Cytokine gene polymorphism in denture stomatitis patients: A clinical study.

OBJECTIVE: This clinical study investigated the association between cytokine gene polymorphism and Candida growth in denture stomatitis (DS) patients. SUBJECTS AND METHODS: Saliva and blood samples of 160 complete denture wearers (80 healthy controls and 80 with DS) were collected for mycological and gene polymorphism testing, respectively. Salivary Candida growth and TNF-α, TGF-ß, IL-6, and IL-10 genotypes were investigated. Data were analyzed using Student's t test, Mann-Whitney U test, chi-square analysis, and continuity (yates) correction tests (p < .05). RESULTS: Candida albicans colony counts in saliva were significantly higher in the DS group and in the TNF-α GG genotype (p < .05). TGF-ß TC GG and TGF-ß CC GG haplotypes were significantly higher in DS and control groups, respectively (p < .05). C. albicans colony counts were significantly higher in control group in the TGF-ß TC GG haplotype (p < .05). Candida glabrata colony counts were significantly higher in the DS group than the control group in IL-6 GG genotype (p < .05). The difference between DS types in IL-6 genotypes was significant with lower expression level in DS type 3 than DS type 1 and also type 2 (p ≤ .01). CONCLUSION: The significant differences in some genotypes of the TNF-α, TGF-ß, and IL-6 in DS patients are promising in understanding the host defense in DS.

Cutaneous drug reactions to antiepileptic drugs and relation with HLA alleles in the Turkish population.

Summary: Background and objective. Many studies have shown associations between HLAB*15:02, HLA-A*31:01 and carbamazepine (CBZ)-induced delayed cutaneous hypersensitivity reactions. The aim of this study is to evaluate a possible association between delayed cutaneous reactions to antiepileptic drugs (AEDs) and certain HLA-A and HLA-B alleles in the Turkish population. Methods. The study consisted of 3 groups: Group I (reactive group) included the patients who had documented delayed cutaneous reactions to any antiepileptic drug. Group II (non-reactive group) included the patients who have been on antiepileptic treatment at least for three months without any adverse reactions. Group III consisted of healthy subjects. The HLA-A and B alleles were analyzed in all groups. Results. Forty patients (29 female) had experienced different hypersensitivity reactions due to AEDs: maculopapular exanthema (26 patients), Stevens-Johnson syndrome (6 patients), drug rash with eosinophilia and systemic symptoms (7 patients), toxic epidermal necrolysis (1 patient). Lamotrigine (11) and CBZ (10) were the most common culprit drugs involved in the reactions. The HLA-B*15:02 was not present in any of the study groups. However, HLA-B*35:02 was found in 4 patients from the reactive group, while it was not observed in non-reactive patients and was detected in only one healthy subject (p = 0.021). Conclusion. Although our preliminary results did not indicate a strong allele association with AED hypersensitivity, HLA-B*35:02 appears to be a candidate allele for MPE / DRESS / DIHSS induced by AED's in Turkish population. Further studies with a larger sample size may result in more comprehensive data about the genetic tendency for AED hypersensitivity in the Turkish population.

A Novel Biomarker for Post-Transplant Recurrent IgA Nephropathy.

BACKGROUND: The serum levels of galactose-deficient immunoglobulin (Ig)A1 (Gd-IgA1) represent the most promising candidate biomarker for IgA nephropathy (IgAN). The aim of this study was to evaluate the serum levels of Gd-IgA1 as a novel noninvasive biomarker for post-transplant IgAN recurrence. METHODS: Serum Gd-IgA1 levels of 18 patients with recurrent IgAN were compared with control renal transplant recipients (n = 23) with non-recurrent IgAN and control non-transplant IgAN patients (n = 44) and healthy relatives (n = 11). Serum Gd-IgA1 levels of patients were measured with the use of KM55 enzyme-linked immunosorbent assay (ELISA). The effects of serum Gd-IgA1 concentrations on IgAN recurrence, post-transplant events, and graft survival were evaluated. RESULTS: All recurrent IgAN patients presented with renal dysfunction (mean serum creatinine, 1.62 ± 0.39 mg/dL) and detectable proteinuria at the time of diagnosis. Serum Gd-IgA1 levels of recurrent IgAN patients (8735 ± 10854 ng/mL [log10: 3.71 ± 0.45]) were significantly higher than those of non-recurrent IgAN patients (4790 ± 6089 ng/µL [log10: 3.31 ± 0.64]) (P = .027). Serum Gd-IgA1 levels of non-transplant IgAN patients were significantly higher (8791 ± 8700 ng/µL [log10: 3.79 ± 0.36]) than those of non-recurrent IgAN patients (4790 ± 6089 ng/µL [log10: 3.31 ± 0.64]) and healthy relatives (2615 ± 1611 ng/µL [log10: 3.34 ± 0.27]) (P < .001 and P = .021, respectively). Receiver-operating characteristic curve analysis revealed that the area under the curve for recurrence of IgAN was 0.69 (0.53-0.85) for serum Gd-IgA1 (P = .038). Biopsy-confirmed allograft rejection rates were similar in the recurrent IgAN group [3 (17%)] compared with the non-recurrent IgAN [6 (26%)] group (P = .47). Graft failure rate was not also significantly different in the recurrent IgAN group [4 (22.2%)] compared with the non-recurrent IgAN group [2 (8.7%)] (P = .224). CONCLUSIONS: This novel lectin-independent Gd-IgA1 ELISA that can detect serum Gd-IgA1 in patients with recurrent IgAN can be used as a biomarker for diagnosis and activity assessment of post-transplant recurrent IgAN.

