Publications by authors named "Sophie Brouard"

167 Publications

Endothelial cell, myeloid, and adaptive immune responses in SARS-CoV-2 infection.

FASEB J 2021 05;35(5):e21577

INSERM U976, Institut de Recherche Saint Louis, Paris, France.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is an emerging respiratory pathogen that has rapidly spread in human populations. Severe forms of infection associate cytokine release syndrome and acute lung injury due to hyperinflammatory responses even though virus clearance is achieved. Key components of inflammation include immune cell recruitment in infected tissues, a step which is under the control of endothelial cells. Here, we review endothelial cell responses in inflammation and infection due to SARS-CoV-2 together with phenotypic and functional alterations of monocytes, T and B lymphocytes with which they interact. We surmise that endothelial cells function as an integrative and active platform for the various cells recruited, where fine tuning of immune responses takes place and which provides opportunities for therapeutic intervention.
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http://dx.doi.org/10.1096/fj.202100024RDOI Listing
May 2021

Connection of BANK1, Tolerance, Regulatory B cells, and Apoptosis: Perspectives of a Reductionist Investigation.

Front Immunol 2021 18;12:589786. Epub 2021 Mar 18.

CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.

BANK1 transcript is upregulated in whole blood after kidney transplantation in tolerant patients. In comparison to patients with rejection, tolerant patients display higher level of regulatory B cells (Bregs) expressing granzyme B (GZMB) that have the capability to prevent effector T cells proliferation. However, BANK1 was found to be decreased in these GZMB Bregs. In this article, we investigated seven different transcriptomic studies and mined the literature in order to make link between BANK1, tolerance and Bregs. As for GZMB Bregs, we found that BANK1 was decreased in other subtypes of Bregs, including IL10 and CD24CD38 transitional regulatory B cells, along with BANK1 was down-regulated in activated/differentiated B cells, as in CD40-activated B cells, in leukemia and plasma cells. Following a reductionist approach, biological concepts were extracted from BANK1 literature and allowed us to infer association between BANK1 and immune signaling pathways, as STAT1, FcγRIIB, TNFAIP3, TRAF6, and TLR7. Based on B cell signaling literature and expression data, we proposed a role of BANK1 in B cells of tolerant patients that involved BCR, IP3R, and PLCG2, and a link with the apoptosis pathways. We confronted these data with our experiments on apoptosis in total B cells and Bregs, and this suggests different involvement for BANK1 in these two cells. Finally, we put in perspective our own data with other published data to hypothesize two different roles for BANK1 in B cells and in Bregs.
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http://dx.doi.org/10.3389/fimmu.2021.589786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015775PMC
March 2021

Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (2a and 2b) trial.

Trials 2021 Mar 9;22(1):199. Epub 2021 Mar 9.

CHU Nantes, Department of Infectious Disease, Clinical Investigation, Nantes, France.

Background: Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2.

Methods: Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population.

Discussion: This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis.

Trial Registration: ClinicalTrials.gov NCT04453384 , registered on 1 July 2020, and EUDRACT 2020-002574-27, registered 6 June 2020.
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http://dx.doi.org/10.1186/s13063-021-05132-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942514PMC
March 2021

Preformed T-cell alloimmunity and HLA eplet mismatch to guide immunosuppression minimization with Tacrolimus monotherapy in Kidney Transplantation. Results of the CELLIMIN trial.

Am J Transplant 2021 Mar 16. Epub 2021 Mar 16.

Kidney Transplant Unit, Nephrology department, Bellvitge University Hospital. IDIBELL. Barcelona University, Barcelona, Spain.

Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogenous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard-of-care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI(n=53) or SOC(n=48), E+ received the same SOC. Six and 12-month BPAR was higher among LI than SOC/E- (4/35[13%] vs 1/43[2%], p=0.15 and 12/48[25%] vs 6/53[11.3%], p=0.073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/66[18%] and 13/66[20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28[14%] low-risk vs 8/20[40%] high-risk, p=0.043). Eplet mismatch also predicted anti-class-I (p=0.05) and anti-DQ (p=0.001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly Polyoma-virus associated nephropathy (p=0.021). Preformed T-cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.
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http://dx.doi.org/10.1111/ajt.16563DOI Listing
March 2021

High neutralizing potency of swine glyco-humanized polyclonal antibodies against SARS-CoV-2.

Eur J Immunol 2021 Feb 12. Epub 2021 Feb 12.

CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France.

