Impact of Cytokine Gene Polymorphisms on Risk and Treatment Outcomes of Aplastic Anemia In Korea

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4432-4432
Author(s):  
Yun-Gyoo Lee ◽  
Ji-Hyun Kwon ◽  
Dong-Yeop Shin ◽  
Eun-Young Song ◽  
Hyun Kyung Kim ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Conflicts Of Interest ◽  
Recessive Model ◽  
Multivariate Logistic Regression Model ◽  
Control Group ◽  
Dominant Model ◽  
Cytokine Genes ◽  
Hematologic Response ◽  
Tnf Α ◽  
Ifn Γ

Abstract Abstract 4432 Introduction The clinical evidence of responsiveness to immunosuppressive therapy (IST) supports immune pathophysiology for acquired aplastic anemia (AA). Recent studies suggested that auto-reactive cytotoxic T-cells against hematopoietic cells play a key role in the pathogenesis of AA with various cytokines. The purpose of this study is to investigate whether single nucleotide polymorphisms (SNP) of cytokine genes are related to the risk of AA and, furthermore, the response to IST. Methods We analyzed 80 adult patients diagnosed as acquired AA. The 84 unrelated, age and sex matched healthy subjects served as a control group. In 3 cytokine genes (IFN-γ, TNF-α, TGF-β) and one FAS gene, we selected 10 polymorphisms on the basis of allelic frequency and the assumption of clinical relevance from previously reported associations. To assess the association between polymorphisms and risk of AA, we calculated statistical differences in allele, genotype, and haplotype distributions between patients and controls using chi-square test in 3 genetic models (dominant, recessive, and additive). For the association between polymorphisms and response to initial course of IST, we analyzed 44 patients who were treated with IST using a multivariate logistic regression model. Results Among 10 SNPs in 4 genes, one SNP and one haplotype in IFN-γ gene were significantly associated with the development of AA: IFN-γ -2353A/T; the presence of the T allele in dominant model was protective and was related to a 2.3-fold reduction in the risk for AA (P =.012); the presence of the IFN-γ TCA haplotype was related to a two-fold reduced risk for AA (P =.038). The IFN-γ -2353 T allele was shown to be resistant to IST; the presence of T allele and TCA haplotype in IFN-γ gene (dominant model) was related to a 13.2-fold reduced hematologic response at 6 months following initial IST (P =.034). However, 4 SNPs and 2 haplotypes in TNF-α gene did not show any significant associations with the response at 3 and 6 months. In terms of 2 SNPs in TGF-β gene, TGF-β P10L T/C was independently related; the T allele (recessive model) was related to a 4.3-fold reduced response to IST at 3 months (P =.038). Accordingly, the response was related to the TGF-β haplotype; the TC haplotype homozygote (recessive model) was related to a 4.6-fold reduced response to IST at 6 months (P =.036); the presence of CT haplotype (dominant model) was favorable to IST and was related to a 5.7-fold higher response at 3 months than the absence of the CT haplotype (P =.038). Conclusion This exploratory study found that the genetic polymorphism of IFN-γ was susceptible to the development of AA and was related to the hematologic response following initial IST. In case of TGF-β, the polymorphisms were related to the response to IST, though they were not be related to the disease susceptibility. Large studies with a prospective design are needed to better understand the determinants of risk of AA and responsiveness to IST. Disclosures: No relevant conflicts of interest to declare.

Impact of Cytokine Gene Polymorphisms on Risk and Treatment Outcomes of Aplastic Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4369-4369
Author(s):  
Eunyoung Lee ◽  
Yun-Gyoo Lee ◽  
Inho Kim ◽  
Ji-Hyun Kwon ◽  
Dong-Yeop Shin ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Conflicts Of Interest ◽  
Treatment Modalities ◽  
Dominant Model ◽  
Necrosis Factor Alpha ◽  
Hematopoietic Stem ◽  
Cytokine Genes ◽  
Ifn Γ