Genetic association of interleukin-2, interleukin-4, interleukin-6, transforming growth factor-ß, tumour necrosis factor-α and blood concentrations of calcineurin inhibitors in Turkish renal transplant patients.

Cytokines are essential for the control of the immune response as most of the immunosuppressive drugs target cytokine production or their action. The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are immunosuppressive drugs widely used after renal transplantation to prevent allograft rejection. They are characterized by large interindividual variability in their pharmacokinetics; therefore, monitoring their blood concentrations is important to predict their optimal dosage following transplantation. Calcineurin inhibitors inhibit the phosphatase activity of calcineurin, thereby suppressing the production of other cytokines such as transforming growth factor (TGF-ß), tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-2, and IL-4. The aim of this study was to investigate the relationship between polymorphisms of cytokines and blood concentrations of CNIs in renal transplant patients. The study included 53 CsA-treated renal transplant patients and 37 tacrolimus-treated renal transplant patients. Cytokine polymorphisms were analysed using polymerase chain reaction (PCR) sequence-specific primers with the cytokine CTS-PCR-sequence-specific primers Tray Kit; University of Heidelberg. Blood concentrations of CNIs were determined with Cloned Enzyme Donor Immunoassay (CEDIA) method. Patients with TC genotype of TGF-ß at codon 10 had lower CsA blood concentrations than the TT and CC genotypes (P = 0.005) at 1 month in CsA treatment group. The ratio of blood concentration/dose of CsA for patients with TGF-ß1-codon 10 TC genotype was lower than for patients with TT, CC genotypes, and the dose given to these patients was higher in the first month (P = 0.046). The ratio of blood concentration/dose of CsA for patients with IL-2-330 GG genotype was higher than for patients with GT, TT genotypes, and the dose given to these patients was lower at first month and sixth months (P = 0.043, P = 0.035 respectively). The tacrolimus blood concentrations were significantly higher in patients with the genotype GG of IL-2-330 (P = 0.012) at the third month. Patients who had the TC genotype TGF-ß codon 10 had lower CsA blood concentrations and this group had higher acute rejection (P = 0.033). These results suggest that the genotyping for TGF-ß-codon 10, IL-2-330 and IL-6-174 polymorphisms may help individualized immunosuppressive dosage regiments.

The effect of anti-human leukocyte antigen, anti-major histocompatibility complex class 1 chain-related antigen a, and anti-glutathione transferase-T1 antibodies on the long-term survival of renal allograft.

BACKGROUND: One of the most important mechanisms of allograft rejection is the production of donor-specific antibodies (DSA). Anti-major histocompatibility complex class-I chain-related antigen A (MICA) and anti-glutathione S transferase-T1 (GSTT1) antibodies cause graft dysfunction and reduce graft survival. The aim of this study was to examine the effects of anti-human leukocyte antigen class I-II, anti-MICA, and anti-GSTT1 antibodies in development of antibody-mediated rejection. METHODS: Among the 32 renal transplant patients included in this study 65% experienced antibody-mediated rejection (AMR; chronic active AMR [CAMR], n = 17; acute AMR [AAMR], n = 4) and 35%, ACR. The anti-HLA class I-II and anti-MICA antibodies were determined by using LUMINEX, anti-GSTT1 antibodies by enzyme-linked immunosorbent assay. GSTT1 genotyping of patients and donors was performed by polymerase chain reaction. RESULTS: Antibody was detected in 19 of 21 patients undergoing antibody-mediated rejection (90%). We detected anti-GSTT1 in 4, anti-MICA in 8, anti-HLA class I in 5, and anti-HLA class II in 9 patients with CAMR (P = .007). If the patients were divided into 2 groups according to being C4d(+) and C4d(-) both anti-HLA class I and class II antibodies were found significantly more frequently among the C4d(+) group (P = .019, P = .024). No difference was determined between AMR and ACR groups in terms of anti-GSTT1 and anti-MICA antibodies. CONCLUSIONS: In this study, we observed the role of anti-HLA class II antibodies in the development of CAMR and in long-term allograft survival. It is observed that anti-MICA and anti-GSTT1 antibodies showed no effect on rejection mechanisms.