Heterologous polyclonal antibodies might represent an alternative to the use of convalescent plasma or monoclonal antibodies (mAbs) in coronavirus disease (COVID-19) by targeting multiple antigen epitopes. However, heterologous antibodies trigger human natural xenogeneic antibody responses particularly directed against animal-type carbohydrates, mainly the N-glycolyl form of the neuraminic acid (Neu5Gc) and the α1,3-galactose, potentially leading to serum sickness or allergy. Here, we immunized cytidine monophosphate-N-acetylneuraminic acid hydroxylase and α1,3-galactosyl-transferase (GGTA1) double KO pigs with the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor binding domain to produce glyco-humanized polyclonal neutralizing antibodies lacking Neu5Gc and α1,3-galactose epitopes. Animals rapidly developed a hyperimmune response with anti-SARS-CoV-2 end-titers binding dilutions over one to a million and end-titers neutralizing dilutions of 1:10 000. The IgG fraction purified and formulated following clinical Good Manufacturing Practices, named XAV-19, neutralized spike/angiotensin converting enzyme-2 interaction at a concentration <1 μg/mL, and inhibited infection of human cells by SARS-CoV-2 in cytopathic assays. We also found that pig GH-pAb Fc domains fail to interact with human Fc receptors, thereby avoiding macrophage-dependent exacerbated inflammatory responses and a possible antibody-dependent enhancement. These data and the accumulating safety advantages of using GH-pAbs in humans warrant clinical assessment of XAV-19 against COVID-19.
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http://dx.doi.org/10.1002/eji.202049072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014652PMC
February 2021

Overexpression of the Msk1 Kinase in Patients With Chronic Lung Allograft Dysfunction and its Confirmed Role in a Murine Model.

Transplantation 2020 Feb 3. Epub 2020 Feb 3.

Laboratoire d'Innovation Thérapeutique UMR 7200, LabEx Medalis, CNRS, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France. Institute of Veterinary Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland. Plateforme de Chimie Biologie Intégrative de Strasbourg (PCBIS) UMS 3286 CNRS, Université de Strasbourg, Labex Medalis, 300 Bld Brant, Illkirch, France. Service de pneumologie, HEGP, Paris, France. Hôpital Foch, Suresnes; Université de Versailles Saint-Quentin Paris-Saclay; INRAe UMR 0892, Paris, France. Service de pneumologie, CHU Strasbourg, France. Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France. Service de pneumologie, L'institut du thorax, CHU Nantes, Nantes, France. Centre d'Investigation Clinique en Biothérapie, Centre de ressources biologiques (CRB), Labex IGO, Nantes, France. Present address: Center for Physiopathology of Toulouse-Purpan (CPTP), UMR 1043, University of Toulouse, INSERM, CNRS, Toulouse, France.

Background: Chronic lung allograft dysfunction (CLAD) and its obstructive form, the obliterative bronchiolitis (OB), are the main long-term complications related to high mortality rate post-lung transplantation. CLAD treatment lacks a significant success in survival. Here, we investigated a new strategy through inhibition of the pro-inflammatory Mitogen and Stress Activated Kinase 1 (MSK1) kinase.

Methods: MSK1 expression was assessed in a mouse OB model after heterotopic tracheal allotransplantation. Pharmacological inhibition of MSK1 (H89, fasudil, PHA767491) was evaluated in the murine model and in a translational model using human lung primary fibroblasts in pro-inflammatory conditions. MSK1 expression was graded over time in biopsies from a cohort of CLAD patients.

Results: MSK1 mRNA progressively increased during OB (6.4-fold at D21 posttransplantation). Inhibition of MSK1 allowed to counteract the damage to the epithelium (56% restoration for H89), and abolished the recruitment of MHCII+ (94%) and T cells (100%) at the early inflammatory phase of OB. In addition, it markedly decreased the late fibroproliferative obstruction in allografts (48%). MSK1 inhibitors decreased production of IL-6 (whose transcription is under the control of MSK1) released from human lung fibroblasts (96%). Finally, we confirmed occurrence of a 2.9-fold increased MSK1 mRNA expression in lung biopsies in patients at 6 months prior to CLAD diagnosis as compared to recipients with stable lung function.

Conclusions: These findings suggest the overall interest of the MSK1 kinase either as a marker or as a potential therapeutic target in lung dysfunction posttransplantation.
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http://dx.doi.org/10.1097/TP.0000000000003606DOI Listing
February 2020

Microbiota and Immunoregulation: A focus on regulatory B Lymphocytes and transplantation.

