Translational opportunities for targeting the Th17 axis in acute graft-vs.-host disease

International audienceAllogeneic stem cell transplantation (allo-SCT) is a curative therapy for different life-threatening malignant and non-malignant hematologic disorders. Acute graft-vs.-host disease (aGVHD) and particularly gastrointestinal aGVHD remains a major source of morbidity and mortality following allo-SCT, which limits the use of this treatment in a broader spectrum of patients. Better understanding of aGVHD pathophysiology is indispensable to identify new therapeutic targets for aGVHD prevention and therapy. Growing amount of data suggest a role for T helper (Th)17 cells in aGVHD pathophysiology. In this review, we will discuss the current knowledge in this area in animal models and in humans. We will then describe new potential treatments for aGVHD along the Th17 axis

Elevated Adiponectin Serum Levels in Women with Systemic Autoimmune Diseases

Adipose tissue produces a wide range of proteins that may influence the immune system. In this study, we assessed the serum levels of leptin, adiponectin, and ghrelin, in association with the measurements of body composition, in 15 female patients with various autoimmune diseases (systemic lupus erythematosus, primary Sjögren's syndrome, sarcoidosis, mixed connective tissue disease, vasculitis, CREST syndrome, and polymyositis) and in 15 healthy female controls. There were no statistically significant differences between the patients and controls with regard to serum leptin, serum ghrelin, global fat mass, adiposity, and fat mass in the android or gynoid regions, whereas serum adiponectin levels were higher in patients than controls (16.3 ± 1.6 μg/mL versus 9.7 ± 0.6 μg/mL; P = .01). As adiponectin is known to exhibit potent anti-inflammatory properties, a high adiponectinemia in patients with systemic autoimmune disease may mitigate the inflammatory response. However, the precise consequences of these elevated serum adiponectin levels on the metabolic syndrome development and atherosclerotic cardiovascular risk in this patient population still needs to be determined

The Interleukin-6 Gene Promoter Polymorphism -174 and Atherosclerotic Events in Overweight Transplanted Patients

Chronic inflammation plays a pivotal role in atherosclerosis. We hypothesized that combining overweight and a greater genetic capacity to produce IL-6 predicted by IL-6 gene promoter polymorphism at position -174 (G→C) may allow to identify individuals exhibiting higher IL-6 and C-reactive protein (CRP) concentrations with a higher risk of atherosclerotic events (AE). The occurrence of AE was analyzed with respect to body mass index, IL-6 gene promoter polymorphism at position -174 (G→C), and other relevant risk factors, retrospectively, in 217 renal transplant recipients and, prospectively, in 132. Circulating IL-6 concentrations were closely related to BMI (r = 0.55, P = .0005). In overweight patients, serum IL-6 concentration was found to be significantly lower in C carriers than in GG patients (4.2 [1.0–5.1] versus 7.3 pg/mL [4.4–100]; P = .025). The incidence of AE was higher in overweight GG patients (29.5% versus 10.1%; P = .0003). In multivariate analysis, overweight-GG had an increased risk to develop AE (HR 2.96 [95% CI 1.09–8.04], P = .034 in the retrospective cohort, and HR 2.99 [95% CI 0.92–9.33], P = .069 in the prospective cohort). All these data are consistent with a role for both genetic and environmental determinants of inflammation (white adipose tissue mass) in the development of AE in renal transplanted patients

A New Antigen Recognized by Cytolytic T Lymphocytes on a Human Kidney Tumor Results from Reverse Strand Transcription

By stimulating blood lymphocytes from a renal cell carcinoma patient in vitro with the autologous tumor cells, we obtained cytolytic T lymphocyte (CTL) clones that killed several autologous and allogeneic histocompatibility leukocyte antigen (HLA)-B7 renal carcinoma cell lines. We identified the target antigen of these CTLs by screening COS cells transfected with the HLA-B7 cDNA and with a cDNA library prepared with RNA from the tumor cells. The antigenic peptide recognized by the CTLs has the sequence LPRWPPPQL and is encoded by a new gene, which we named RU2. This gene is transcribed in both directions. The antigenic peptide is not encoded by the sense transcript, RU2S, which is expressed ubiquitously. It is encoded by an antisense transcript, RU2AS, which starts from a cryptic promoter located on the reverse strand of the first intron and ends up on the reverse strand of the RU2S promoter, which contains a polyadenylation signal. This mechanism of antigen expression is unprecedented and further illustrates the notion that many peptides recognized by T cells cannot be predicted from the primary structure of the major product of the encoding gene. Antisense transcript RU2AS is expressed in a high proportion of tumors of various histological types. It is absent in most normal tissues, but is expressed in testis and kidney, and, at lower levels, in urinary bladder and liver. Short-term cultures of normal epithelial cells from the renal proximal tubule expressed significant levels of RU2AS message and were recognized by the CTLs. Therefore, this antigen is not tumor specific, but corresponds to a self-antigen with restricted tissue distribution

Inflammatory cytokines and dendritic cells in acute graft-versus-host disease after allogeneic stem cell transplantation.

International audienceThe wider use of allogeneic stem cell transplantation (allo-SCT) is still limited by the immunologic recognition and destruction of host tissues, termed graft-versus-host disease (GVHD). The role of inflammatory cytokines such as TNF-alpha and IL-1, and their impact on immune effectors (mainly CD4+ and CD8+ T) cells has been extensively studied in the context of GVHD occurring after standard myeloablative allo-SCT. However, recent data suggested that GVHD pathophysiology is likely to involve more complex interactions where antigen-presenting cells, especially dendritic cells (DCs), may play a major role at time of initiation of acute GVHD. In addition, the wider use of reduced intensity and less toxic conditioning (RIC) regimens prior to allo-SCT would allow better visualization of the fine functions of immune effectors, thereby offering a window of opportunities to better decipher the intimate pathophysiological mechanisms underlying GVHD. The aim of this work is to review the available research evidence on the role of DCs as in vivo regulators of alloimmune reactivity, and their interactions with other immune effectors

Effets immunomodulateurs du traitement par interféron-alpha chez des patients atteints de mélanome

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Mise en évidence de gènes exprimés dans les leucémies par hybridation soustractive différentielle

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Introduction to host microbiome symbiosis in health and disease

International audienceHumans share a core intestinal microbiome and yet human microbiome differs by genes, species, enterotypes (ecology), and gene count (microbial diversity). Achievement of microbiota metagenomic analysis has revealed that the microbiome gene count is a key stratifier of health in several immune disorders and clinical conditions. We review here the progress of the metagenomic pipeline analysis, and how this has allowed us to define the host–microbe symbiosis associated with a healthy status. The link between host–microbe symbiosis disruption, the so-called dysbiosis and chronic diseases or iatrogenic conditions is highlighted. Finally, opportunities to use microbiota modulation, with specific nutrients and/or live microbes, as a target for personalized nutrition and therapy for the maintenance, preservation, or restoration of host–microbe symbiosis are discussed