Over the past few years, the number of publications concerning the human leukocyte antigen (HLA)-G molecule, its functions, and its pathological implications has greatly increased, largely exceeding ...those focusing simply on fetal-maternal activity. The role of this molecule in other situations of tolerance such as transplantation, tumor dissemination, or virus infections has also been reported. In this paper, we focus our attention on the relevance of HLA-G in transplantation in the light of recent data associating regulatory T cells and HLA-G, and which provide evidence of the role of HLA-G in improving graft acceptance.
Little research has explored pre-transplantation psychological factors as predictors of outcome after liver or kidney transplantation. Our objective is to determine whether report of depressive ...symptoms on waiting list predicts outcome of liver and kidney transplantation.
Patients on waiting list for liver or kidney transplantation were classified for report or non-report of depressive symptoms on waiting list. 339 were transplanted 6 months later on average, and followed prospectively. The main outcome measures were graft failure and mortality 18 months post-transplantation.
Among the 339 patients, 51.6% reported depressive symptoms on waiting list, 16.5% had a graft failure and 7.4% died post-transplantation.Report of depressive symptoms on waiting list predicted a 3 to 4-fold decreased risk of graft failure and mortality 18-months post-transplantation, independently from age, gender, current cigarette smoking, anxiety symptoms, main primary diagnosis, UNOS score, number of comorbid diagnoses and history of transplantation. Data were consistent for liver and kidney transplantations. Other baseline predictive factors were: for graft failure, the main primary diagnosis and a shorter length since this diagnosis, and for mortality, older age, male gender and the main primary diagnosis.
Further studies are needed to understand the underlying mechanisms of the association between report of depressive symptoms on waiting list and decreased risk of graft failure and mortality after transplantation.
Although enterococci expressing acquired vancomycin resistance phenotype have been reported increasingly worldwide, they have been rarely reported in France. From August to December 2004 we faced an ...outbreak of vancomycin-resistant Enterococcus faecium (VRE) isolates in the nephrology department at Bicêtre Hospital (K.-Bicêtre, France). The expression of the glycopeptide resistance varied among the 26 VRE isolates, with vancomycin MICs ranging from 12 to >256 microg/ml, whereas teicoplanin MICs ranged from 4 to 48 microg/ml. However, several strains appeared to be susceptible to glycopeptides according to disk diffusion testing and expressed resistance only after subculture with glycopeptides. In addition, a heterogeneous expression of glycopeptide resistance was also observed. This so-called VanD-like phenotype of resistance (low-level resistance to vancomycin and mostly susceptibility to teicoplanin) was surprisingly associated with a vanA gene. Plasmid extraction and mating-out experiments indicated that the vanA gene was located on a 200-kb self-transferable plasmid. Pulsed-field gel electrophoresis identified mostly dissemination of a single clone, whereas diffusion of the VanA-positive plasmid in different genomic backgrounds had also occurred. The vanA gene was part of a vanA-type operon for expression of resistance located on a Tn1546-like transposon. Sequencing of this transposon identified insertion of insertion sequence IS16 in the vanY gene that encodes a D,D-carboxypeptidase that might explain in part the peculiar VanD-type phenotype of resistance. This report is the first description of a VRE outbreak in France and underlines the difficulty in detecting this organism due to variability on the expression of the glycopeptide resistance trait, if any.
This study aimed to determine the influence of gene candidates on mycophenolic acid (MPA) response during the first year of renal transplantation.
A total of 218 renal transplant recipients who ...received MPA from the first day of transplantation at a fixed dose of 2 g/day were genotyped for ABCB1, ABCC2, UGT2B7, UGT1A9, SLCO1B1, SLCO1B3 and IMPDH1 polymorphisms. Clinical end points were MPA-related adverse drug reactions (ADRs) and acute rejection episodes during the first year post-transplantation.
After correction for multiple statistical testing, SLCO1B1 (encoding the hepatic uptake transporter OATP1B1) was the only gene associated with MPA-related ADRs, showing a 75% risk reduction in favor of a protective effect of the SLCO1B1*5 allele (p = 0.002). In vitro experiments showed that MPA metabolites MPA-phenyl-glucuronide and MPA-acyl-glucuronide are substrates of OATP1B1. Their transport was decreased in the presence of the variant transporter (OATP1B1*5).
These results suggest for the first time that carriers of the SLCO1B1*5 allele seem to be protected from MPA-related ADRs.
Corynebacterium ulcerans causes zoonotic infections, such as diphtheria and extrapharyngeal infections. We report here the first case of a diphtheria-like illness caused by C. ulcerans in France and ...transmitted likely by a dog to an immunocompromised woman.
Mesenchymal stem cells (MSCs) are powerful immunomodulators that regulate the diverse functions of immune cells involved in allogeneic reactions, such as T cells and natural killer (NK) cells, ...through cell-cell contact or secreted factors. Exosomes secreted by MSCs may be involved in their regulatory functions, providing new therapeutic tools. Here, we showed that fetal liver (FL) MSC-derived exosomes inhibit proliferation, activation, and cytotoxicity of NK cells. Exosomes bearing latency associated peptide (LAP), TGFβ, and thrombospondin 1 (TSP1), a regulatory molecule for TGFβ, induced downstream TGFβ/Smad2/3 signaling in NK cells. The inhibition of TGFβ, using a neutralizing anti-TGFβ antibody, restored NK proliferation, differentiation, and cytotoxicity, demonstrating that FL-MSC-derived exosomes exert their inhibition on NK cell function via TGFβ. These results suggest that FL-MSC-derived exosomes regulate NK cell functions through exosome-associated TGFβ.