Am J Transplant 2021 Feb 8. Epub 2021 Feb 8.

Centre De Recherche En Transplantation Et Immunologie, UMR1064, INSERM, Université De Nantes, Nantes, France.

The microbiota plays a major role in the regulation of the host immune functions thus establishing a symbiotic relationship that maintains immune homeostasis. Among immune cells, regulatory B cells (Bregs), which can inhibit effector T cell responses, may be involved in the intestinal homeostasis. Recent works suggest that the interaction between the microbiota and Bregs appears to be important to limit autoimmune diseases and help to maintain tolerance in transplantation. Short-chain fatty acids, recognized as major metabolites of the microbiota, seem to be involved in the generation of a pro-tolerogenic environment in the gut, particularly through the regulation of B cell differentiation, limiting mature B cells and promoting the function of Bregs. In this review, we show that this B cells-microbiota interaction may open a path towards new potential therapeutic applications not only for patients with autoimmune diseases but also in transplantation.
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http://dx.doi.org/10.1111/ajt.16522DOI Listing
February 2021

New Method for the Expansion of Highly Purified Human Regulatory Granzyme B-Expressing B Cells.

Methods Mol Biol 2021 ;2270:203-216

CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.

Granzyme B (GZMB)-expressing B cells inhibit CD4 T-lymphocyte proliferation in a contact- and GZMB-dependent manner, through degradation of TCR zeta or induction of T-cell apoptosis. This regulatory B-cell population is present in human healthy individuals and represents about 1% of circulating B cells. Their small proportion requires the development of expansion methods to enable their study and envision clinical applications. We describe here how to expand GZMB-expressing B cells to obtain more than 90% of highly purified GZMB B cells, and the protocol of B/T cells coculture for the evaluation of the suppressive function of the GZMB B-cell population.
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http://dx.doi.org/10.1007/978-1-0716-1237-8_11DOI Listing
April 2021

Toward a better definition of hematopoietic progenitors suitable for B cell differentiation.

PLoS One 2020 15;15(12):e0243769. Epub 2020 Dec 15.

Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.

The success of inducing human pluripotent stem cells (hIPSC) offers new opportunities for cell-based therapy. Since B cells exert roles as effector and as regulator of immune responses in different clinical settings, we were interested in generating B cells from hIPSC. We differentiated human embryonic stem cells (hESC) and hIPSC into B cells onto OP9 and MS-5 stromal cells successively. We overcame issues in generating CD34+CD43+ hematopoietic progenitors with appropriate cytokine conditions and emphasized the difficulties to generate proper hematopoietic progenitors. We highlight CD31intCD45int phenotype as a possible marker of hematopoietic progenitors suitable for B cell differentiation. Defining precisely proper lymphoid progenitors will improve the study of their lineage commitment and the signals needed during the in vitro process.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243769PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737978PMC
January 2021

Tetraspanins: useful multifunction proteins for the possible design and development of small-molecule therapeutic tools.

Drug Discov Today 2021 Jan 1;26(1):56-68. Epub 2020 Nov 1.

Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France.

Tetraspanins constitute a well-conserved superfamily of four-span small membrane proteins (TM4SF), with >30 members in humans, with important roles in numerous mechanisms of cell biology. Moreover, tetraspanins associate with either specific partner proteins or another tetraspanin, generating a network of interactions involved in cell and membrane compartmentalization and having a role in cellular development, proliferation, activation, motility, and membrane fusions. Therefore, tetraspanins are considered regulators of cellular signaling and are often depicted as 'molecular facilitators'. In view of these many physiological functions, it is likely that these molecules are important actors in pathological processes. In this review, we present the main characteristics of this superfamily, providing a more detailed description of some significant representatives and discuss their relevance as potential targets for the design and development of small-molecule therapeutics in different pathologies.
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http://dx.doi.org/10.1016/j.drudis.2020.10.022DOI Listing
January 2021

Clinical and immunological follow-up of very long-term kidney transplant recipients treated with calcineurin inhibitors indicates dual phenotypes.

Kidney Int 2020 Nov 1. Epub 2020 Nov 1.

Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, France; Service de Néphrologie et Immunologie Clinique, CHU Nantes, Nantes Université, ITUN, Nantes, France.

