Clinical efficacy of omalizumab in chronic spontaneous urticaria is associated with a reduction of FcεRI-positive cells in the skin.

Treatment with omalizumab, a humanized recombinant monoclonal anti-IgE antibody, results in clinical efficacy in patients with Chronic Spontaneous Urticaria (CSU). The mechanism of action of omalizumab in CSU has not been elucidated in detail. To determine the effects of omalizumab on levels of high affinity IgE receptor-positive (FcεRI) and IgE-positive (IgE) dermal cells and blood basophils.

Phase II metabolism in human skin: skin explants show full coverage for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation.

Although skin is the largest organ of the human body, cutaneous drug metabolism is often overlooked, and existing experimental models are insufficiently validated. This proof-of-concept study investigated phase II biotransformation of 11 test substrates in fresh full-thickness human skin explants, a model containing all skin cell types. Results show that skin explants have significant capacity for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation.

An original approach was used to better evaluate the capacity of a prognostic marker using published survival curves.

Objectives: Predicting chronic disease evolution from a prognostic marker is a key field of research in clinical epidemiology. However, the prognostic capacity of a marker is not systematically evaluated using the appropriate methodology. We proposed the use of simple equations to calculate time-dependent sensitivity and specificity based on published survival curves and other time-dependent indicators as predictive values, likelihood ratios, and posttest probability ratios to reappraise prognostic marker accuracy.

Identification of tribbles-1 as a novel binding partner of Foxp3 in regulatory T cells.

In a previous study, we identified TRIB1, a serine-threonine kinase-like molecule, as a biomarker of chronic antibody-mediated rejection of human kidneys when measured in peripheral blood mononuclear cells. Here, we focused our analysis on a specific subset of peripheral blood mononuclear cells that play a dominant role in regulating immune responses in health and disease, so-called CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). We isolated both human and murine Treg and non-Treg counterparts and analyzed TRIB1 and Foxp3 mRNA expression by quantitative PCR on the freshly isolated cells or following 24 h of activation.

The natural history of clinical operational tolerance after kidney transplantation through twenty-seven cases.

We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.

The Tribbles-1 protein in humans: roles and functions in health and disease.

This review describes the key role of the serine-threonine kinase like protein Tribbles-1 in health as well as in diverse human pathologies. Tribbles-1 is a homolog protein of the Drosophila Tribbles. In Drosophila, the Tribbles protein is involved in the cell-cycle progression during mitosis and in mammals initial data showed TRIB1 to be involved in cell proliferation.

Development of commercial gene-expression-based signatures: review of the scientific strategies.

Many scientific articles have been published that use gene-expression-based technologies to discriminate a trait of interest, typically a disease subgroup, within a patient population. However, few gene-expression-based signatures have at present reached the market and become a financially and clinically successful product. The technological, scientific and medical challenges, the regulatory environment and the financial considerations are all essential parts of the development process.

Market access challenges in the EU for high medical value diagnostic tests.

The clinical utility and medico-economic value of several personalized diagnostic tests has been well described in the literature. Development of such tests, including generation of the necessary supportive clinical validation data, is a complex and expensive endeavor. In general, sponsors of such tests lack sufficient clarity on appropriate reimbursement and regulatory pathways to provide the clear development framework necessary to incentivize the required level of investment.

Elaboration of gene expression-based clinical decision aids for kidney transplantation: where do we stand?

Successful kidney transplant management throughout the graft lifespan depends on adequate diagnosis (i.e., recognition of a particular type of graft rejection or injury) and prognosis (i.

Analysis of the peripheral T-cell repertoire in kidney transplant patients.

The long-term stability of renal grafts depends on the absence of chronic rejection. As T cells play a key role in rejection processes, analyzing the T-cell repertoire may be useful for understanding graft function outcomes. We have therefore investigated the power of a new statistical tool, used to analyze the peripheral blood TCR repertoire, for determining immunological differences in a group of 229 stable renal transplant patients undergoing immunosuppression.

Company Profile: TcLand Expression.