Abstract Abstract 4369 Immunosuppressive therapy (IST) is one of the main treatment modalities for acquired aplastic anemia (AA). Approximately 70% of AA patients have been known to achieve clinical improvements with IST consisting of antithymocyte globulin (ATG) and cyclosporine. This remarkably high response rate supports us to tell the immunogenic pathophysiology of AA. Autoreactive cytotoxic T cells play a key role in this immunogenic pathogenesis of AA by working with myelosuppressive cytokines like interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNFα), and transforming growth factor beta (TGFβ), which induce apoptosis in hematopoietic stem cells, partially through the Fas-dependent pathway. The purpose of this study is to find out which single nucleotide polymorphisms (SNPs) in cytokine genes were relevant to the risk of AA and whether the relevant SNPs were associated with response to IST in AA patients. Between January 2000 and December 2008 84 patients were screened and 80 patients confirmed as having acquired AA by bone marrow biopsy, and 84 age- and sex-matched healthy controls were analyzed consecutively. We genotyped the polymorphisms in three cytokine genes (IFNG, TNF, and TGFB1) and FAS gene, which are known to be involved in T cell-mediated marrow destruction. We assessed the association between polymorphisms in those selected genes and risk for AA, and the association between those polymorphisms and response to IST in three genetic models (dominant, recessive, and additive). The IFNG -2353 T allele (dominant model, OR=0.43, p=.012) and TCA haplotype (dominant model, OR=0.50, p=.038) were significantly associated with the development of AA. In addition, this relevant IFNG -2353 T allele and TCA haplotype were related to the response of IST (dominant model, OR=0.076, p=.034). The presence of the minor T allele was protective and related to a 2.3-fold reduction in the risk for AA (p=.012), and the presence of the IFNG TCA haplotype was related to a 2-fold reduced risk for AA (p=.038). Concerning TGFB1, although its polymorphisms are not related to AA susceptibility, P10L T allele (recessive model, OR=0.18, p=.038) and CT haplotype (dominant model, OR=5.68, p=.038) were associated with response to IST. The T allele was related to a 4.3-fold reduced response to IST at 3 months (p=.038) and the presence of the CT haplotype was favorable to IST and was related to a 5.7-fold higher response at 3 months compared with the response in patients without the CT haplotype (p=.038). This exploratory study concurred with prior studies indicating that polymorphisms in IFNG are related to AA susceptibility. In addition, it was found that polymorphisms in IFNG and TGFB1 are associated with response to IST. AA patients with intracellular IFN-γ expression in peripheral lymphocytes showed almost 3-fold higher response to IST than patients without IFN-γ-expressing lymphocytes (p<0.0001) and this finding puts weight on the immunogenic association of responsiveness. Regarding TGFβ, the functionality of polymorphisms and in TGFB1 has rarely been reported. However, the significant relationship between TGFB1 polymorphisms and therapeutic response to IST in our study suggests their late effects on marrow suppression. Our results may help explain the variability of response to IST in AA and suggests that patients with a high probability of response might be treated first with IST rather than conventional marrow transplantation.Table 1.Factors relevant to response to ISTFactorCorrected for Patient CharacteristicsUncorrected DataGenotypeOR (95% CI)POR (95% CI)PResponse at 3-month after IST (n=43)    Age1.00 (0.96–1.05).841.02 (0.98–1.06).46    Sex (male vs female)1.13 (0.26–4.84).871.26 (0.37–4.23).71    Severity (severe vs non-severe)1.03 (0.23–4.53).0971.63 (0.48–5.47).43    TGFB P10L C/TTT vs CT + CC0.18 (0.03–0.90).0380.23 (0.06–0.95).043    TGFB haplotypeCT-CT + CT-other vs Other-other5.68 (1.11–29.15).0384.28 (1.05–17.42).043Response at 6-month after IST (n=43)    Age1.00 (0.95–1.05).911.02 (0.97–1.06).45    Sex (male vs female)0.38 (0.072–2.01).250.60 (0.16–2.21).44    Severity (severe vs non-severe)2.53 (0.47–13.62).282.22 (0.59–8.26).24    IFNG -2353 A/TTT+AT vs AA0.076 (0.007–0.82).0340.40 (0.10–1.56).19    IFNG haplotypeTCA-TCA + TCA-other vs Other-other0.076 (0.007–0.82).0340.40 (0.10–1.56).19    TGFB haplotypeTC-TC vs TC-other + Other-other0.22 (0.05–0.90).0360.19 (0.03–1.09).063 Disclosures: No relevant conflicts of interest to declare.

