The myth of the subclinical rejection: Is it real?

Introduction: Subclinical rejection (SCAR) of renalallografts refers to graft lymphocytic infiltrationtaking acute rejection histologic pattern despitestable renal function. There are no data to suggestthat subclinical tubulointerstitial inflammation isregulatory or in any way beneficial to the graft. Wehave investigated whether C57BL/6 CD8 T cellshome to long term engrafted (LTE) DBA/2 skinallografts and if it is protecting or rejecting.Methods and results: We transplanted two groupsof B6 CD4 KO mice, 6 mice each, with MHCmismatched DBA/2 skin. Only the 1st group wastreated with Rapamycin (RPM) as reported. After100 days of LTE, we challenged RPM treated hostswith a 2nd DBA/2 skin graft. The 2nd but not the 1stgraft was rejected. Then we investigated thefunctional effects of graft inflitrating CD8 T cells.DBA/2 skin grafts were harvested 100 daysposttransplantation from (i) RPM treated B6 CD4ko mice (N=5) and (ii) skin autografts (N=5) inDBA/2 recipients. LTE DBA/2 allografts or controlDBA/2 autografts were then transplanted ontoC57BL/6-Rag KO hosts, and peripheral bloodlymphocytes (PBL) samples were collected 30 dayspost skin transplantation. CD8T cells can not bedetected in PBL of nae RAG-/- mice. 4.6 % CD8T cells are detected in PBL of RAG-/- recipients ofLTE allografts, but not in recipients of syngeneicgrafts. To test the protective function of the grafthoming CD8 T cells (from LTE RPM mice) thatexpanded by homeostatic proliferation and arepresent in PBL of the RAG-/-, 0.2 x 106 CD8 Tcells from naive CD4KO mice were adoptivelytransferred into the RAG-/- hosts bearing the LTEDBA/2 allografts or DBA/2 autografts 30 daysfollowing skin transplantation. Survival of LTEDBA/2 skin allografts transplanted onto RAG-/-mice were significantly prolonged.Conclusion: Graft infiltrating CD8 T cells areregulatory and functionally active to protectallograft from rejection

HYPERPHOSPHATEMIA IN END STAGE RENAL DISEASE: PREVALENCE AND PATIENTS CHARACTERISTICS OF MULTIETHNIC POPULATION OF UNITED ARAB EMIRATES

Objective: Hyperphosphatemia is significantly associated with increased mortality among end stage renal disease (ESRD) patients on hemodialysis. There is paucity of data on hyperphosphatemia in ESRD patients of the multiethnic population of United Arab Emirates (UAE). The study aimed to investigate the prevalence and characteristics of hyperphosphatemia in ESRD patients of the multiethnic population of UAE undergoing maintenance hemodialysis.Methods: Adults ESRD patients undergoing maintenance hemodialysis for more than six months at the study site were included. Demographic, clinical and biological data of the patients were collected. Patient characteristics were compared as per the serum phosphate level, between patients with or without hyperphosphatemia. Univariate and multivariate logistic regression analyses were carried out to identify the predictors of hyperphosphatemia.Results: Hyperphosphatemia was present in 73.8% of the study population, while 31.3% presented with high calcium-phosphate product. Univariate logistic analysis revealed that hyperphosphatemia was inversely correlated with age, hemoglobin, serum calcium, and hypertensive nephropathy as cause of renal disease, and positively correlated with female gender, expatriate status, body mass index (BMI), higher number of comorbidities, calcium-phosphate product and parathyroid hormone (PTH). Multivariate logistic regression model revealed that only age, BMI, hemoglobin and PTH independently correlated with hyperphosphatemia.Conclusion: We report a high prevalence of hyperphosphatemia in multiethnic study population undergoing maintenance hemodialysis at a secondary care hospital in UAE. In this study population, only age, BMI, hemoglobin and PTH were identified as independent predictors of hyperphosphatemia

Prostaglandin E2 Stimulates the Expansion of Regulatory Hematopoietic Stem and Progenitor Cells in Type 1 Diabetes

