well as clinical and laboratory parameters. Methods Thirty-seven newly diagnosed CN-AML patients were enrolled in our study along with 22 healthy individuals. The expression of the IDO and FOXP3 genes was analyzed by SYBR Green real-time PCR. Results Both IDO and FOXP3 were highly upregulated in CN-AML patients compared to control groups (P=0.004 and P=0.031, respectively). A positive correlation was observed between IDO and FOXP3 expression among AML patients (r=0.512, P=0.001). Expression of IDO and FOXP3 showed no significant correlation with laboratory parameters such as white blood cell and platelet counts, hemoglobin levels, bone marrow blast percentage, gender, and FLT3 mutation status (P>0.05). Conclusion Higher IDO expression in CN-AML patients may be associated with an increased Treg phenotype which may promote disease progression and lead to poor prognosis of CN-AML patients.

• IMMUNE NETWORK
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• v.7 no.1
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• pp.1-9
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• 2007

[ $CD4^+CD25^+$ ] regulatory T cells (Tregs) expressing the lineage-specific marker Foxp3 represent an important regulatory T cell that is essential for maintaining peripheral tolerance. Although it was believed that Treg development is solely dependent on the thymus, accumulating evidence demonstrates that Tregs can also be induced in the periphery. Considering the various origins of peripherally developed $CD4^+CD25^+Foxp3^+$ regulatory T cells, it seems likely that multiple factors are involved in the peripheral generation of Tregs.

• IMMUNE NETWORK
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• v.12 no.5
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• pp.217-221
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• 2012

Fibroblast-like synoviocytes (FLS) colocalize with leukocyte infiltrates in rheumatoid synovia. Proinflammatory leukocytes are known to amplify inflammation by signaling to FLS, but crosstalk between FLS and regulatory T cells (Tregs) remains uncharacterized. To address this possibility, we cocultured FLS lines derived from arthritic mice with Tregs. FLS that expressed the ligand for glucocorticoid-induced TNF receptor family-related gene (GITR) decreased expression of Foxp3 and GITR in Tregs in a contact-dependent manner. This effect was abolished by blocking antibody to GITR. On the other hand, the Tregs caused the FLS to increase IL-6 production. These results demonstrate that inflamed FLS license Tregs to downregulate Foxp3 expression via the GITRL/GITR interaction while the Tregs induce the FLS to increase their production of IL-6. Our findings suggest that the interaction between FLS and Tregs dampens the anti-inflammatory activity of Tregs and amplifies the proinflammatory activity of FLS, thereby exacerbating inflammatory arthritis.

• Annals of Laboratory Medicine
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• v.38 no.6
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• pp.591-598
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• 2018

Background: Forkhead box P3 (FOXP3) is an important marker of regulatory T cells. FOXP3 polymorphisms are associated with autoimmune diseases, cancers, and allograft outcomes. We examined whether single nucleotide polymorphisms (SNPs) at the FOXP3 locus are associated with clinical outcomes after allogenic hematopoietic stem cell transplantation (HSCT). Methods: Five FOXP3 SNPs (rs5902434, rs3761549, rs3761548, rs2232365, and rs2280883) were analyzed by PCR-sequencing of 172 DNA samples from allogenic HSCT patients. We examined the relationship between each SNP and the occurrence of graft-versus-host disease (GVHD), post-HSCT infection, relapse, and patient survival. Results: Patients with acute GVHD (grades II-IV) showed higher frequencies of the rs3761549 T/T genotype, rs5902434 ATT/ATT genotype, and rs2232365 G/G genotype than did patients without acute GVHD (P =0.017, odds ratio [OR]=5.3; P =0.031, OR=2.4; and P =0.023, OR=2.6, respectively). Multivariate analysis showed that the TT genotype of rs3761549 was an independent risk factor for occurrence of acute GVHD (P =0.032, hazard ratio=5.6). In contrast, the genotype frequencies of rs3761549 T/T, rs5902434 ATT/ATT, and rs2232365 G/G were lower in patients with post-HSCT infection than in patients without infection (P =0.026, P =0.046, and P =0.031, respectively). Conclusions: rs3761549, rs5902434, and rs2232365 are associated with an increased risk of acute GVHD and decreased risk of post-HSCT infection.

