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Cytokine gene polymorphisms have been associated with poor outcomes after renal transplantation such as chronic allograft nephropathy (CAN), graft rejection (GR) and graft failure (GF), but the effects of these polymorphisms are still controversial. We therefore conducted a systematic review, with individual patient data (IPD) where possible, to determine the association between cytokine polymorphisms (TGF-beta1, TNF-alpha and IL-10) and outcomes after renal transplantation.Five investigators were willing to participate and provided IPD. The outcomes of interest were GF, GR and CAN. Subjects with at least one of these were classified as having poor outcomes. Heterogeneity of gene effects was assessed. Multiple logistic regression was applied to assess gene effects, adjusting for clinical variables such as HLA matching and age.One-thousand and eighty-seven subjects were included in the IPD meta-analysis. Pooled results showed no evidence of heterogeneity and indicated that the strongest variables determining poor outcomes are HLA mismatching (OR = 1.6-1.8 for/=3 HLA-A, -B, -DR mismatches compared with those with3 mismatches) and age (OR = 1.2-1.4 for age 45 years or more). Incremental information on risk of a poor outcome is provided by the TGF-beta1c10 polymorphism (OR = 1.5, P = 0.034, 95% CI: 1.0-2.2 for TC genotype compared to TT genotype). Haplotypes of TGF-beta1 at c10 and c25 were inferred and the C-C haplotype was a marker of a poor outcome (OR = 1.3, P = 0.177, 95% CI: 1.0-2.3). Three polymorphisms of the IL-10 gene at -1082, -819, -592 are in strong linkage disequilibrium with each other (correlation coefficients: 0.6-1) and inferred haplotypes between these three loci show some association, with ACC increasing the risk of poor events compared to GCC (OR = 1.3, P = 0.044, 95% CI: 0.9-1.6).Pooled results to date suggest possible association between both the TGF-beta1 c10 polymorphism and a 3-SNP-haplotype of IL-10 and poor outcomes in renal transplantation, but this needs to be confirmed in larger studies.

We sought to determine whether placental cytokine expression is altered in patients with preeclampsia.Whole placental tissue was collected at cesarean delivery, and total ribonucleic acid was extracted. Reverse transcriptase-polymerase chain reaction was performed to determine cytokine expression. Product bands were quantitated by scanning densitometry, and results were expressed as a ratio of cytokine/housekeeping gene (cytokine expression index). Statistical analysis was performed by the Student t test and the Mann-Whitney U test.Placentas from 6 patients with preeclampsia and 4 normotensive patients were analyzed. Placental expression of interleukin 1beta and interleukin 10 was greater in preeclamptic women than in normotensive subjects (median interleukin 1beta cytokine expression index, 0.675; range, 0.394-0. 953; vs 0.106; range, 0.084-0.166; P =.011; median interleukin 10 cytokine expression index, 1.042; range, 0.672-1.192; vs 0.126; range, 0.062-0.398; P.011). Tumor necrosis factor alpha messenger ribonucleic acid was detected in placentas of preeclamptic subjects but not in normotensive control subjects.Placentas from preeclamptic patients demonstrated increased expression of interleukin 1beta, interleukin 10, and tumor necrosis factor alpha. This may be in association with placental hypoxia and may contribute to the global endothelial dysfunction observed in preeclampsia.

Injury has been hypothesized to cause inflammation through systemic release of lipopolysaccharide and pro-inflammatory cytokines, but this has proved difficult to demonstrate in humans. We looked for evidence of an inflammatory pattern of cytokine gene expression by peripheral blood mononuclear cells (PBM) in six polytraumatized patients (ISS = 25 +/- 8) upon ER admission, and in six matched healthy controls. PBM tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-4, IL-6, IL-10, and interferon (IFN)-gamma message was assessed by semi-quantitative reverse-transcription polymerase chain reaction. No increase in expression of any of the pro-inflammatory cytokines (tumor necrosis factor-alpha, IL-1 beta, or IL-6) was found after trauma, and IFN-gamma tended to decrease. Of the immunosuppressive cytokines, IL-10 expression increased 5-fold (p < .05) but no change in IL-4 was discerned. This pattern is fundamentally different from the cytokine expression patterns expected with sepsis or exposure to lipopolysaccharide. These findings are inconsistent with the occurrence of systemic endotoxemia and subsequent global immunocyte activation early after trauma.