Study on Mechanism of Human Marrow Mesenchymal Stem Cell in Treating Patients with Aplastic Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4099-4099
Author(s):  
Zhenhua Qiao ◽  
Xiujuan Zhao
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
Aplastic Anemia ◽  
Hematopoietic Cell ◽  
Control Group ◽  
Rt Pcr ◽  
Tnf Α ◽  
Ifn Γ ◽  
Tgf Β1

Abstract Objective: To explore mechanism of human marrow mesenchymal stem cells (MSCs) in treating patients with aplastic anemia(AA). Methods: MSCs in patients with aplastic anemia(AA) and the control group were separated with Percoll(1.073g/m L) and cultured in low glucose DMEM. Then, observed their morphologies,checked their molecule surface antigen by flow cytometry and examined the process of adipogenic differention. The mononuclear cells (MNC)of marrow in patients with AA were enriched based 1.077g/L density centrifuge and cultured in the 1640 medium. (1)MSC in control group and MNC in AA group were co-cultured with or without cytokines. The function of supporting hematopoiesis for MSC was to be observed in single confluence layer after plating by counting the total cells and the clones in every well every week. Then analyzed the dynamics of proliferation. T cells were harvested by using nylon column. MSC in control group and T cells in AA group were co-cultured. The proliferation of T cell was measured by MTT method. The CD25,CD69,CD4,CD8,Annexin-V expression rates of CD3+T cells were analyzed by flow cytometry .The gene and protein of IL-2, IL-4,IL-10,TNF-α,IFN-γ,TGF-β1 were examined by RT-PCR and ELISA respectively. MSC treated to the model of AA, by the examination of peripheral hemogram, bone marrow biopsy, pathological section of spleen. Results: There was no significant difference between control group MSC and AA-MSC in morphologies but adipogenic differentiation in AA patients is earlier than controls. The clones of CFU-GM in group(MSC)(78.46±3.58)/2×105 cells, after 14 days cultured was significantly higher than(9.21±4.32)/2×105 cells in group(CK + DMEM medium), while lower than (99.32±4.34)/2×105 cells in group(MSC+CK). (1)the Treg cells (TCD4+CD25+) in AA group (2.01±1.21)/ 2×105 was significantly lower than (4.43±1.67)/2×105 cells in control group, while(5.43±2.31) / 2×105 in group (MSC+AAT) was no more than (4.43±1.67)/2×105 cells in control group. (2) MSCs significantly inhibited T cell proliferation (P< 0. O5)by MTT. (3) RT-PCR and ELISA analysis showed that MSCs induced the expression of IL-4, IL-10, TGF-β1 and decreased significantly the expression of IL-2, TNF-α, IFN -γ in T cells of AA. the model of AA treated by MSCs showed improvements in 3 blood components greatly(p<0.05), Bone marrow proliferated and restored to the normal level, hematopoietic cell increased obviously (hematopoietic cell capacity was more than 40%), and atrophied spleen restore to normality. Conclusions: morphologies of AA’MSC had no evident different with the control but was more easy adipogenic differention. aplastic anemia belongs to autoimmune diseases in which T cells effect organ-specific destruction. The fundamental mechanism of MSC in treating AA should be potential to promote hematopoietic cell proliferation by adjusting immunity.

The Targeting Repair of UC-MSCs Homing on Immune Inflammatory Microenvironment and Thrombophilia in CIA Rats

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5412-5412
Author(s):  
Xinzhen Cai ◽  
Jun Ni ◽  
Wei Wu ◽  
Qingqing Shi ◽  
Zou Li ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Conflicts Of Interest ◽  
Medical Science ◽  
Control Group ◽  
Group Model ◽  
Joint Tissue ◽  
Inflammatory Microenvironment ◽  
Tnf Α ◽  
Significant Difference ◽  
Ifn Γ

