Sex-specific differences in ICOS T helper cell differentiation in systemic lupus erythematosus patients with low disease activity.

Systemic lupus erythematosus (SLE) is a sex biased chronic autoimmune disease affecting predominantly females during reproductive ages. Changes in the ratio of inducible costimulatory molecule (ICOS) regulatory (Treg) and non-regulatory responder (Tresp) CD4 T cells proved to be crucial for the occurrence of high disease activity. Here, we investigated how the differentiation of ICOSCD45RACD31 recent thymic emigrant (RTE) Tresps into CD45RACD31 memory Tresps affects the percentages of ICOS Tresps within total CD4 T cells.

Exhaustion of CD8 central memory responder T cell differentiation provokes non-melanoma skin cancer in elderly kidney transplant recipients.

Introduction: Immunosuppressive therapy prevents graft rejection but increases the risk of non-melanoma skin cancer (NMSC), especially in elderly kidney transplant recipients (KTR).

Methods: In this study, we separately investigated the differentiation of CD8 regulatory T cells (Tregs) and responder T cells (Tresps) between healthy KTR without NMSC, KTR developing NMSC within two years after the enrolment, and KTR with NMSC at the time of enrolment. Antigen-unexperienced CCR7CD45RACD31 recent thymic emigrant (RTE) cells differentiate CD45RACD31 memory (CD31 memory) cells, resting mature naïve (MN) cells or direct proliferation into CD45RACD31 memory (CD31 memory) cells, consisting of both CCR7CD45RA central memory (CM) and CCR7CD45RA effector memory (EM) cells.

Chronic Kidney Failure Provokes the Enrichment of Terminally Differentiated CD8 T Cells, Impairing Cytotoxic Mechanisms After Kidney Transplantation.

Chronic kidney failure (KF) provokes the development of immune senescent CD8 cytotoxic T cells, affecting the occurrence of graft rejection, viral infections, and malignancies after kidney transplantation. In this study, we analyzed the impact of KF, subsequent dialysis treatment, and kidney transplantation on the differentiation of CD8CD31CD45RACCR7 recent thymic emigrant (CCR7 RTE) Tregs/Tresps into CD8CD31CD45RA memory (CD31 memory) Tregs/Tresps and its effect on the release of cytokines, Fas receptor, Fas ligand as well as cytotoxic mediators by naïve, central memory (CM), effector memory (EM), and terminally differentiated effector memory (TEMRA) Tresps. We found that normal age-dependent differentiation of CD8 Tregs/Tresps generally differs in the way that TEMRA cells only arise in Tresps.

Impaired Differentiation of Highly Proliferative ICOS-Tregs Is Involved in the Transition from Low to High Disease Activity in Systemic Lupus Erythematosus (SLE) Patients.

Dysregulations in the differentiation of CD4-regulatory-T-cells (Tregs) and CD4-responder-T-cells (Tresps) are involved in the development of active systemic lupus erythematosus (SLE). Three differentiation pathways of highly proliferative inducible costimulatory molecule (ICOS)- and less proliferative ICOS-CD45RACD31-recent-thymic-emigrant (RTE)-Tregs/Tresps via CD45RACD31-memory-Tregs/Tresps (CD31-memory-Tregs/Tresps), their direct proliferation via CD45RACD31-mature naïve (MN)-Tregs/Tresps, and the production and differentiation of resting MN-Tregs/Tresp into CD45RACD31-memory-Tregs/Tresps (CD31-memory-Tregs/Tresps) were examined in 115 healthy controls, 96 SLE remission patients, and 20 active disease patients using six color flow cytometric analysis. In healthy controls an appropriate sequence of these pathways ensured regular age-dependent differentiation.

The onset of active disease in systemic lupus erythematosus patients is characterised by excessive regulatory CD4+-T-cell differentiation.

Objectives: An imbalance between CD4+-regulatory T-cells (Tregs) and CD4+-responder T-cells (Tresps) correlates with active disease flares in systemic lupus erythematosus (SLE) patients. Both cell subsets consist of highly proliferating Tregs/Tresps expressing inducible T-cell co-stimulatory molecule (ICOS) and less proliferating ICOS--Tregs/Tresps.

