Comparison of pregnancy outcomes in Dutch kidney recipients with and without calcineurin inhibitor exposure:a retrospective study

Within pregnancies occurring between 1986 and 2017 in Dutch kidney transplant recipients (KTR), we retrospectively compared short-term maternal and foetal outcomes between patients on calcineurin inhibitor (CNI) based (CNI+) and CNI-free immunosuppression (CNI-). We identified 129 CNI+ and 125 CNI- pregnancies in 177 KTR. Demographics differed with CNI+ having higher body mass index (P = 0.045), shorter transplant-pregnancy interval (P < 0.01), later year of transplantation and -pregnancy (P < 0.01). Serum creatinine levels were numerically higher in CNI+ in all study phases, but only reached statistical significance in third trimester (127 vs. 105 mu m; P < 0.01), where the percentual changes from preconceptional level also differed (+3.1% vs. -2.2% in CNI-; P = 0.05). Postpartum both groups showed 11-12% serum creatinine rise from preconceptional level. Incidence of low birth weight (LBW) tended to be higher in CNI+ (52% vs. 46%; P = 0.07). Both groups showed equal high rates of preterm delivery. Using CNIs during pregnancy lead to a rise in creatinine in the third trimester but does not negatively influence the course of graft function in the first year postpartum or direct foetal outcomes. High rates of preterm delivery and LBW in KTR, irrespective of CNI use, classify all pregnancies as high risk

A combination of immune cell types identified through ensemble machine learning strategy detects altered profile in recurrent pregnancy loss: a pilot study

OBJECTIVE: To compare the immunologic profiles of peripheral and menstrual blood (MB) of women who experience recurrent pregnancy loss and women without pregnancy complications. DESIGN: Explorative case-control study. Cross-sectional assessment of flow cytometry-derived immunologic profiles. SETTING: Academic medical center. PATIENT(S): Women who experienced more than 2 consecutive miscarriages. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Flow cytometry-based immune profiles of uterine and systemic immunity (recurrent pregnancy loss, n = 18; control, n = 14) assessed by machine learning classifiers in an ensemble strategy, followed by recursive feature selection. RESULT(S): In peripheral blood, the combination of 4 cell types (nonswitched memory B cells, CD8+ T cells, CD56bright CD16- natural killer [NKbright] cells, and CD4+ effector T cells) classified samples correctly to their respective cohort. The identified classifying cell types in peripheral blood differed from the results observed in MB, where a combination of 6 cell types (Ki67+CD8+ T cells, (Human leukocyte antigen-DR+) regulatory T cells, CD27+ B cells, NKbright cells, regulatory T cells, and CD24HiCD38Hi B cells) plus age allowed for assigning samples correctly to their respective cohort. Based on the combination of these features, the average area under the curve of a receiver operating characteristic curve and the associated accuracy were >0.8 for both sample sources. CONCLUSION(S): A combination of immune subsets for cohort classification allows for robust identification of immune parameters with possible diagnostic value. The noninvasive source of MB holds several opportunities to assess and monitor reproductive health

Umbilical cord-mesenchymal stem cells induce a memory phenotype in CD4+ T cells

Inflammation is a physiological state where immune cells evoke a response against detrimental insults. Finding a safe and effective treatment for inflammation associated diseases has been a challenge. In this regard, human mesenchymal stem cells (hMSC), exert immunomodulatory effects and have regenerative capacity making it a promising therapeutic option for resolution of acute and chronic inflammation. T cells play a critical role in inflammation and depending on their phenotype, they can stimulate or suppress inflammatory responses. However, the regulatory effects of hMSC on T cells and the underlying mechanisms are not fully elucidated. Most studies focused on activation, proliferation, and differentiation of T cells. Here, we further investigated memory formation and responsiveness of CD4+ T cells and their dynamics by immune-profiling and cytokine secretion analysis. Umbilical cord mesenchymal stem cells (UC-MSC) were co-cultured with either αCD3/CD28 beads, activated peripheral blood mononuclear cells (PBMC) or magnetically sorted CD4+ T cells. The mechanism of immune modulation of UC-MSC were investigated by comparing different modes of action; transwell, direct cell-cell contact, addition of UC-MSC conditioned medium or blockade of paracrine factor production by UC-MSC. We observed a differential effect of UC-MSC on CD4+ T cell activation and proliferation using PBMC or purified CD4+ T cell co-cultures. UC-MSC skewed the effector memory T cells into a central memory phenotype in both co-culture conditions. This effect on central memory formation was reversible, since UC-MSC primed central memory cells were still responsive after a second encounter with the same stimuli. The presence of both cell-cell contact and paracrine factors were necessary for the most pronounced immunomodulatory effect of UC-MSC on T cells. We found suggestive evidence for a partial role of IL-6 and TGFβ in the UC-MSC derived immunomodulatory function. Collectively, our data show that UC-MSCs clearly affect T cell activation, proliferation and maturation, depending on co-culture conditions for which both cell-cell contact and paracrine factors are needed

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

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Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, alpha FH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls. Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients. In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome

Background: The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS. Methods: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls. Results: Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients. Conclusions: In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well

Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits

Effective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from ∼500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans

Biosynthetic homeostasis and resilience of the complement system in health and infectious disease

Background: The complement system is a central component of the innate immune system. Constitutive biosynthesis of complement proteins is essential for homeostasis. Dysregulation as a consequence of genetic or environmental cues can lead to inflammatory syndromes or increased susceptibility to infection. However, very little is known about steady state levels in children or its kinetics during infection. Methods: With a newly developed multiplex mass spectrometry-based method we analyzed the levels of 32 complement proteins in healthy individuals and in a group of pediatric patients infected with bacterial or viral pathogens. Findings: In plasma from young infants we found reduced levels of C4BP, ficolin-3, factor B, classical pathway components C1QA, C1QB, C1QC, C1R, and terminal pathway components C5, C8, C9, as compared to healthy adults; whereas the majority of complement regulating (inhibito

Favorable effect of adefovir on the number and functionality of myeloid dendritic cells of patients with chronic HBV

In patients with chronic hepatitis B virus (HBV), 2 predominant precursor dendritic cell (DC) subtypes, the myeloid dendritic cell (mDC) and the plasmacytoid dendritic cell (pDC), were recently found to be functionally impaired. HBV DNA was found to be present in the DC subtypes, but no viral replication could be detected. The question remains whether simply the presence of the virus and viral proteins causes this dysfunction of DCs. To address this issue, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the number and functionality of circulating DCs was studied during 6 months of treatment. Treatment resulted in a mean 5 log(10) decrease in the viral load and normalization of alanine aminotransferase within 3 months. The number of mDCs, but not of pDCs, increased significantly over 6 months of treatment to a level comparable to that of uninfected healthy controls. The allostimulatory capacity of isolated and in vitro matured mDCs increased significantly after 3 months of treatment. Accordingly, mDCs exhibited an increased capacity to produce tumor necrosis factor alpha and interleukin-12 after 3-6 months of treatment. There was no change in interferon alpha production by pDCs during treatment. In conclusion, adefovir treatment results in an improvement in the number and functionality of mDCs, but not of pDCs. Our findings provide clues for the reasons why current antiviral therapy does not lead to consistently sustained viral eradicatio