William H. Barber

Expression of the placental cytokines tumor necrosis factor α, interleukin 1β, and interleukin 10 is increased in preeclampsia ☆ ☆☆ ★

Abstract Objective: We sought to determine whether placental cytokine expression is altered in patients with preeclampsia. Study Design: 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. Results: Placentas from 6 patients with preeclampsia and 4 normotensive patients were analyzed. Placental expression of interleukin 1β and interleukin 10 was greater in preeclamptic women than in normotensive subjects (median interleukin 1β 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 Conclusion: Placentas from preeclamptic patients demonstrated increased expression of interleukin 1β, interleukin 10, and tumor necrosis factor α. This may be in association with placental hypoxia and may contribute to the global endothelial dysfunction observed in preeclampsia. (Am J Obstet Gynecol 1999;181:915-20.)

Peripheral blood chimerism in renal allograft recipients transfused with donor bone marrow.

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 32P-incorporated PCR was established. The 32P 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. Immediately posttransplant, 26.4% of marrow recipients demonstrated the presence of allogeneic chimerism prior to the marrow transfusion as did 18% in the untransfused controls. In transfused patients, chimerism was detected most frequently during the 1–3-month interval after marrow transfusion (65%), and then diminished to 50–56% at 3–12 months posttransfusion. In the control group the frequency of allogeneic chimerism was gradually decreased and was undetectable in the majority of the patients beyond 3 months posttransplant while marrow-transfused recipients were more likely to have chimeric cells detected consistently beyond 3 months. Rejection episodes were significantly effected by the presence of chimerism in the recipients. Of the transfused patients, 91.3% who demonstrated allogeneic chimerism were rejection-free as compared with 8.7% who experienced at least one rejection episode (P=0.01). While the presence of allogeneic chimerism in the control group was correlated with rejection-free graft survival, this difference did not reach statistical significance.

First‐Trimester Human Chorionic Villi Express Both Immunoregulatory and Inflammatory Cytokines: A Role for Interleukin‐10 in Regulating the Cytokine Network of Pregnancy

PROBLEM: T‐helper 2 (TH2)‐type cytokines [i.e., interleukin (IL)‐6. IL‐10, and IL‐13] and transforming growth factor (TGF)‐β are expressed by the murine decidua and/or placenta and are likely to suppress inflammatory cytokine [i.e., IL‐2, interferon (IFN)‐γ, tumor necrosis factor (TNF)‐α, IL‐1α, and IL‐1β] 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.

Association between cytokine gene polymorphisms and outcomes in renal transplantation: a meta-analysis of individual patient data

BACKGROUND 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. METHODS 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. RESULTS 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 with <3 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). CONCLUSION 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.

Cytokine Expression by First‐Trimester Human Chorionic Villi

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.

Human peripheral mononuclear cells do not show proinflammatory patterns of cytokine transcription in early trauma: a preliminary report.

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)-α, interleukin (IL)-1 β, IL-4, IL-6, IL-10, and interferon (IFN)-γ 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-α, IL-1β, or IL-6) was found after trauma, and IFN-γ 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.

Differential association of cytochrome P450 3A4 genotypes with onsets of breast tumors in African American versus Caucasian patients.

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.