Methods: Six-colour-flow-cytometric analysis was used to examine the effect of ICOS+- and ICOS--Treg/Tresp cell differentiation on the composition of the total CD4+-T-helper cell pool with ICOS+- and ICOS--Tregs/Tresps.

Immunosuppressive therapy influences the accelerated age-dependent T-helper cell differentiation in systemic lupus erythematosus remission patients.

Background: CD4 T cells are of great importance in the pathogenesis of systemic lupus erythematosus (SLE), as an imbalance between CD4 regulatory T cells (Tregs) and CD4 responder T cells (Tresps) causes flares of active disease in SLE patients. In this study, we aimed to find the role of aberrant Treg/Tresp cell differentiation for maintaining Treg/Tresp cell balance and Treg functionality.

Methods: To determine differences in the differentiation of Tregs/Tresps we calculated the percentages of CD45RACD31 recent thymic emigrant (RTE) Tregs/Tresps and CD45RACD31 mature naive (MN) Tregs/Tresps, as well as CD45RACD31 and CD45RACD31 memory Tregs/Tresps (CD31 and CD31 memory Tregs/Tresps) within the total Treg/Tresp pool of 78 SLE remission patients compared with 94 healthy controls of different ages.

End-stage renal disease, dialysis, kidney transplantation and their impact on CD4 T-cell differentiation.

Premature aging of both CD4 regulatory T (Treg) and CD4 responder-T (Tresp) cells in patients with end-stage renal disease (ESRD) is expected to affect the success of later kidney transplantation. Both T-cell populations are released from the thymus as inducible T-cell co-stimulator-positive (ICOS ) and ICOS recent thymic emigrant (RTE) Treg/Tresp cells, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS and ICOS RTE Treg/Tresp cells into ICOS  CD31 or ICOS  CD31 memory Treg/Tresp cells and examined whether diverging pathways affected the suppressive activity of ICOS and ICOS Treg cells in co-culture with autologous Tresp cells.

The role of age-related T-cell differentiation in patients with renal replacement therapy.

Dialysis patients have deficiencies regarding the generation of immune responses and show an increased susceptibility for infections. Persisting uremic conditions are made responsible for the increased aging of their immune system. In this study, we analyzed whether age-related differences in the differentiation of both recent-thymic-emigrant-(RTE)-regulatory (Tregs) and RTE-responder T cells (Tresps) into CD31-memory Tregs/Tresps led to differences in the suppressive activity of naive and memory Tregs on autologous Tresps between healthy volunteers and dialysis patients.

Aberrant ICOS -T cell differentiation in women with spontaneous preterm labor.

Problem: Recent studies revealed appropriate differentiation of recent thymic emigrant (RTE)-regulatory T cells (Tregs) to be crucial for maintaining healthy pregnancy. Currently, the role of responder T cells (Tresps) is not known.

Method Of Study: Six-color flow cytometric analysis was used to detect differences in the differentiation of highly proliferative inducible co-stimulatory (ICOS) -RTE-Tregs/Tresps and apoptosis-sensitive ICOS -RTE-Tregs/Tresps into mature naïve (MN)-, CD31 -memory and CD31 -memory Tregs/Tresps in women with spontaneous preterm labor (sPL) compared to healthy pregnancy.

The role of recent thymic emigrant-regulatory T-cell (RTE-Treg) differentiation during pregnancy.

During pregnancy, regulatory T cells (Tregs) have a key role in maternal immune tolerance to the semi-allogeneic fetus. Our previous results showed that the naive CD45RA(+)-Treg pool is functionally improved in pregnant women compared with non-pregnant women. Therefore, we examined the thymic output and differentiation of CD45RA(+)CD31(+) recent thymic emigrant (RTE)-Tregs during normal pregnancy and in the presence of preeclampsia.

