β-(1→3)-Glucans can be found as structural polysaccharides in cereals, in algae or as exo-polysaccharides secreted on the surfaces of mushrooms or fungi. Research has now established that β-(1→3)-glucans can trigger different immune responses and act as efficient immunostimulating agents. They constitute prevalent sources of carbons for microorganisms after subsequent recognition by digesting enzymes. Nevertheless, mechanisms associated with both roles are not yet clearly understood. This review focuses on the variety of elucidated molecular interactions that involve these natural or synthetic polysaccharides and their receptors, i.e., Dectin-1, CR3, glycolipids, langerin and carbohydrate-binding modules.

A substantial proportion of long-term kidney graft recipients, including those with a stable renal function in the absence of immunosuppressive therapy, present a skewed T cell receptor (TCR) V␤ chain usage, essentially in the CD8 ؉ subset. This study analyzed in more detail phenotypical and functional alterations of CD8 ؉ lymphocytes in drug-free tolerant patients (DF-Tol) compared with recipients with chronic rejection (CR D rug-free tolerance, defined as long-term maintenance of graft integrity and function without immunosuppression, is a rare event in human kidney transplantation because interruption of immunosuppressive treatment usually leads to acute or chronic graft rejection. Nevertheless, this phenomenon is of unique interest to study the physiologic basis of graft tolerance in humans. On the one hand, long-term drug-free tolerant patients (DF-Tol) represent a unique model to study the extent to which mechanisms of tolerance defined experimentally, such as active suppression by regulatory lymphocytes, ignorance of alloantigens, chimerism, homeostatic regulation or clonal deletion, are relevant to this human situation (1-4). Most studies in rodents analyzed the induction rather than the maintenance phase of tolerance, and discrepancies with the human situation may exist, as exemplified by the role of alloreactive CD8 ϩ central memory cells in rejection and tolerance induction (5,6). On the other hand, the characterization of peculiar immunologic profiles in DF-Tol may be clinically important to identify biologic signatures that are associated with graft tolerance. Considering the major medical and economic burden of chronic immunosuppression and that operational tolerance may be more common than expected but could be masked in long-term immunosuppressed patients, the identification of specific biologic signatures of tolerance could open new perspectives for rational rather than empiric minimizing of immunosuppressive drugs in well-selected patients (6 -10).As a proof of concept of the relevance of the DF-Tol model to study human tolerance, we described recently a number of specific immunologic features in these patients. First, DF-Tol Received February 16, 2005. Accepted October 17, 2005 Published online ahead of print. Publication date available at www.jasn.org.S.B. and J.-P.S. contributed equally to this work.

New sulfatase-based assay for the selective identification of sulfate esters in human urine and fecal samples.

Rare kidney allograft recipients enjoy unaltered graft function years after interruption of their immunosuppressive treatment. To assess the extent to which this state of 'operational tolerance' (TOL) is specific to the graft and not the result of a global immunodeficiency, we analyzed the response of such patients following influenza vaccination. Hemagglutination inhibition titers and frequency of IFNc -secreting T cells were measured before 1 and 3 months after vaccination. The proportion of healthy volunteers (HV) responding to vaccine was significantly higher than that of immunosuppressed (IS) patients. Three 'TOL' patients presented a humoral response similar to that of HV, whereas the two others had a poor response, like the IS recipients. Although the small number of patients does not allow for definitive conclusions to be made, these data suggest that the status of tolerance may be heterogeneous, with some patients with a global immunodeficiency and others with an adapted response to vaccination.

Patients with multiple sclerosis (MS) display significant peripheral blood CD8 + T cell receptor biases, suggesting clonal selection. Our objective was to identify relevant myelinderived peptides capable of eliciting responses of fresh blood CD8 + T cells in MS patients.We focused our analysis on the HLA supertypes (HLA-A3, -A2, -B7, -B27, -B44) predominant in a patient cohort. Three myelin protein (MBP, PLP and MOG) sequences were screened for HLA binding motifs and peptides were tested for their binding to HLA molecules. The cellular responses of 27 MS patients and 19 age-and sex-matched healthy controls (HC) were tested in IFN-c ELISPOT assays only detecting pre-committed CD8 + T cells. Sixty-nine new epitopes elicited positive responses, with MOG-derived peptides being the most immunogenic and peptides binding to HLA-A3 being the most frequent. However, MS patients and HC displayed the same frequency of autoreactive cells. The epitopes inducing the strongest responses were not those with the highest HLA binding, suggesting an effective thymic selection in MS patients. Our data extend the concept that the frequency of myelin-reactive T cells in MS patient blood is not increased compared to HC. The description of this set of myelin-derived peptides (MHC class I restricted, recognized by CD8 + T cells)offers new tools to explore the CD8 + cell role in MS.

While metabolites derived from gut microbiota metabolism have been linked to disease development in the human host, the chemical tools required for their detailed analysis and the discovery of biomarkers are limited. A unique and multifunctional chemical probe for mass spectrometric analysis, which contains p-nitrocinnamyloxycarbonyl as a new bioorthogonal cleavage site has been designed and synthesized. Coupled to magnetic beads, this chemical probe allows for straightforward extraction of metabolites from human samples and release under mild conditions. This isolation from the sample matrix results in significantly reduced ion suppression, an increased mass spectrometric sensitivity, and facilitates the detection of metabolites in femtomole quantities. The chemoselective probe was applied to the analysis of human fecal samples, resulting in the discovery of four metabolites previously unreported in this sample type and confirmation of the presence of medically relevant gut microbiota-derived metabolites.

Priming of recipients by DST induces long-term survival of mismatched allografts in adult rats. Despite these recipients developing inducible T regulatory cells able to transfer long-term graft survival to a secondary host, a state of chronic rejection is also observed. We revisited the molecular donor MHC targets of the cellular response in acute rejection and analyzed the cellular and humoral responses in recipients with long-term graft survival following transplantation. We found three immunodominant peptides, all derived from LEW.1W RT1.D u molecules to be involved in acute rejection of grafts from unmodified LEW.1A recipients. Although the direct pathway of allorecognition was reduced in DST-treated recipients, the early CD4 + indirect pathway response to dominant peptides was almost unimpaired. We also detected early and sustained antidonor class I and II antibody subtypes with diffuse C4d deposits on graft vessels. Finally, long-term accepted grafts displayed leukocyte infiltration, endarteritis and fibrosis, which evolved toward vascular narrowing at day 100. Altogether, these data suggest that the chronic graft lesions developed in long-term graft recipients are the result of progressive humoral injury associated with a persisting indirect T helper response. These features may represent a useful model for understanding and manipulating chronic active antibodymediated rejection in human.

Thus initial steroid avoidance or withdrawal associated with ALG induction has a weak influence on phenotype and transcriptional pattern of blood leukocytes. In contrast, ALG therapy induces an early and strong depletion of all T-cell subsets with contrasted long-lasting homeostatic regulation.