Hematopoietic stem and progenitor cells (HSPCs) are multipotent stem cells that have been harnessed as a curative therapy for patients with hematological malignancies. Notably, the discovery that HSPCs are endowed with immunoregulatory properties suggests that HSPC-based therapeutic approaches may be used to treat autoimmune diseases. Indeed, infusion with HSPCs has shown promising results in the treatment of type 1 diabetes (T1D) and remains the only “experimental therapy” that has achieved a satisfactory rate of remission (nearly 60%) in T1D. Patients with newly diagnosed T1D have been successfully reverted to normoglycemia by administration of autologous HSPCs in association with a non-myeloablative immunosuppressive regimen. However, this approach is hampered by a high incidence of adverse effects linked to immunosuppression. Herein, we report that while the use of autologous HSPCs is capable of improving C-peptide production in patients with T1D, ex vivo modulation of HSPCs with prostaglandins (PGs) increases their immunoregulatory properties by upregulating expression of the immune checkpoint-signaling molecule PD-L1. Surprisingly, CXCR4 was upregulated as well, which could enhance HSPC trafficking toward the inflamed pancreatic zone. When tested in murine and human in vitro autoimmune assays, PG-modulated HSPCs were shown to abrogate the autoreactive T cell response. The use of PG-modulated HSPCs may thus provide an attractive and novel treatment of autoimmune diabetes

Influence du polymorphisme des gènes impliqués dans l'hypertension artérielle tels que ACE, AGT, AT1-R et ecNOS sur les résultats en transplantation rénale

Introduction : Le système rénine-angiotensine (SRA) joue un rôle majeur dans la régulation de la pression artérielle mais aussi dans le développement et la progression de la néphropathie chronique de l allogreffe. La pression artérielle après greffe rénale a une influence hautement significative sur la survie du greffon rénal à long terme. Matériel et méthodes : Il s agit d une étude d association, prospective sur une cohorte historique de 560 patients ayant été greffés entre le 1/08/1984 et le 31/07/1994. Tous ces patients sont traités par la ciclosporine A comme immunosuppresseur principal associé au début à l azathioprine et prednisolone. Le but de l étude est de déterminer l influence du polymorphisme des gènes de l enzyme de conversion de l angiotensine I (ACE), de l angiotensinogène (AGT), du récepteur AT1 de l angiotensine II (AT1-R), et de l enzyme synthétase du monoxyde d azote (NOS) dans sa forme endothéliale constitutive (ecNOS) sur les résultats à long terme en transplantation rénale : survie du greffon, qualité de fonction du greffon ; prévalence et nombre des crises de rejet aigu, et enfin fréquence et sévérité de l hypertension artérielle post-greffe. Finalement, 430 receveurs sont entrés dans l étude et ont été génotypés par les techniques classiques de biologie moléculaire. Résultats : Il s agit de 296 hommes (68.8 %) et de 134 femmes. L âge moyen au moment de la greffe était de 42.1 + 12.7 ans. La cohorte étudiée était représentative de la cohorte initiale sauf en ce qui concerne le nombre de décès ; nous n avons donc pas étudié la survie des patients. La distribution des différents génotypes et allèles chez les receveurs n était pas différente d une population contrôle locale (N=303). Nous n avons décelé aucune influence de ces différents polymorphismes sur la survie et la qualité de fonction du greffon. Les seuls résultats positifs sont les suivants : - l allèle a (génotypes aa+ab) de ecNOS est associé à une fréquence plus faible (P=0.005) et une sévérité plus faible (P=0.0003) de l HTA post-greffe (rôle protecteur ?) - le rare génotype CC de AT1-R est associé à une HTA plus sévère (P=0.009). Ce même génotype est associé à des rejets multiples chez les receveurs (P=0.002). Conclusion : Les résultats de cette étude sont globalement négatifs bien qu obtenus sur une large cohorte de patients. Ils soulignent le caractère multifactoriel des résultats en transplantation rénale.ST ETIENNE-BU Médecine (422182102) / SudocSudocFranceF

eATP and autoimmune diabetes

Purpose of review: The purine nucleotide adenosine triphosphate (ATP) is released into extracellular spaces as extracellular ATP (eATP) as a consequence of cell injury or death and activates the purinergic receptors. Once released, eATP may facilitate T-lymphocyte activation and differentiation. The purpose of this review is to elucidate the role of ATP-mediated signaling in the immunological events related to type 1 diabetes (T1D). Recent findings: T lymphocytes mediate immune response during the onset of T1D and promote pancreatic islet or whole pancreas rejection in transplantation. Recent data suggest a potential role for eATP in early steps of T1D onset and of allograft rejection. In different preclinical experimental models and clinical trials, several drugs targeting purinergic signaling have been employed to abrogate lymphocyte activation and differentiation, thus representing an achievable treatment to prevent/revert T1D or to induce long-term islet allograft function. Summary: In preclinical and clinical settings, eATP-signaling inhibition induces immune tolerance in autoimmune disease and in allotransplantation. In this view, the purinergic system may represent a novel therapeutic target for auto- and allo-immunity

Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease

Diabetic kidney disease (DKD) is the first cause of end-stage kidney disease in patients with diabetes and its prevalence is increasing worldwide. It encompasses histological alterations that mainly affect the glomerular filtration unit, which include thickening of the basement membrane, mesangial cell proliferation, endothelial alteration, and podocyte injury. These morphological abnormalities further result in a persistent increase of urinary albumin-to-creatinine ratio and in a reduction of the estimated glomerular filtration rate. Several molecular and cellular mechanisms have been recognized, up to date, as major players in mediating such clinical and histological features and many more are being under investigation. This review summarizes the most recent advances in understanding cell death mechanisms, intracellular signaling pathways and molecular effectors that play a role in the onset and progression of diabetic kidney damage. Some of those molecular and cellular mechanisms have been already successfully targeted in preclinical models of DKD and, in some cases, strategies have been tested in clinical trials. Finally, this report sheds light on the relevance of novel pathways that may become therapeutic targets for future applications in DKD

Copper, Nickel, and Zinc Cyclam–Amino Acid and Cyclam–Peptide Complexes May Be Synthesized with “Click” Chemistry and Are Noncytotoxic

We describe the synthesis of cyclam metal complexes derivatized with amino acids or a tripeptide using a copper(I)-catalyzed Huisgen “click” reaction. The linker triazole formed during the synthesis plays an active coordinating role in the complexes. The reaction conditions do not racemize the amino acid stereocenters. However, a methylene group adjacent to the triazole is susceptible to H/D exchange under ambient conditions, an observation which has potentially important implications for structures involving stereocenters adjacent to triazoles in click-derived structures. The successful incorporation of several amino acids is described, including reactive tryptophan and cysteine side chains. All complexes are formed rapidly upon introduction of the relevant metal salt, including synthetically convenient cases where trifluoroacetate salts of cyclam derivatives are used directly in the metalation. None of the metal complexes displayed any cytotoxicity to mammalian cells, suggesting that the attachment of such complexes to amino acids and peptides does not induce toxicity, further supporting their potential suitability for labeling/imaging studies. One Cu­(II)–cyclam–triazole–cysteine disulfide complex displayed moderate activity against MCF-10A breast nontumorigenic epithelial cells

Two dimensional Correlated Spectroscopy (2D COSY) results of the kidney allograft.

<p>(A) Table of 2D COSYcrosspeak volumes shows significantly lower threonine, taurine, creatine and choline content in T3 individuals with low glomerular filtration rate and severe allograft dysfunction when compared to T1 individuals with more conserved graft function. “-”indicates a p value greater than 0.05. (B) Representative 2D COSY spectra show higher content of lipid-derived metabolites and reduced levels of threonine, taurine, creatine and choline in T3 individuals carrying a failing allograft. B1 shows a topological map of crosspeaks and B2 shows the 3D reconstruction. (C) Representative 2D COSY of T1 allograft patients with more conserved graft function with two-dimensional (C1) and three-dimensional (C2) reconstruction of the 2D COSY data. Data are expressed as median (25^th, 75^th percentile). <b>Abbreviations.</b> Arbitrary Units (AU).</p

Demographic and metabolic characteristics of kidney transplant individuals.

<p>Results are expressed as median (25^th, 75^th percentile).</p

The IGFBP3/TMEM219 pathway regulates beta cell homeostasis

In this new study the Authors demonstrated that the IGFBP3/TMEM219 pathway is a physiological regulator of pancreatic beta cell homeostasis and it is dysregulated in diabetes. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes. Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes.Funding Agencies|SID Lombardia Grant; EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research; Italian Ministry of HealthMinistry of Health, Italy [RF-2016-02362512]; Universita di Milano; NIHUnited States Department of Health &amp; Human ServicesNational Institutes of Health (NIH) - USA [DK104155]; Juvenile Diabetes Research FoundationJuvenile Diabetes Research Foundation; Enthera S.r.l.</p