Abstract Introduction To preliminary study the repair effect of umbilical cordmesenchymal stem cells (UC-MSCs) homing on local and systemic inflammatory microenvironment and immune inflammatory thrombophilia states of the CIA rata by observing the distribution of the UC-MSCs in the CIA rate and the influence of the UC-MSCs on the expression of the inflammatory cytokines IL-10, TNF-α IL-6, IFN-γ and the thrombosis indicators TF, VWF, DD, FIB's. Methods The clean grade, female, 5-week-old SD rats were randomly divided into a control (C) group, model (M) group, UC-MSCs treatment (SU) group, adding AMD3100 to labled UC-MSCs therapy (ASU) group. Except for control group, the other rats were induced as CIA rats model. Treatment group were injected UC-MSCs suspension by tail vein. The rats were sacrificed in the first, the third and the fifth week after transplantation. HE staining was used to observe the pathological changes of joint tissues. The distribution of UC-MSCs in the joint tissue was detected by FISH. ELISA assay was used to observe the expression of inflammation and thrombosis indicators in peripheral blood. The expression of inflammatory factors in the joint tissue were detected by western blot. Results: 1. One week after injection, the expression of SDF-1 in the injuried joint of the group SU was significantly increased compared with the control group, at the same time, the large number of UC-MSCs occured in injured sites. While, adding AMD3100 to labled UC-MSCs were not expressed in the joint tissue. The expression of SDF-1 in the labled UC-MSCs treating group decreased over time, and the number of UC-MSCs reduced in the inflammatory joints. 2. After given UC-MSCs treatment, the levels of pro-inflammatory cytokines IL-6, TNF-α, IFN-γ in the knee and serum were conspicuously reduced compared with the group M since the first week. While the level of anti-inflammatory cytokine IL-10 was increased (p <0.05). After adding AMD3100, the expression of above indicators in the group ASU showed no significant difference compared to the group C. 3. After given UC-MSCs treatment, the levels of TF in serum and DD, FIB, VWF in plasma were conspicuously reduced compared to the group M since the first week (p <0.05). The expression of the above indicators in the group ASU showed no significant difference compared to the group C. Conclusion: 1. UC-MSCs homing to the injured joint tissue is influnced by the local inflammation environment, which is an important way to play its role of immune regulation to improve the immune inflammatory thrombophilia state in CIA rsts. 2. SDF-1/CXCR4 axis is important to the UC-MSCs homing, the antagonist AMD3100 can suppress the UC-MSC homing to the injured site. Funded by Jiangsu Provincial Special Program of Medical Science (BL2012005) Disclosures No relevant conflicts of interest to declare.

scholarly journals High Levels of TNF-α and TIM-3 as a Biomarker of Immune Reconstitution Inflammatory Syndrome in People with HIV Infection

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 527
Author(s):  
Lucero A. Ramon-Luing ◽  
Ranferi Ocaña-Guzman ◽  
Norma A. Téllez-Navarrete ◽  
Mario Preciado-García ◽  
Dámaris P. Romero-Rodríguez ◽  
...  
Keyword(s):  
Immune Reconstitution Inflammatory Syndrome ◽  
Immune Reconstitution ◽  
Control Group ◽  
Hiv Patients ◽  
Art Initiation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Α Level ◽  
Inflammatory Syndrome

Immune reconstitution inflammatory syndrome (IRIS) is an exacerbated immune response that can occur to HIV+ patients after initiating antiretroviral therapy (ART). IRIS pathogenesis is unclear, but dysfunctional and exhausted cells have been reported in IRIS patients, and the TIM-3/Gal-9 axis has been associated with chronic phases of viral infection. This study aimed to evaluate the soluble levels of TIM-3 and Gal-9 and their relationship with IRIS development. TIM-3, Gal-9, TNF-α, IFN-γ, IL-6, TNFR1, TNFR2, E-cadherin, ADAM10, and ADAM17 were measured to search for IRIS-associated biomarkers in plasma samples from 0-, 4-, 8-, 12-, and 24-weeks after ART initiation of 61 HIV+ patients (15 patients developed IRIS, and 46 did not). We found that patients who developed IRIS had higher levels of TIM-3 [median 4806, IQR: 3206–6182] at the time of the IRIS events, compared to any other follow-up time evaluated in these patients or compared with a control group of patients who did not develop IRIS. Similarly, IRIS patients had a higher TNF-α level [median 10.89, IQR: 8.36–12.34] at IRIS events than any other follow-up time evaluated. Other molecules related to the TIM-3 and TNF-α pathway (Gal-9, IL-6, IFN-γ, TNFR1, TNFR2, ADAM-10, and ADAM-17) did not change during the IRIS events. In conclusion, our data suggest that a high level of soluble TIM-3 and TNF-α could be used as an IRIS biomarker.

scholarly journals Cytokine expression in the duodenal mucosa of patients with visceral leishmaniasis