The extent of HLA-DR expression on HLA-DR(+) Tregs allows the identification of patients with clinically relevant borderline rejection.

Regulatory T cells (Tregs) were shown to be involved into the pathogenesis of acute rejection after transplantation. The suppressive activity of the total regulatory T cell pool depends on its percentage of highly suppressive HLA-DR(+) -Treg cells. Therefore, both the suppressive activity of the total Treg pool and the extent of HLA-DR expression of HLA-DR(+) -Tregs (MFI HLA-DR) were estimated in non transplanted volunteers, patients with end-stage renal failure (ESRF), healthy renal transplant patients with suspicion on rejection, due to sole histological Bord-R or sole acute renal failure (ARF), and patients with clinically relevant borderline rejection (Bord-R and ARF).

Methylprednisolone treatment increases the proportion of the highly suppressive HLA-DR(+)-Treg-cells in transplanted patients.

Methylprednisolone is widely used to improve immune suppression in transplanted patients threatened by acute rejection. Recently, we showed that the suppressive activity of a Treg cell population depends decisively on their percentage of highly suppressive HLA-DR(high+)-Treg cells, which are strongly reduced in rejecting transplant patients. In order to examine whether the composition of the total CD4(+)CD127(low+/-)FoxP3(+)-Treg cell pool with different Treg-subsets (DR(high+)CD45RA(-)-Tregs, DR(low+)CD45RA(-)-Tregs, DR(-)CD45RA(-)-Tregs, DR(-)CD45RA(+)-Tregs) is affected by methylprednisolone bolus therapy we compared the percentages of these four different Treg cell subsets in transplant patients with biopsy proven rejection before and after steroid bolus therapy (n=23).

Term and preterm labor: decreased suppressive activity and changes in composition of the regulatory T-cell pool.

Regulatory T cells (Tregs) exert a key role in tolerance induction to the semi-allogeneic fetus. Currently, it is not known whether immunological rejection processes are involved in the induction of normal term or irresistible preterm labor. In this study, we examined whether there were differences in the percentage of the total CD4(+)CD127(low+/-)CD25(+)FoxP3(+)-Treg-cell pool, its suppressive activity and its composition with distinct Treg subsets (HLA-DR(low+)-, HLA-DR(high+)-, HLA-DR(-)- and naive CD45RA(+)-Tregs) between preterm and term laboring women.

DR(high+)CD45RA(-)-Tregs potentially affect the suppressive activity of the total Treg pool in renal transplant patients.

Recent studies show that regulatory T cells (Tregs) play an essential role in tolerance induction after organ transplantation. In order to examine whether there are differences in the composition of the total CD4(+)CD127(low+/-)FoxP3(+)- Treg cell pool between stable transplant patients and patients with biopsy proven rejection (BPR), we compared the percentages and the functional activity of the different Treg cell subsets (DR(high+)CD45RA(-)-Tregs, DR(low+)CD45RA(-)-Tregs, DR(-)CD45RA(-)-Tregs, DR(-)CD45RA(+)-Tregs). All parameters were determined during the three different periods of time after transplantation (0-30 days, 31-1,000 days, >1,000 days).

Breast cancer cell-derived cytokines, macrophages and cell adhesion: implications for metastasis.

Background: Liver metastasis is associated with a proinflammatory microenvironment and up-regulation of cell adhesion molecules expressed by endothelial cells. The aim of this study was to characterize the interrelations between breast cancer cell-secreted cytokines, macrophages and E-selectin-mediated cancer cell adhesion and their role in metastasis of breast cancer.

Materials And Methods: Three metastatic breast cancer cell lines (1590, KM22, ZE) were studied.

A distinct subset of HLA-DR+-regulatory T cells is involved in the induction of preterm labor during pregnancy and in the induction of organ rejection after transplantation.