Operationally tolerant kidney transplant recipients harbor an immunological signature, associated with low rejection risk, and focused on B lymphocytes. Here, we investigated whether patients with long-term transplantation and still on immunosuppressive therapy would present such a signature of low immunological rejection risk, compared to more recently transplanted patients. Of 114 kidney transplant recipients enrolled, 38 with more than 25 years of graft survival and stable graft function under calcineurin inhibitors, were matched with two different groups of transplanted patients (10-15 and 5-7 years after transplantation). Three phenotypes associated with low immunological rejection risk (Tfh, B and regulatory T cells), initially found in operationally tolerant kidney transplant recipients, and the composite score of tolerance (combination of six transcriptomic markers, age at transplantation and age at sampling) were analyzed. We found that very long-term patients were characterized by a significantly lower percentage of total B cells, a significantly higher proportion of CD24CD38 memory B cells, significantly fewer CD24CD38 naive B cells, and a significantly lower proportion of PD1CCR7 Tfh lymphocytes than more recently transplanted patients. This phenotype is associated with a positive composite score of tolerance in patients transplanted for more than 25 years. Thus, our study suggests a dual phenotype in very long-term kidney transplanted patients with an immunological profile associated with low rejection risk.
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http://dx.doi.org/10.1016/j.kint.2020.09.036DOI Listing
November 2020

Multiscale fluorescent tracking of immune cells in the liver with a highly biocompatible far-red emitting polymer probe.

Sci Rep 2020 10 16;10(1):17546. Epub 2020 Oct 16.

Université de Nantes, INSERM, UMR1064, Centre de Recherche en Transplantation et Immunologie, ITUN, 44000, Nantes, France.

The development of innovative immune cell therapies relies on efficient cell tracking strategies. For this, multiscale fluorescence-based analyses of transferred cells into the host with complementary techniques, including flow cytometry for high-throughput cell analysis and two-photon microscopy for deep tissue imaging would be highly beneficial. Ideally, cells should be labelled with a single fluorescent probe combining all the properties required for these different techniques. Due to the intrinsic autofluorescence of most tissues and especially the liver, far-red emission is also an important asset. However, the development of far-red emitting probes suitable for two-photon microscopy and compatible with clearing methods to track labelled immune cells in thick samples, remains challenging. A newly-designed water-soluble far-red emitting polymer probe, 19K-6H, with a large Stokes shift, was thus evaluated for the tracking of primary immune CD8 T cells. These cells, prepared from mouse spleen, were efficiently labelled with the 19K-6H probe, which was internalized via endocytosis and was highly biocompatible at concentrations up to 20 μM. Labelled primary CD8 T cells were detectable in culture by both confocal and two-photon microscopy as well as flow cytometry, even after 3 days of active proliferation. Finally, 19K-6H-labelled primary CD8 T cells were injected to mice in a classical model of immune mediated hepatitis. The efficient tracking of the transferred cells in the liver by flow cytometry (on purified non-parenchymal cells) and by two-photon microscopy on 800 μm thick cleared sections, demonstrated the versatility of the 19K-6H probe.
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http://dx.doi.org/10.1038/s41598-020-74621-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567820PMC
October 2020

Efficient Expansion of Human Granzyme B-Expressing B Cells with Potent Regulatory Properties.

J Immunol 2020 11 18;205(9):2391-2401. Epub 2020 Sep 18.

CHU Nantes, Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France;

Granzyme B-expressing B cells have been shown to be an important regulatory B cell subset in humans. However, it is unclear which subpopulations of B cells express GZMB under normal conditions and which protocols effectively induce ex vivo expansion of GZMB B cells. We found that in the peripheral blood of normal individuals, plasmablasts were the major B cell subpopulation that expressed GZMB. However, when using an in vitro plasmablast differentiation protocol, we obtained only 2% GZMB B cells. Nevertheless, using an expansion mixture containing IL-21, anti-BCR, CpG oligodeoxynucleotide, CD40L, and IL-2, we were able to obtain more than 90% GZMB B cells after 3 d culture. GZMB B cells obtained through this protocol suppressed the proliferation of autologous and allogenic CD4CD25 effector T cells. The suppressive effect of GZMB B cells was partially GZMB dependent and totally contact dependent but was not associated with an increase in effector T cell apoptosis or uptake of GZMB by effector T cells. Interestingly, we showed that GZMB produced by B cells promoted GZMB B cell proliferation in ERK1/2-dependent manner, facilitating GZMB B cell expansion. However, GZMB B cells tended to undergo apoptosis after prolonged stimulation, which may be considered a negative feedback mechanism to limit their uncontrolled expansion. Finally, we found that expanded GZMB B cells exhibited a regulatory phenotype and were enriched in CD307b, CD258CD72, and CD21loPD-1 B cell subpopulations. Our study, to our knowledge, provides new insight into biology of GZMB B cells and an efficient method to expand GZMB B cells for future cell therapy applications.
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http://dx.doi.org/10.4049/jimmunol.2000335DOI Listing
November 2020

Time-dependent lymphocyte count after transplantation is associated with higher risk of graft failure and death.