2010 ◽  
Vol 43 (4) ◽  
pp. 393-395 ◽  
Author(s):  
Kleber Giovanni Luz ◽  
Felipe Francisco Tuon ◽  
Maria Irma Seixas Duarte ◽  
Guilherme Mariz Maia ◽  
Paulo Matos ◽  
...  
Keyword(s):  
Immune Response ◽  
Gastrointestinal Tract ◽  
Visceral Leishmaniasis ◽  
Intestinal Bacteria ◽  
Duodenal Mucosa ◽  
Control Group ◽  
Tnf Α ◽  
Organ Specific ◽  
Ifn Γ

INTRODUCTION: Visceral leishmaniasis (VL) is a neglected tropical disease with a complex immune response in different organs. This pattern of organ-specific immune response has never been evaluated in the gastrointestinal tract. The aim of this study was to determine the in situ immune response in duodenal biopsies on patients with VL. METHODS: A case-control study was conducted on 13 patients with VL in comparison with nine controls. The immune response was evaluated using immunohistochemistry, for CD4, CD8, CD68, IL-4, IFN-γ, TNF-α and IL-10. Histological findings from the villi, crypts and inflammatory process were analyzed. RESULTS: All the cases of VL presented Leishmania antigens. No antigen was detected in the control group. The villus size was greater in the VL patients (p < 0.05). CD68 (macrophages) and CD4 levels were higher in the VL patients (p < 0.05). No differences in the expression of CD8, TNF-α, IL-10 or IL-4 were demonstrated. The number of cells expressing IFN-γ was lower in the VL patients (p < 0.05). CONCLUSIONS: Low levels of cytokines were found in the gastrointestinal tract of patients with VL. This pattern was not found in other organs affected by the disease. Immunotolerance of this tissue against Leishmania could explain these findings, as occurs with intestinal bacteria.

Increased Expression of TLR2 and TLR4 in Mononuclear Cells in Patient with Immune Thrombocytopenic Purpura.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3847-3847 ◽  
Author(s):  
Yunfeng Cheng ◽  
Shanhua Zou ◽  
Feng Li
Keyword(s):  
Plasma Concentration ◽  
Mrna Expression ◽  
Mononuclear Cells ◽  
Control Group ◽  
Gene Expressions ◽  
Expression Levels ◽  
Tnf Α ◽  
Healthy Control ◽  
Ifn Γ ◽  
Mrna Expression Levels

Abstract Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by platelet destruction resulting from autoantibodies against self-antigens and T-cell mediated cytotoxicity. Toll-like receptors (TLRs) are pattern recognition receptors important in mediating the immune response and their activation can lead to production of cytokines. Recent data suggest that TLR2 and TLR4 are crucial for the production of inflammatory cytokines and play central role in autoimmune diseases, yet little is known about their roles in ITP. Here we examined the gene expressions of TLR2 and TLR4 in ITP patients. We hypothesize that significant differences will exist between pre-treatment and post-treatment in ITP patients with similar changes reflected in the plasma concentration of cytokines. Total RNA was extracted from mononuclear cells obtained from 12 ITP patients and 15 healthy subjects. TLR2 and TLR4 mRNA expression levels were analyzed using a quantitative real-time PCR method and their protein expressions were validated by western blot. Plasma concentrations of cytokines IL-2, IFN-γ and TNF-α were measured by ELISA. Correlation analyses were carried out between the mRNA expression levels of TLR2 or TLR4 and the plasma levels of IL-2, IFN-γ and TNF-α. The gene expression of TLR2 and TLR4 were significantly increased in ITP patients comparing to healthy control group (p < 0.05 and p < 0.01, respectively). In addition their mRNA expression levels were decreased back into normal range after remission in 8 patients (p > 0.05, compared to healthy control group). Significantly positive correlations were found between the TLR2 mRNA expression level and the plasma concentration of IFN-γ or TNF-α (R = 0.75, p < 0.05; R = 0.83, p < 0.05, respectively). Changes in the gene expression of TLR4 and in the plasma concentration of IFN-γ or TNF-α were also significantly correlated (R = 0.82, p < 0.05; R = 0.88, p < 0.05, respectively). Directional changes in TLR2 / TLR4 and IFN-γ /TNF-α expression were concordant. However, there was no correlation found between TLR2 / TLR4 and IL-2. Differences in TLR2 and TLR4 expression strongly correlated with changes in IFN-γ and TNF-α suggest that the increased gene expressions of TLR2 and TLR4 in ITP patients may contribute to the pathophysiological progression of this disease by increasing the secretion of IFN-γ and TNF-α. Additional studies need to be performed to further clarify the role of TLRs -cytokines pathway in ITP.