Experimental studies have shown that administration of antilymphocyte serum combined with donor bone marrow cells can induce tolerance to allograft tissue. We have initially reported application of these protocols in clinical studies of cadaveric renal allograft recipients who were treated with MALG and donor-specific bone marrow cells. To evaluate the effectiveness of the donor marrow cells in the production of chimerism, a detection method based on 32 P-incorporated PCR was established. The 32 P PCR was utilized with primers specific for the HLA class II, VNTR (D17S5 and D1S111), and/or Y-chromosome genes to detect the presence of allogeneic chimerism in the recipients

Introduction Malignant breast tumors are often hormone-dependent, and to this end, both estrogen and progesterone receptors are good prognostic markers for evaluation of the outcomes after therapy. In addition, HER-2/neu, whose expression is increasingly being associated with poor prognosis of breast cancer, has predictive potential after immunotherapy. Cytochrome P450 3A4 is highly involved in the metabolism of steroids. Thus, we investigated the impact of CYP 3A4 gene variants in association with clinical outcomes in African American (AFAM) versus Caucasian (CAU) patients with breast cancer diagnosis. Methods Patients who had undergone biopsy procedures for diagnosis or for partial or radical mastectomy were recruited. The CYP 3A4 genotypes (A or G) were detected using polymerase chain reaction amplification and primers designed for a single nucleotide polymorphism. The messenger RNA (mRNA) transcripts were screened by reverse transcription-polymerase chain reaction. Clinical data including tumor staging, pathology grades, and family history were evaluated. Results Frequency of the CYP 3A4-G (mutated variant) was significantly increased in AFAM patients as compared with controls ( P < 0.001). No statistically significant difference was observed between the genotypes comparing the benign versus ductal carcinomas in situ (DCIS) or infiltrating ductal carcinomas (IDCAs). In AFAM patients, GG alleles were increased in IDCA with stage III tumors, and in CAU patients, the AA alleles were increased with stage III tumors. The mRNA expression was reduced in patients with IDCA versus DCIS or benign tumors (benign vs IDCA, P < 0.0009; DCIS vs IDCA, P < 0.005), as well in HER-2/neu-positive tumors versus samples negative for receptors ( P < 0.0024). Conclusions Genotype association was affected by race. Expression levels of total CYP 3A4 mRNA were inversely correlated with clinical diagnosis. This may suggest mRNA testing as an additional tool that accelerates improvement in the diagnosis of the onsets of breast cancer.

Background. Socioeconomic variables including low income and noncompliance impact negatively upon long-term renal allograft survival, especially in African Americans. We sought to determine whether other socioeconomic variables contributed to noncompliance and allograft survival. Methods. A detailed history of socioeconomic variables was made at the time of renal transplant evaluation in 450 consecutive candidates, 128 of whom (89 African American, 39 Caucasian) have thus far undergone transplantation. Variables evaluated included household income, zip code income, insurance coverage, years of education, literacy, marital status, pretransplantation compliance, and history of substance abuse as well as the usual pre- and posttransplantation demographics. Results. Immunologic graft loss occurred primarily in young African Americans with income below the federal poverty level, whereas nonimmunologic graft loss was distributed across racial, income, and other socioeconomic variables. Immunologic graft loss was also associated with a greater number of HLA mismatches, lower levels of education, and noncompliance with transplant medications and follow-up visits. Recipients with gross illiteracy, however, had excellent graft survival. Pretransplantation substance abuse, but not pretransplantation compliance, was predictive of posttransplantation noncompliance. By multivariate analysis, posttransplantation compliance emerged as the single most important factor predictive of graft survival. Conclusions. Immunologic graft loss in our population is related to noncompliance with transplant medications, which occurred primarily in recipients with a pretransplantation history of substance abuse and is not related to an inability to pay for medications at the time of graft loss. A change in criteria for acceptance of transplant candidates with a prior history of substance abuse might significantly improve graft survival in this patient population.