Kidney Int 2020 Sep 3. Epub 2020 Sep 3.

CRTI UMR 1064, Inserm, Université de Nantes, ITUN, CHU Nantes, RTRS Centaure, Nantes, France; Centre Hospitalier Universitaire de Nantes, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Labex IGO, Nantes, France.

The transplantation field requires the identification of specific risk factors associated with the level of immunosuppression. Here, our aim was to analyze the association between the number of circulating lymphocytes, monitored routinely by complete blood cell counts during outpatient visits, and patient and graft survival. In total, 2,999 kidney or combined kidney-pancreas recipients transplanted between 2000 and 2016, from two University hospitals, were enrolled. We investigated the etiological relationship between time-dependent lymphocyte count beyond one year after transplantation and patient and graft survival, viral infection and cancer risk using time-dependent multivariate Cox models. Model 1 considered kidney function at one year and model 2 as time-dependent variable. At the time of inclusion (one year after transplantation), 584 patients (19.4%) had deep lymphopenia (under 750 /mm) and 1,072 (35.7%) had a normal count (over 1,500 /mm). A patient with deep lymphopenia at a given follow-up time had significantly higher risks of graft failure, death and viral infection than comparable patients with a normal lymphocyte count at the same time point. Thus, after the first year of transplantation, the occurrence of deep lymphopenia within a patient's follow-up is a risk factor for long-term graft failure, death and viral infection.
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http://dx.doi.org/10.1016/j.kint.2020.08.010DOI Listing
September 2020

B cells and extracellular vesicles: New key players in solid organ transplantation?

Am J Transplant 2021 04 29;21(4):1361-1362. Epub 2020 Aug 29.

Centre De Recherche En Transplantation Et Immunologie, UMR1064, INSERM, Université De Nantes, Nantes, France.

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http://dx.doi.org/10.1111/ajt.16253DOI Listing
April 2021

Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis.

J Hepatol 2020 12 8;73(6):1379-1390. Epub 2020 Jul 8.

Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France. Electronic address:

Background & Aims: In most autoimmune disorders, crosstalk of B cells and CD4 T cells results in the accumulation of autoantibodies. In autoimmune hepatitis (AIH), the presence of anti-soluble liver antigen (SLA) autoantibodies is associated with reduced overall survival, but the associated autoreactive CD4 T cells have not yet been characterised. Herein, we isolated and deeply characterised SLA-specific CD4 T cells in patients with AIH.

Methods: We used brief ex vivo restimulation with overlapping SLA peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNA-seq) to characterise their transcriptome and T-cell receptor (TCR) repertoire. Autoreactive TCRs were cloned and used to identify dominant SLA-derived epitopes. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing to identify their phenotypic niche. We further characterised disease-associated peripheral blood T cells by high-content flow cytometry in 42 patients with AIH and 17 controls with non-alcoholic steatohepatitis.

Results: Autoreactive SLA-specific CD4 T cells were only detected in patients with anti-SLA autoantibodies and had a memory PD-1CXCR5CCR6CD27 phenotype. ScRNA-seq revealed their pro-inflammatory/B-helper profile. SLA and SLA contain dominant T-cell epitopes. Autoreactive TCR clonotypes were predominantly found in the memory PD-1CXCR5CD4 T cells, which were significantly increased in the blood of patients with AIH and supported B-cell differentiation through IL-21. Finally, we identified specific T-cell phenotypes linked to disease activity and IgG level during AIH.

Conclusions: We provide a deep characterisation of rare circulating autoreactive CD4 T cells and identify their peripheral reservoir in AIH. We also propose a specific phenotype of autoreactive T cells related to AIH disease activity, which will be essential to track, delineate, and potentially target these pathogenic cells.