HLA and Aplastic Anemia: associations In Large Brazilian Cohorts

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1237-1237
Author(s):  
Marco Aurelio Salvino ◽  
Larissa A Medeiros ◽  
Alessandro Moura ◽  
Marianna Batista ◽  
Marilda Souza Goncalves ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Aplastic Anemia ◽  
Protective Factor ◽  
Conflicts Of Interest ◽  
Hla Antigens ◽  
Hla Typing ◽  
Control Group ◽  
Hla Alleles ◽  
Northeast Region

Abstract Introduction Aplastic anemia (AA) is perceived as an immune mediated disease where T-lymphocytes recognize and destroy bone marrow elements leading to varying degrees of failure of hematopoiesis. Many autoimmune diseases have been linked to certain HLA alleles and such a relationship has been also been reported in AA. Expansion of CD8+ oligoclones has been reported in AA and likely contributes to pathogenesis. However, the interaction of CD4+ and CD8+ T cells and their targets mediated by human leukocyte antigen (HLA) class I and II peptides remain elusive. Thus, it has been speculated that polymorphic loci of these genes could be implicated in the susceptibility to the disease. Various alleles and haplotypes of HLA molecules have been implicated in the predisposition of AA development. The influence of HLA has been studied in North America, European and Asian countries. Data from Latin America, where there is a large mixture of Hispanic, European, and African descendants, is still lacking. This study focuses on the association between HLA alleles in AA patients in different regions of Brazil with particular ethnic groups. Patients and methods From 2000 to 2013, all patients with a diagnosis of acquired AA in the Brazilian state of Bahia (BA) followed at the Federal University of Bahia Hospital/ Foundation Hemoba who tested the HLA typing were included, totaling 215 patients. In this northeast region there is a predominance of African descendant (25% white, 75% brown/black). The genes in the analysis included HLA A, B, DR and DQ. SPSS was used to statistical calculations. Qui-square test/Fisher test were using the p-value correction of Bonferroni (p significant <0,0016) for comparison of genetic varieties.The HLA of patients with acquired AA Bahia (n = 215) were compared to the control group (3680 healthy non-related bone marrow volunteers donors from Bahia). To address regional differences within the country we also analyzed the HLA of AA patients (n = 344) from the State of Paraná located in the southern portion of the country and is characterized by a diverse ethnic mixture (71.3% white and 27% black/brown). Thus, we compared the findings of HLA associated with acquired AA in the two states, Bahia (northeast region) and Parana( south region). Of those statistically associated with AA (p<0,0016), we considered HLA clinically relevant only those present in at least 10% of cases and/or controls. Results From the 559 AA patients analysed, 45,1% were women, and 54.9% were men.The mean age was 23.4 (± 12.3). Among the HLA antigens with OR of risk or protection only HLA DR15 and B15, were significant, respectively (in both populations: Bahia and Parana). Identified as a risk factor for development of AA, HLA DR15 was found in 41.6% of patients (Bahia) versus 24% in controls (OR: 2.23 - CI: 1.68 to 2.9) (p <0.0001). As protective factor for AA development the HLA B15 was found in only 6% of patients (Bahia) versus 21.3% of controls (OR: 0.213, CI 0.12 to 0.370) (p <0.0001). A stratified analysis was conducted to assess the presence of interaction between the antigens DR15 and B15 in AA patients. When analyzing synergistically, the effects of HLA DR15 and B15, we observed that, in the AA group, the positivity of DR15+ of 41,6% falls significantly to 14,8%, when concurrently with the presence of B15+. The AA risk factor of HLA DR15+ loses its statistical risk power in presence of B15+. The incidence of B15+ patients (6% in AA patients) falls to 4% in the presence of DR15 negativity (p=ns). Conclusion We observed in 2 large AA cohorts (totaling 559 patients) from very distinct ethnic regions of Brazil, that, in both, HLA DR15 positivity was associated with a higher risk of disease, while B15 positivity was associated with a lesser likelihood of developing AA. The synergic combination of these alleles appears to be further associated with AA development. New studies analyzing synergic effect between HLA antigens/alleles should be conducted in immuno-mediated diseases. Disclosures: No relevant conflicts of interest to declare.