• Microbiology and Biotechnology Letters
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• v.39 no.3
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• pp.313-316
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• 2011

We isolated and identified a novel probiotic strain, Lactobacillus sakei proBio65 from Kimchi. To determine whether L. sakei proBio65 has an immunomodulatory effect, we investigated cells via an in vitro screening system which co-cultured freshly isolated mesenteric lymphocyte with probiotics. A significant increase of $Foxp3^+$ transcription regulatory factor expression was observed, followed by an increase in anti-inflammatory cytokines transcription regulatory factor. L. sakei proBio65 exhibited high levels of the IL-10/IL-12 production ratio and enhanced Foxp3 expression in vitro. L. sakei proBio65 may thus be therapeutically useful for the modulation of inflammatory immune disorders.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.2
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• pp.83-88
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• 2015

CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs) have been shown to play a regulatory or suppressive role in the immune response and are possibly relevant to the pathogenesis of autoimmune diseases. In the present study, we attempted to investigate the frequency of CD4+CD25+ Tregs in peripheral blood (PB) of collagen-induced arthritis (CIA) rats during the development of arthritis, to determine whether their frequency is involved in the immunoregulation of this disease. The results showed that normal rats had similar frequencies of CD4+CD25+ Tregs in PB during the experiment time, expressed as a percentage of CD4+CD25+Foxp3+ T cells among the CD4+ T lymphocyte population. In contrast, the frequency of CD4+CD25+Foxp3+ T cells in CIA rats was found to change during the development of arthritis. In CIA rats, there is a significant negative correlation between the frequency of CD4+CD25+Foxp3+ T cells and paw swelling (r=-0.786, p< 0.01). The relationship between the frequency of CD4+CD25+Foxp3+ T and immune activation was not found in normal rats. During the time course, the frequency of CD4+CD25+Foxp3+ T was lower in CIA rats than in normal ones. The data suggest that the frequency of PB CD4+CD25+ Tregs may be a promising marker for arthritis activity.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3955-3960
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• 2012

Objective: To investigate the effects of $CD4^+$, IL17 and Foxp3 expression on prognosis of operable non-small cell lung cancer (NSCLC) with different pTNM stages. Methods: Expression of $CD4^+$, IL17 and Foxp3 in 102 cases of NSCLC tissues and adjacent cancer tissues was detected by immunohistochemistry and associations with prognosis with different pTNM stages were analyzed. The Chi-square test was used to compare count data. Survival differences were evaluated by Kaplan-Meier single factor analysis and the COX regression model was used to analyze the relationship between influential factors and the disease prognosis. The significance level was ${\alpha}$=0.05. Results: Expression of CD4, IL-17 and Foxp3 significantly varied in different pTNM stages of NSCLC tissues (P < 0.05). The same was true for CD4 expression (P < 0.05). The median survival time (MST) in the positive CD4 expression group was evidently higher than that in the negative group (25.8/23.9 months). Compared with stage III, the MST difference of stages I and II in the positive CD4 expression group were statistically significant (P < 0.05). The MST in positive IL-17 and Foxp3 expression groups was obviously lower than that in the corresponding negative group (P < 0.05) (25.6/35.1 months and 24/35.3 months, respectively). There was a significant difference of MST between any two of three stages of positive IL-17 expression group (P < 0.05), and it was the same with positive Foxp3 expression group. TNM stage, negative CD4 expression, and positive IL-17 and Foxp3 expression were the main risk factors for the prognosis of NSCLC. Conclusion: Surgical prognosis of NSCLC can be better assessed by the combination of clinical staging and expression of IL17 and Foxp3.

• Biomedical Science Letters
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• v.21 no.4
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• pp.172-180
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• 2015

It is well reported that tumor cells can regulate host immune systems. To identify the detailed changes of immune cells between tumor bearing mice and normal mice, we evaluated the systemic immune cell phenotype of B16F10 tumor bearing mice in a time dependent manner. The lymphocytic population (CD4+ and CD8+ T cells) of tumor bearing mice significantly decreased compared to that of normal mice. We found that the Foxp3+CD25+ CD4 T cell decreased, but the Foxp3+$CD25^{high}$ CD4 T cell significantly increased. All subpopulations of CD8 T cells decreased, except the CD62L-CD44+ CD8 T cell subpopulation. The myeloid cell population (CD11b+ and Gr-1+ cells) of tumor bearing mice significantly increased. Specifically, Foxp3+$CD25^{high}$ CD4 T cell and CD11b+Gr-1+ cells significantly increased in early phase of tumor progression. These results are helpful to understand the change of the systemic immune cell subpopulation of tumor bearing mice in a time-dependent manner.