Lay Summary: One principal characteristic of autoimmune hepatitis (AIH), like for many other autoimmune diseases, is the accumulation of autoantibodies produced by B lymphocytes following their interaction with autoreactive CD4 T lymphocytes. In this study, we identified and characterised with high resolution these CD4 T cells. This will be essential to track, delineate, and potentially target them during AIH.
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http://dx.doi.org/10.1016/j.jhep.2020.05.053DOI Listing
December 2020

Diagnostic performance of kSORT, a blood-based mRNA assay for noninvasive detection of rejection after kidney transplantation: A retrospective multicenter cohort study.

Am J Transplant 2021 02 4;21(2):740-750. Epub 2020 Aug 4.

French National Institute of Health and Medical Research (Inserm) Unit 1111, Lyon, France.

The Kidney Solid Organ Response Test (kSORT) blood gene expression assay was developed to noninvasively detect acute rejection (AR) after kidney transplantation. Its performance in a setting with natural disease prevalence has not been evaluated. A retrospective, multicenter cohort study was conducted across all single kidney transplant recipients, transplanted between 2011 and 2015, with samples within the first year after transplantation available in existing biobanks. The primary objective was to determine the diagnostic performance of the kSORT assay to detect AR (T cell-mediated and/or antibody-mediated rejection) as compared to a concomitant renal biopsy. AR was reported on the concomitant biopsy in 188 of 1763 (10.7%) blood samples and any rejection (including borderline changes) in 614 of 1763 (34.8%) blood samples. In 320 of 1763 samples (18.2%) the kSORT risk category was indeterminate. The kSORT assay had no diagnostic value for AR (area under the curve [AUC] 0.51, 95% confidence interval [CI] 0.50-0.56; P = .46) overall, or when considering indication biopsies (N = 487) and protocol-specified biopsies (N = 1276) separately (AUC of 0.53, 95% CI 0.50-0.59, P = .44 and 0.55, 95% CI 0.50-0.61, P = .09, respectively). This large retrospective study utilizing samples obtained under real-world clinical conditions, was unable to validate the kSORT assay for detection of AR in the first year after transplantation.
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http://dx.doi.org/10.1111/ajt.16179DOI Listing
February 2021

Transcriptional meta-analysis of regulatory B cells.

Eur J Immunol 2020 11 23;50(11):1757-1769. Epub 2020 Jun 23.

Inserm, CHU Nantes, Université de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.

Regulatory B cells (Bregs) have the ability to regulate inflammation in various pathological situations, making them key players in immune regulation. Several mechanisms have been described and we recently identified a GZMB expressing Breg population in kidney transplanted patients who tolerate a kidney graft. To further investigate their biology and mechanisms, we conducted a transcriptomic analysis by RNAseq of these cells and we performed the first weighted meta-analysis of publicly available transcriptomic data from published Breg studies both in humans and mice. We identified two distinct and unique transcriptional signatures of 126 and 93 genes, respectively, associated with these Bregs. While we highlighted genes coding for proteins with potent involvement in regulatory functions, proliferation, and coding for transcription factors, the comparison between humans and mice did not allow identifying a common pattern. Thus, our results suggest distinct species-restricted Breg transcriptional signatures in humans and mice.
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http://dx.doi.org/10.1002/eji.201948489DOI Listing
November 2020

Distinct peripheral blood molecular signature emerges with successful tacrolimus withdrawal in kidney transplant recipients.

Am J Transplant 2020 12 27;20(12):3477-3485. Epub 2020 May 27.

Department of Medicine, Icahn School of Medicine at Mount Sinai, Translational Transplant Research Center, New York, New York, USA.

Tacrolimus (Tac) is an effective anti-rejection agent in kidney transplantation, but its off-target effects make withdrawal desirable. Although studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs unsuccessful Tac removal are unknown. We performed microarray analyses of peripheral blood mononuclear cells (PBMC) RNA from subjects enrolled in the Clinical Trials in Organ Transplantation-09 study in which we randomized stable kidney transplant recipients to Tac withdrawal or maintenance of standard immunosuppression beginning 6 months after transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a downregulatory and proapoptotic gene program enriched within T cells. Functional analyses suggested stronger donor-reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data from a small, but unique, patient cohort support the conclusion that successful Tac withdrawal is not simply due to absence of donor-reactive immunity but rather is associated with an active immunological process.
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http://dx.doi.org/10.1111/ajt.15979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704683PMC
December 2020

Targeting the interleukin-7 receptor alpha by an anti-CD127 monoclonal antibody improves allergic airway inflammation in mice.

Clin Exp Allergy 2020 07 16;50(7):824-834. Epub 2020 Jun 16.