Recombinant Human Thrombopoietin Promotes The Recovery Of Megakaryocyte Lineage In Patients With Severe Aplastic Anemia Receiving Immunosuppressive Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2437-2437
Author(s):  
Zonghong Shao ◽  
Qi'e Dong ◽  
Rong Fu
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Platelet Transfusion ◽  
Conflicts Of Interest ◽  
Severe Aplastic Anemia ◽  
Hematologic Response ◽  
Patient Will ◽  
Red Cell Transfusion ◽  
Recombinant Human Thrombopoietin

Abstract Objective To assess the effectiveness of recombinant human thrombopoietin (rhTPO) in severe aplastic anemia (SAA) patients receiving immunosuppressive therapy (IST). Methods Eighty SAA patients receiving IST during a period from January 2007 to December 2011 were included in this retrospective analysis. Thirty-two subjects also received rhTPO treatment (15,000 U, three times a week, subcutaneously). The remaining 48 patients did not receive rhTPO treatment. The choice of using (or not using) rhTPO was based on physician discretion, and more importantly, patient will (partly based on financial capability to afford the medication). rhTPO was discontinued when platelet count returned to normal range. Hematologic response, bone marrow recovery, transfusion interval (platelet or red-cells), and the time to transfusion-free status were compared. Result At 6th months after the treatment, hematologic response along at least one lineage was achieved in 65.6% of the subjects receiving rhTPO vs. 41.7% in those who did not receive rhTPO (p=0.04). Response rate of megakaryocyte and erythroid lineage at 3rd months was also higher in subjects receiving rhTPO than in those who did not (43.8% vs. 10.4%, p=0.001; 50.0% vs. 20.8%, p=0.006). The mean number of megakaryocyte per bone marrow slide was higher in subjects receiving rhTPO than those who did not (9.7±3.1 vs. 2.6±4.2, p=0.002) after three months. The percentage of nucleated erythroid cells in bone marrow was also higher in subjects receiving rhTPO after three months (22.2±13.2% vs. 13.6±13.9% in those who did not receive rhTPO; p=0.007). The percentage of reticulocytes in peripheral blood was higher in subjects receiving rhTPO (1.9±1.4% vs. 0.7±0.4% in those who did not receive rhTPO; p=0.001) after three months. Myeloid percentage in bone marrow did not differ at any time points (3, 6, or 9 months). The need for platelet transfusion was lower in subjects receiving rhTPO (transfusion interval: 13.8±14.3 vs. 6.9±5.2 and 26.3±28.9 vs. 15.7±13.1 days in those who did not receive rhTPO during the first three and six months, respectively; P=0.004, P=0.03). The need for red cell transfusion was also lower in subjects receiving rhTPO (interval: 32.5±22.0 vs. 11.9±7.2 days and 50.4±27.9 vs. 23.9±20.1 days during the first three and six months, respectively; p=0.001 P=0.009). Time to independence from platelet transfusion was significantly shorter in subjects receiving rhTPO (99.9±49.9 vs. 156.3±14.5 days in those who did not receive rhTPO; p=0.01). Conclusion rhTPO improves hematologic response and promotes bone marrow recovery in SAA patients receiving IST. Disclosures: No relevant conflicts of interest to declare.

IL-35 and Rapamycin Reduce Acute Graft-Versus-Host Disease Associated with Decreased Platelet Aggregation in a Mouse Model

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3814-3814 ◽  
Author(s):  
Xiao-Hui Zhang ◽  
Yi Zhou ◽  
Shi-yuan Zhou ◽  
Fei-er Feng ◽  
Qian-ming Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Survival Rate ◽  
Platelet Aggregation ◽  
Inflammatory Cytokine ◽  
Control Group ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Thrombotic Complications ◽  
Ifn Γ ◽  
Acute Graft