TcLand Expression is a fully integrated molecular diagnostics company that holds a pioneering position in personalized medicine focusing on immunology (transplantation and autoimmune disorders). The company has a well-balanced pipeline of blood-based gene-expression biomarkers and companion diagnostics in development. The company's state-of-the-art central laboratories are International Organization for Standardization (ISO) 17025-accredited for quantitative PCR.

Using biomarkers of tolerance and rejection to identify high- and low-risk patients following kidney transplantation.

Despite great improvements in renal allograft survival over the last 3 decades, long-term graft loss, particularly through antibody-mediated rejection, remains the bane of kidney transplantation. Interindividual patient variation means that a given immunosuppressive regimen may be inadequate in certain patients and excessive in others. Currently, there is no way of personalizing such treatments.

Regulatory, effector, and cytotoxic T cell profiles in long-term kidney transplant patients.

Animal studies have suggested a potential role for regulatory T cells (Tregs) in allograft tolerance, but these FOXP3+ cells seem to be an inherent component of acute rejection (AR) in human recipients of renal transplants. The balance between regulatory cells and effector/cytotoxic cells may determine graft outcome; this balance has not been described for chronic allograft injury. We investigated the expression of key regulatory, effector, and cytotoxic transcripts (i.

Contrasted blood and intragraft toll-like receptor 4 mRNA profiles in operational tolerance versus chronic rejection in kidney transplant recipients.

Background: Deciphering the mechanisms of tolerance and chronic rejection (CR) remains a major goal in transplantation. Data in rodents suggest that Toll-like receptors (TLR), regulators of innate immune responses, play a role in determining graft outcome. However, few studies have focused on TLR expression in human kidney transplant recipients.

Superiority of bone marrow-derived dendritic cells over monocyte-derived ones for the expansion of regulatory T cells in the macaque.

Regulatory T cells (Treg) have been identified as playing a pivotal role in the control of tolerance and in the suppression of pathologic immune responses in autoimmune diseases, transplantation, and graft-versus-host disease. Treg expanded ex vivo by dendritic cells could be potential reagents to promote antigen-specific tolerance in vivo. However, in vivo studies have been carried out mostly in rodents and will need validation in primates before clinical application.

Tribbles-1 as a novel biomarker of chronic antibody-mediated rejection.

Diagnosis of the specific cause of late allograft injury is necessary if more personalized and efficient immunosuppressive regimens are to be introduced. This study sought previously unrecognized biomarkers for specific histologic diagnoses of late graft scarring by comparison of gene sets from published microarray studies. Tribbles-1 (TRIB1), a human homolog of Drosophila tribbles, was identified to be a potentially informative biomarker.

Implication of matrix metalloproteinase 7 and the noncanonical wingless-type signaling pathway in a model of kidney allograft tolerance induced by the administration of anti-donor class II antibodies.

In rats, tolerance to MHC-incompatible renal allografts can be induced by the administration of anti-donor class II Abs on the day of transplantation. In this study we explored the mechanisms involved in the maintenance phase of this tolerance by analyzing intragraft gene expression profiles by microarray in long-term accepted kidneys. Comparison of the gene expression patterns of tolerated to syngeneic kidneys revealed 5,954 differentially expressed genes (p < 0.

Spontaneous operational tolerance after immunosuppressive drug withdrawal in clinical renal allotransplantation.

Tolerance is the so-called "Holy Grail" of transplantation, but achieving this state is proving a major challenge, particularly in the clinical setting. Even in rodents, the definition of true transplant tolerance is not applicable to many models, with late graft damage often occurring despite long-term graft survival. Hence the term "operational tolerance," based more on graft function and absence of exogenous immunosuppression, is being adopted.

Immunosuppressive drug-free operational immune tolerance in human kidney transplant recipients: Part I. Blood gene expression statistical analysis.

Survival of solid organ grafts depends on life-long immunosuppression, which results in increased rates of infection and malignancy. Induction of tolerance to allografts would represent the optimal solution for controlling both chronic rejection (CR) and side effects of immunosuppression. Although spontaneous "operational tolerance" can occur in human kidney transplantation, the lack of noninvasive peripheral blood biological markers of this rare phenomenon precludes the identification of potentially tolerant patients in whom immunosuppression could be tapered as well as the development of new tolerance inducing strategies.