Université de Nantes, CHU Nantes, INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.

Background: Interleukin-7 (IL-7) is the most important cytokine for T-cell homeostasis. IL-7 signals through the IL-7 receptor (IL-7R) which is composed of an alpha chain (IL-7Rα), also called CD127 and a common gamma chain. T lymphocytes, especially T helper type 2, play a crucial role in the pathobiology of allergic asthma.

Objective: To study the effects of an anti-CD127 monoclonal antibody (mAb) in a murine model of allergic airway inflammation induced by house dust mite (HDM).

Methods: Allergic airway inflammation was induced in mice using a protocol comprising 4 weekly percutaneous sensitizations followed by 2 weekly intranasal challenges with total HDM extracts and treated by intraperitoneal injections of an anti-CD127 mAb. Because CD127 is shared by both IL-7R and the receptor for thymic stromal lymphopoietin (TSLP), a group of mice was also treated with an anti-IL-7 mAb to block only the IL-7 signalling pathway.

Results: Anti-CD127 mAb-treated mice showed significantly lower airway resistance in response to methacholine and improvement in lung histology compared with isotype mAb-treated animals. Anti-CD127 mAb treatment significantly decreased the mRNA expression of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL5/RANTES) in lung tissue, decreased the secretion of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CXCL1 and CCL11/eotaxin) in bronchoalveolar lavage fluid (BALF), decreased serum HDM-specific IgE, and reduced the number of total leucocytes and leucocyte subpopulations such as eosinophils, macrophages, lymphocytes, T lymphocytes, and ILC2 in BALF and lung tissue. Mice treated with anti-IL-7 mAb also showed less allergic airway inflammation as evidenced by significantly lower airway resistance and fewer leucocytes in BALF and lung tissue compared to mice treated with the corresponding isotype control mAb.

Conclusion And Clinical Relevance: Targeting the IL-7Rα by an anti-CD127 mAb improves allergic airway inflammation in mice and presents as a potential therapeutic approach for allergic asthma.
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http://dx.doi.org/10.1111/cea.13665DOI Listing
July 2020

Terminally Differentiated Effector Memory CD8 T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure.

J Am Soc Nephrol 2020 04 12;31(4):876-891. Epub 2020 Mar 12.

Université de Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, Nantes, France;

Background: Identifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation.

Methods: We investigated the frequency and function of CD8 T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8 T cells-in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8 T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants.

Results: Increased frequency of circulating TEMRA CD8 T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8 T cells associated with reduced risk of graft failure. A distinct TEMRA CD8 T cell subpopulation was identified that was characterized by expression of FcRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8 T cells, CD16 engagement resulted in selective activation of TEMRA CD8 T cells, which mediated antibody-dependent cytotoxicity.

Conclusions: At 1 year post-transplant, the composition of memory CD8 T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8 T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8 T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8 T cell monitoring for predicting risk of kidney transplant failure.
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http://dx.doi.org/10.1681/ASN.2019080847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191929PMC
April 2020

Neutrophils cause a "NET" increase in skin allograft allogenicity.

Am J Transplant 2020 04 7;20(4):922-923. Epub 2020 Jan 7.

Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, Université de Nantes, Nantes, France.

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http://dx.doi.org/10.1111/ajt.15746DOI Listing
April 2020

CXCR5PD1ICOS Circulating T Follicular Helpers Are Associated With Donor-Specific Antibodies After Renal Transplantation.

Front Immunol 2019 10;10:2071. Epub 2019 Sep 10.

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4CD45RACXCR5, and the three following subsets of activated cTfh were analyzed: CXCR5PD1, CXCR5PD1ICOS, an CXCR5PD1CXCR3. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5PD1, CXCR5PD1ICOS, and CXCR5PD1CXCR3 cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5PD1ICOS at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing DSA after the first year ( = 0.018, HR = 0.39), independently of HLA mismatches ( = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.
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http://dx.doi.org/10.3389/fimmu.2019.02071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746839PMC
October 2020

Early Identification of Chronic Lung Allograft Dysfunction: The Need of Biomarkers.

Front Immunol 2019 17;10:1681. Epub 2019 Jul 17.

Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.