Multiple organ transplantations are used to treat chronic multiple organ failure. However, long‐term mortality and graft tolerance remain to be evaluated. We carried out a retrospective and ...comparative analysis of 45 patients who underwent a combined liver and kidney (LK) transplantation (LKT) from the same donor. They were compared to 86 matched patients who underwent kidney (K) transplantation (KT). All patients had an organic renal failure associated with cirrhosis (n = 35) or with inherited disease (n = 10). Nineteen (42.9%) had been transplanted previously. The patients' survival rate was 85% at 1 year and 82% at 3 years. Seven patients died within the first 3 months, due to severe polymicrobial infection. Two patients in the LK population (4.2%) developed acute rejection of the kidney graft compared to 24 of the 86 matched renal transplanted patients (32.6%). In parallel, acute liver rejection was observed in 14 cases (31.1%) in the LK population. The occurrence of acute rejection was not associated with panel‐reactive lymphocytotoxic antibodies (n = 16), nor with positive cross‐matches (n = 3). Four of the 45 patients (8.8%) subsequently developed chronic renal allograft rejection, and 16 cases of chronic hepatic dysfunction were noted (42.2%). In conclusion, the overall survival rate following combined liver kidney transplantation is acceptable, and LKT can be proposed to patients with kidney failure associated with liver dysfunction, primary oxaluria or amyloid neuropathy. The main cause of mortality in this population was severe infectious complications. The frequency of acute kidney rejection was lower than in single transplantation.
NK cells have been long time considered as cytotoxic lymphocytes competent in killing virus-infected cells and tumors. However, NK cells may also play essential immuno-regulatory functions. In this ...context, the real existence of a defined NK subset with negative regulatory properties has been hypothesized but never clearly demonstrated.
Herein, we show the in vitro generation from human peripheral blood haematopoietic progenitors (PB-HP), of a novel subset of non-cytolytic NK cells displaying a mature phenotype and remarkable immuno-regulatory functions (NK-ireg). The main functional hallmark of these NK-ireg cells is represented by the surface expression/release of HLA-G, a major immunosuppressive molecule. In addition, NK-ireg cells secrete two powerful immuno-regulatory factors: IL-10 and IL-21. Through these factors, NK-ireg cells act as effectors of the down-regulation of the immune response: reconverting mature myeloid DC (mDC) into immature/tolerogenic DC, blocking cytolytic functions on conventional NK cells and inducing HLA-G membrane expression on PB-derived monocytes. The generation of "NK-ireg" cells is obtained, by default, in culture conditions favouring cell-to-cell contacts, and it is strictly dependent on reciprocal trans-presentation of membrane-bound IL-15 forms constitutively and selectively expressed by human CD34(+) PB-HP. Finally, a small subset of NKp46(+) HLA-G(+) IL-10(+) is detected within freshly isolated decidual NK cells, suggesting that these cells could represent an in vivo counterpart of the NK-ireg cells.
In conclusion, NK-ireg cells represent a novel truly differentiated non-cytolytic NK subset with a self-sustainable phenotype (CD56(+) CD16(+) NKp30(+) NKp44(+) NKp46(+) CD94(+) CD69(+) CCR7(+)) generated from specific pSTAT6(+) GATA3(+) precursors. NK-ireg cells could be employed to develop new immuno-suppressive strategies in autoimmune diseases, transplant rejection or graft versus host diseases. In addition, NK-ireg cells can be easily derived from peripheral blood of the patients and could constitute an autologous biotherapic tool to be used combined or in alternative to other immuno-regulatory cells.
DAO et al Dao, Myriam; Lecru, Lola; Vandermeersch, Sophie ...
Journal of cellular and molecular medicine,
11/2019, Letnik:
23, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss. The aim of our study was to explore ...the potential role of the cannabinoid receptor 1 (CB1) during CAD. We retrospectively quantified CB1 expression and correlated it with renal fibrosis in 26 kidney-transplanted patients who underwent serial routine kidney biopsies. Whereas CB1 expression was low in normal kidney grafts, it was highly expressed during CAD, especially in tubular cells. CB1 expression significantly increased early on after transplantation, from day 0 (D0) to month 3 post-transplant (M3) (22.5% ± 15.4% vs 33.4% ± 13.8%, P < .01), and it remained stable thereafter. CB1 expression correlated with renal fibrosis at M3 (P = .04). In an in vitro model of tacrolimus-mediated fibrogenesis by tubular cells, we found that tacrolimus treatment significantly induced mRNA and protein expression of CB1 concomitantly to col3a1 and col4a3 up regulation. Administration of rimonabant, a CB1 antagonist, blunted collagen synthesis by tubular cells (P < .05). Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology.
There are no studies which have compared the risk of severe COVID‐19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized ...for COVID‐19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single‐center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID‐19 or mortality. Severe COVID‐19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30‐day cumulative incidence of severe COVID‐19 did not differ between KTR and nontransplant patients; however, 30‐day COVID‐19‐related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C‐reactive protein (CRP) were associated with severe COVID‐19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID‐19‐related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID‐19‐related mortality compared to nontransplant hospitalized patients.
The increased mortality risk observed for hospitalized kidney transplant recipients compared to matched nontransplant patients is primarily driven by altered kidney function.
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