Regulatory T cells (Tregs) are known to suppress alloimmune responses during pregnancy and post organ transplantation. We demonstrate that a distinct subset of FoxP3(+)DR(+)-Tregs among the total CD4(+)CD127(low+/-)CD25(+)-Treg cell pool is critically involved in preterm labor induction and kidney transplant rejection as well. Compared to healthy pregnancies and non-rejecting kidney recipients, we found that the percentage of the FoxP3(+)DR(+)-Treg subset was not reduced, but that the level of HLA-DR expression of such Tregs was strongly diminished in preterm laboring women and in patients with acute renal allograft rejection.

Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells.

Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4(+) T cell subset designated Th9. IRF4-deficient CD4(+) T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4(+) T cells.

Small for gestational age (SGA) neonates show reduced suppressive activity of their regulatory T cells.

Little information exists concerning the role of fetal regulatory T cells (Tregs) during intrauterine development. We examined whether complications such as reduced birth weight or the occurrence of preterm labor were associated with deficiencies in the number or in the immunosuppressive activity of Tregs in the fetal circulation. Their total number did not change during normal or complicated pregnancy.

Distinct subsets of regulatory T cells during pregnancy: is the imbalance of these subsets involved in the pathogenesis of preeclampsia?

Regulatory T cells (CD4(+)CD25(+)FoxP3(+)-Treg cells) are important regulators of tolerance induction during pregnancy. We now found that the number of CD4(+)CD25(+)FoxP3(+)-Treg cells decreases during normal course of pregnancy and even more so in women affected by preeclampsia. The functional activity of these CD4(+)CD25(+)-Treg cells was significantly reduced in comparison to those of healthy pregnants.

Early detection of decreased soluble HLA-G levels in the maternal circulation predicts the occurrence of preeclampsia and intrauterine growth retardation during further course of pregnancy.

Problem: Soluble (s) HLA-G1/G5 molecules may potentially affect immune homeostasis during pregnancy. The aim of this study was to determine changes of sHLA-G1/G5 plasma levels throughout normal pregnancy and to assess its predictive value for the occurrence of characteristic gestation-associated diseases during further course of pregnancy.

Method Of Study: sHLA-G1/G5 levels were estimated in plasma samples of 40 non-pregnant women, 291 women throughout normal pregnancy and 236 women affected by different complications.

Are nuchal translucency, pregnancy associated plasma protein-A or free-beta-human chorionic gonadotropin depending on maternal age? A multicenter study of 8,116 pregnancies.

Introduction: First-trimester screening according to Nicolaides uses maternal age to obtain a common background risk for trisomy 21. The likelihood ratios by nuchal translucency, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A are not with respect to maternal age. It was the aim of this study to investigate if likelihood ratios should better take care of it.

The significance of intracardiac Doppler sonography in terms of fetal growth retardation.

Introduction: The proper function of the fetal heart is indispensable for the fetal development and the normal fetal growth. For prenatal medicine, Doppler sonography offers the possibility of a non-invasive method to examine the fetal cardiovascular function under normal and pathological circumstances. The role of the Doppler sonography is to identify those fetuses who have a high risk factor for developing a pre- or intrapartual asphyxia and therefore have to be delivered promptly.

Quantitative analysis of intact fetal cells in maternal plasma by real-time PCR.

Objective: Fetal genetic materials in maternal circulation might be potentially used for non-invasive prenatal diagnosis (NIPD). In this study, we quantitatively analysed the intact fetal cells existing in maternal plasma, which would be a special method of NIPD.

Study Design: Eleven samples from preeclamptic patients, two samples from patients with RhD incompatibilities, and 30 samples from normal pregnancies as controls were collected.

The presence of gestational diabetes is associated with increased detection of anti-HLA-class II antibodies in the maternal circulation.

Problem: Gestational diabetes (GD) may be associated with temporarily reduced immune tolerance toward alloantigens for the time of pregnancy. The aim of this study was to assess anti-HLA-class I and -II antibodies as markers for an aberrant immunostimulation in women with GD.

Method Of Study: The percentage of anti-HLA-class I and -II antibodies was estimated in women with GD, normal term delivery and fetal distress, which was confirmed by demonstrating low cord blood pH for this patient group.