T-helper 2 (TH2)-type cytokines [i.e., interleukin (IL)-6, IL-10, and IL-13] and transforming growth factor (TGF)-beta are expressed by the murine decidua and/or placenta and are likely to suppress inflammatory cytokine [i.e., IL-2, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-1 alpha, and IL-1 beta] production at the maternal-fetal interface. In addition, class I IFNs may protect the fetus from immunologic rejection and viral infections. This study examines the expression of inflammatory/immunoregulatory cytokines and IL-10 production by first-trimester chorionic villi.Gestational tissues (n = 5) were obtained following elective terminations performed between 7 and 9 weeks of gestation. Chorionic villous tissues were separated from fetal membranes and decidua, and total RNA was extracted. Cytokine expression was assessed by a reverse transcriptase-polymerase chain reaction technique. Chorionic villi (n = 9; 6-12 weeks gestation) were maintained in organ culture, and human chorionic gonadotropin (hCG) and IL-10 levels were determined by immunoradiometric and enzyme-linked immunosorbent assays, respectively.IFN-gamma and IL-2 were generally not expressed by first-trimester chorionic villi. Low to moderate levels of expression were noted for IL-1 alpha, IL-1 beta, and TNF-alpha. High levels of mRNA were noted for IFN-alpha and IFN-beta, but IFN-tau was not expressed. In all tissues, TGF-beta 1 and IL-13 were either weakly expressed or not expressed. In contrast, moderate to high levels of IL-6 and IL-10 mRNA were detected in each chorionic villous sample. In chorionic villous explants obtained at 6-11 weeks gestation production of hCG and IL-10 was greatest during the first 24 hr ([hCG] = 6961 +/- 815 mIU/mL, [IL-10] = 92 +/- 11 pg/mL) and then declined through 72 hr.TH1-type cytokines (IL-2, IFN-gamma) are not expressed by first-trimester chorionic villous tissues: This is possibly due to local production of IL-10. In contrast, macrophage-associated cytokines (IL-1 beta and TNF-alpha) are expressed and their regulation may be critical for fetal survival. Finally, class 1 IFNs expressed by early chorionic tissues may protect the fetus from maternal rejection and viral transmission.

PROBLEM: Communication at the human maternal-fetal interface occurs by an intricate cytokine network. This study examines cytokine expression by normal first-trimester human chorionic villi. METHOD OF STUDY: Tissues were obtained at elective pregnancy terminations (7-9 weeks). Total RNA was isolated from chorionic villi by guanidinium isothiocynate-acid phenol extraction. A reverse transcriptase-polymerase chain reaction technique was used to examine cytokine expression. β-Actin was used as the housekeeping gene, and mitogen-stimulated lymphocytes served as positive controls. RESULTS: β-Actin was uniformly expressed by all chorionic villous samples. Interferon (IFN)-α and -β also were highly expressed. Moderate expression was noted for interleukin (IL)-10, IL-6, tumor necrosis factor (TNF)-α, and IL-1β. In contrast, transforming growth factor-β1, IFN-γ. IL-2, and IL-1α were either weakly expressed or absent in first-trimester villi. CONCLUSIONS: Cytokines may contribute to pregnancy immunotolerance (IFN-α, IFN-β, and IL-10), viral resistance (IFNs), hormone secretion (IL-I and IL-6), and cellular remodeling (IFN-γ and TNF-α) within the chorionic villous.