Abstract Introduction: Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) caused by the activation of donor T lymphocytes by host antigen-presenting cells and the immune-mediated inflammatory response. Epithelial cells of the skin and mucous membranes, biliary ducts, and intestinal tract crypts are the primary tissue systems damaged during the pathobiological course of GVHD. IL-35, a member of the IL-12 family of cytokines, comprising an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). It is an anti-inflammatory cytokine that suppresses the immune response through the expansion of regulatory T cells and suppression of Th17 cell development (Niedbala W, et al. European journal of immunology 2007). Rapamycin (Sirolimus; RAPA), a macrolide antibiotic produced by Streptomyces hygroscopicus, has been used for the prophylaxis and treatment of several immune reactions including GVHD and solid organ rejection (Ho-Jin Shin, et al. Blood 2011). We hypothesized that IL-35 has a protective effect in aGVHD, and that its function may be increased by RAPA. Methods: We used C57BL/6 (B6, H-2b) mice as donors and (B6×DBA/2)F1 (BDF1, H-2b×d) mice as recipients to create an aGVHD model (Kuroiwa T, et al. The Journal of clinical investigation 2001). Mice were divided into five groups, including a BMT control group, aGVHD control group, aGVHD treated with IL-35 group, aGVHD treated with RAPA group and aGVHD treated with IL-35 and RAPA group. Morbidity and mortality related to aGVHD were observed, and 2 weeks after BMT, tissues from the intestine and liver were stained with hematoxylin and eosin and examined by light microscopy. To detect apoptosis in intestinal sections, a modified terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) method was applied. CD4+CD25+Foxp3+ regulatory T cells were measured by flow cytometry. Quantitative RT-PCR was used to measure the production of IFN-γ, TNF-α and IL-17A in the spleen and intestine of each group of mice. We also measured platelet aggregation using a turbidimetric aggregation-monitoring device. Finally, western blotting was conducted to test the signaling pathways of IL-35. Results: Mice receivingIL-35 exhibited a higher survival rate compared with GVHD mice as well as those mice receiving RAPA. When the two drugs were given together, the survival rate was much higher than that in the other groups. The aGVHD control group had the highest morbidity rate of aGVHD, and IL-35 plus RAPA could prevent the occurrence of aGVHD. Additionally, this treatment inhibited apoptosis of intestinal epithelial cells as well as donor T-cell infiltration into the liver, thereby ameliorating the enteropathy and liver injury caused by aGVHD. The importance of the inflammatory cytokine cascade in the pathogenesis of both clinical and experimental GVHD is now well accepted. We found that IL-35 and RAPA also markedly suppressed IFN-γ, TNF-α and IL-17A expression in the intestine and liver. Because studies by other have showed that Tregs have the ability to inhibit aGVHD, we measured Tregs in serum and found that IL-35 and RAPA treatment expanded serum Tregs. We further explored the relationship between IL-35 and platelet aggregation. Platelet aggregation was high in aGVHD mice, and the ratio of platelet aggregation was inhibited by IL-35 and RAPA. Finally, we found that the phosphorylation of STAT1 and STAT4 were inhibited in GVHD mice, and thatSTAT1 and STAT4 were phosphorylated when mice were treated with IL-35. Conclusions: IL-35 may be useful for controlling aGVHD after allo-HSCT. IL-35 suppresses inflammatory cytokines and expands anti-inflammatory cells in aGVHD. IL-35 also prevents platelet aggregation in aGVHD mice, which could be helpful in treating thrombotic complications after HSCT. These results are readily translatable to the clinic in future clinical trials. IL-35 and RAPA may have potential clinical use for the prevention or treatment of aGVHD and thrombotic complications after HSCT. Disclosures No relevant conflicts of interest to declare.

The content of cytokines IL-6, IL-8, TNF-α, IL-4 and the level of expression in macrophages CD86 and CD163 in peritoneal fluid has a reverse correlation with the degree of severity of external genital endometriosis

2019 ◽  
Vol 65 (5) ◽  
pp. 432-436
Author(s):  
A.M. Krasnyi ◽  
A.A. Sadekova ◽  
T.G. Sefihanov ◽  
V.V. Vtorushina ◽  
E.G. Krechetova ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Peritoneal Fluid ◽  
Inflammatory Marker ◽  
Inflammatory Activity ◽  
Control Group ◽  
Reverse Correlation ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Degree Of Severity

Concentrations of eight different cytokines and the level of expression of CD86 and CD163 macrophages were studied in peritoneal fluid in women with endometriosis. It was found that the concentration of both inflammatory (IL-6, IL-8, TNF-α) and anti-inflammatory cytokines (IL-4) as well as the level of macrophage expression of the proinflammatory marker CD86 and anti-inflammatory marker CD163 increased in women with mild external genital endometriosis (1-2 stage), and did not differ from the control group in women with severe endometriosis (3-4 stage). The content of IL-2, IL-10, CM-CSF and IFN-γ in the peritoneal fluid of women with endometriosis did not differ significantly from the control group. The results of the study indicate that the development of external genital endometriosis may be based on insufficient both inflammatory and anti-inflammatory activity of macrophages in the peritoneal fluid.

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