Influence of cytokine gene polymorphisms on graft rejection in Turkish patients with renal transplants from living related donors.

BACKGROUND: Certain cytokine gene polymorphisms (CGPs) have been shown to be associated with renal transplant rejection episodes or graft outcomes. We sought to evaluate the relationships between gene polymorphisms and acute rejection episodes (RG, n = 19) versus stable graft function (NRG, n = 71) in transplant recipients compared with healthy control subjects (HCG, n = 150). The follow-up time period was 18 months. Using polymerase chain reaction sequence-specific primers with the Heidelberg kit we genotyped 22 single nucleotide polymorphisms distributed across 13 cytokine and cytokine receptor genes. RESULTS: Interleukin (IL)-2 TT/GT haplotype was found in 36.8% of RG patients and 6.7% of HCG but not among the NRG (P < .0001; .0007). The IL-2 GG/TT haplotype was observed among 13 NRG and nine HCG patients (P = .007); the IL-2 GG/GG haplotype, 18.7% HCG and 4.2% NRG patients (P = .0033); and the IL-2 TT/TT haplotype, five NRG and eight HCG patients, but none of the RG cohort (P > .05). The transforming-growth factor-beta 1 CG/CC haplotype was noted in 15 NRG (21.1%) and four HCG but no RG patients (P < .0001). The IL-2 +166 GT genotype was detected in 36.8% of RG, 8.5% of NRG, and 14.7% of HCG patients (P = .005, .0244). The IL-2 -330 GG genotype was demonstrated in 32 healthy controls and three nonrejection transplant patients (P = .0007). Significant differences were concluded between NRG and HCG for IL-6 565 AG, IL-1beta -511 TT and +3962 CC/CT/TT genotypes. DISCUSSION: We observed significant differences among the frequencies of IL-2 gene polymorphisms among RG and NRG subjects, which agreed with previous clinical, but not in vitro studies.

The effect of glutathion S-transferase polymoprhisms and anti-GSTT1 antibodies on allograft functions in recipients of renal transplant.

The balance between oxidative stress and anti-oxidant defense systems after renal transplantation may explain the development and progression of allograft dysfunction. Glutathione S-transferase (GST) decreases the damage from oxidative stress. In contrast, recipient antibodies against GSTT1 expressed on the graft are believed to cause its dysfunction. The aim of our research was to study the probable relationship to rejection between GST gene polymorphisms and anti-GSTT1 antibodies. We included 122 patients transplantations from living donors and 51 healthy individuals as controls group in our study. The patient groups were comprised of 57 patients who did and 65 who did not experienced rejection episode. Polymerase chain reactions were used to detect GSTM1 and GSTT1 polymorphisms, whereas PCR-RFLP (restriction fragment length polymorphism), for GSTP1 polymorphism. An enzyme-linked immunosorbent assay method was used for anti-GSTT1 antibody scans. There was no significant difference between the groups for allele and genotype frequencies of GSTT1, GSTM1, GSTP1 polymorphisms of the recipients, donors, and controls. Within the rejection group the frequency of patients with the GSTM1 null genotype was higher among subjects prescribed cyclosporine A versus tacrolimus (P = .029). Among the entire patient group, 46 subjects with GSTT1 null genotype were scanned for anti-GSTT1 antibody which was detected in 5 of 8 patients with an acute rejection episode (P = .04). Anti-GSTT1 antibody was observed more frequently albeit not significantly, among the cyclosporine versus tacrolimus patient group (P = .16). This study suggested that GSTM1 genotype may be important for cyclosporine detoxification and for allograft outcomes due to drug nephrotoxicity. After transplantation, antigens distinct from the HLA system such as GSTT1 protein may also be targets for alloimmune responses.

Influence of cytokine gene polymorphisms on graft rejection in Turkish patients with renal transplants from living related donors.

INTRODUCTION: Certain cytokine gene polymorphisms (CGPs) have been shown to be associated with renal transplant rejection or graft outcomes. We sought to evaluate the relationship between gene polymorphisms in patients with acute rejection episodes (rejection group, RG, n = 19) versus those with stable graft function (nonrejection group, NRG, n = 71) in comparison with healthy control subjects (HCG, n = 150). The follow-up time period was 18 months. In the present study, 22 single nucleotide polymorphisms distributed across 13 cytokine and cytokine receptor genes were genotyped by polymerase chain reaction sequence-specific primers (PCR-SSP) using the Heidelberg kit. RESULTS: The interleukin-2 (IL-2) TT/GT haplotype was observed among 36.8% of patients in the RG and 6.7% of those in the HCG but not in any NRG patient (P < .0001; .0007). The IL-2 GG/TT haplotype was observed among 13 NRG and 9 HCG patients (P = .007). The IL-2 GG/GG haplotype was noted in 18.7% of HCG and 4.2% of NRG patients (P = .0033) and the IL-2 TT/TT haplotype in 5 and 8 patients of NRG and HCG, respectively, but not in any RG patient (P > .05). The transforming growth factor beta1 CG/CC haplotype was noted in 15 NRG (21.1%) and 4 HCG patients but not any RG (P < .0001). The IL-2 + 166 GT genotype was detected in 36.8% of RG, 8.5% of NRG, and 14.7% of HCG patients (P = .005, .0244). The IL-2 -330 GG genotype was demonstrated in 32 healthy controls and 3 nonrejection transplant patients (P = .0007). Significant differences were found between NRG and HCG for IL-6 565 AG, IL-1 beta -511 TT and +3962 CC/CT/TT genotypes. DISCUSSION: We observed significant differences among the frequencies of IL-2 gene polymorphisms between the RG and the NRG, which were consistent with previous clinical but not in vitro studies.

The frequency of HLA class I and II alleles in Turkish childhood acute leukaemia patients.

In this study, blood samples were taken from 200 patients with childhood acute leukaemias, including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), and from 100 healthy volunteers (controls). The frequency of the human leucocyte antigen (HLA)-DRB1*04 allele was significantly higher, and the frequencies of the HLA-A23 and HLA-B7 antigens were significantly lower, in patients with ALL compared with controls. Among patients with AML, the frequency of the HLA-B49 antigen and the HLA-DRB1*15 allele were significantly higher, whereas the frequencies of the HLA-A11 and HLA-B38 antigens were significantly lower compared with controls. The frequency of the HLA-DRB1*04 allele was also significantly higher in male patients with ALL and AML, whereas the HLA-DRB1*13 allele was found significantly less frequently in male AML and female ALL patients than in controls. To date, this is the only study to evaluate the associations between HLA molecules and leukaemia in a Turkish population with acute childhood leukaemia.

Anti-HLA antibody profile of Turkish patients with end-stage renal disease.

Exposure to human leukocyte antigens (HLA) via blood transfusions, pregnancies, and previous transplantations can result in anti-HLA antibody production. The presence of anti-HLA antibodies in recipient sera before transplantation is an important risk factor. To demonstrate the anti-HLA antibody status of Turkish end-stage renal disease (ESRD) patients, 674 patients (mean age, 40.35 +/- 13.15 years; female/male, 328/346) were enrolled into the study. Anti-HLA antibody screening and identification tests were performed using an enzyme-linked immunosorbent assay (ELISA) method. The panel-reactive antibody (PRA)-negative group consisted of 564 (83.6%) and the PRA-positive group consisted of 110 (17.3%) patients. Of the 110 (17.3%) PRA-positive patients, 43 (6.4%) were class I (+) and class II (-); 19 (2.8%) were class I (-) and class II (+); 48 (7.1%) were both class I and II (+). The most frequent antibodies were directed against the A2 crossreactive group (CREG) and the A10 CREG with less frequent reactions against the B7 CREG, indicating antibodies to both frequent (members of A2 CREG) and relatively rare (members of A10 CREG and B7 CREG antigens). These data also suggested that some antibodies occur at greater than expected frequency because of shared epitopes. Our findings confirmed the significant correlation between female gender, pregnancy, failed graft history, long dialysis duration, and blood transfusions with PRA positivity (P < .05).

Relationship between HLA tissue type, CMV infection, and acute graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: single-center experience.

After allogeneic hematopoietic stem cell transplantation, risk factors for cytomegalovirus (CMV) reactivation include pretransplantation donor and recipient CMV serologic status and posttransplantation development of acute graft-vs-host disease (aGvHD). Human leukocyte antigen (HLA) allele type is an additional factor in CMV infection. The present study included 108 patients who received an allogeneic stem cell graft from an HLA-identical sibling between 1993 and 2004. All recipients and donors were typed for HLA-A, HLA-B, and HLA-DR alleles using serologic or molecular methods. All recipients received grafts because of a hematologic disease from HLA full-matched donors. In pretransplantation seropositive patients with aGvHD, no significant difference was observed in patients who developed CMV infection compared with those without CMV infection. Seropositive patients without aGvHD but with posttransplantation CMV infection demonstrated a higher incidence of HLA-A30, HLA-B40, and HLA-DRB1*15 compared with those without CMV infection. In conclusion, it seems that certain HLA alleles may have either a protective or predisposing role in CMV reactivation, which might be helpful in estimating the risk of aGvHD and designing individualized therapy.