A growing number of patients with end-stage lung disease have benefited from lung transplantation (LT). Improvements in organ procurement, surgical techniques and intensive care management have greatly increased short-term graft survival. However, long-term outcomes remain limited, mainly due to the onset of chronic lung allograft dysfunction (CLAD), whose diagnosis is based on permanent loss of lung function after the development of irreversible lung lesions. CLAD is associated with high mortality and morbidity, and its exact physiopathology is still only partially understood. Many researchers and clinicians have searched for CLAD biomarkers to improve diagnosis, to refine the phenotypes associated with differential prognosis and to identify early biological processes that lead to CLAD to enable an early intervention that could modify the inevitable degradation of respiratory function. Donor-specific antibodies are currently the only biomarkers used in routine clinical practice, and their significance for accurately predicting CLAD is still debated. We describe here significant studies that have highlighted potential candidates for reliable and non-invasive biomarkers of CLAD in the fields of imaging and functional monitoring, humoral immunity, cell-mediated immunity, allograft injury, airway remodeling and gene expression. Such biomarkers would improve CLAD prediction and allow differential LT management regarding CLAD risk.
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http://dx.doi.org/10.3389/fimmu.2019.01681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650588PMC
September 2020

Unique and specific Proteobacteria diversity in urinary microbiota of tolerant kidney transplanted recipients.

Am J Transplant 2020 01 9;20(1):145-158. Epub 2019 Sep 9.

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.

Host-microbiota interactions can modulate the immune system both at local and systemic levels, with potential consequences for organ transplantation outcomes. In this study, we hypothesized that differences in the urinary microbiome following kidney transplantation would be associated with posttransplantation status: stable, minimally immunosuppressed, or tolerant. One hundred thirteen urine samples from stable (n = 51), minimally immunosuppressed (n = 19), and spontaneously tolerant (n = 16) patients, paired with age-matched controls (n = 27) were profiled and compared to each other at a taxonomic level with special interest in the immunosuppressive regimen. All comparisons and correlations were adjusted on sex and time posttransplantation. Our results highlighted a unique and specific urinary microbiota associated with spontaneous tolerance characterized by a high diversity and a clear Proteobacteria profile. Finally, we report that this profile is (1) impacted by gender, (2) inversely correlated with immunosuppressive drugs (calcineurin inhibitors and mammalian target of rapamycin inhibitors), and (3) stable in time.
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http://dx.doi.org/10.1111/ajt.15549DOI Listing
January 2020

Interleukin-7 receptor blockade by an anti-CD127 monoclonal antibody in nonhuman primate kidney transplantation.

Am J Transplant 2020 01 14;20(1):101-111. Epub 2019 Aug 14.

Centre de Recherche en Transplantation et Immunologie (CRTI), UMR 1064, INSERM, Université de Nantes, Nantes, France.

IL-7 is an important cytokine for T cell lymphopoiesis. Blockade of the IL-7 signaling pathway has been shown to induce long-term graft survival or graft tolerance in murine transplant models through inhibiting T cell homeostasis and favoring immunoregulation. In this study, we assessed for the first time the effects of a blocking anti-human cluster of differentiation 127 (CD127) mAb administered in combination with low-dose tacrolimus or thymoglobulin in a life-sustaining kidney allograft model in baboons. Contrary to our expectation, the addition of an anti-CD127 mAb to the treatment protocols did not prolong graft survival compared to low-dose tacrolimus alone or thymoglobulin alone. Anti-CD127 mAb administration led to full CD127 receptor occupancy during the follow-up period. However, all treated animals lost their kidney graft between 1 week and 2 weeks after transplantation. Unlike in rodents, in nonhuman primates, anti-CD127 mAb treatment does not decrease the absolute numbers of lymphocyte and lymphocyte subsets and does not effectively inhibit postdepletional T cell proliferation and homeostasis, suggesting that IL-7 is not a limiting factor for T cell homeostasis in primates.
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http://dx.doi.org/10.1111/ajt.15543DOI Listing
January 2020

Blood CD9 B cell, a biomarker of bronchiolitis obliterans syndrome after lung transplantation.

Am J Transplant 2019 11 21;19(11):3162-3175. Epub 2019 Aug 21.

Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, Université de Nantes, Nantes, France.

Bronchiolitis obliterans syndrome is the main limitation for long-term survival after lung transplantation. Some specific B cell populations are associated with long-term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow-up. CD24 CD38 transitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24 CD38 transitional B cells specifically secrete IL-10 and express CD9. Thus, patients with a total CD9 B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL-10-secreting CD24 CD38 transitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9-expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long-term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome-free survival.
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http://dx.doi.org/10.1111/ajt.15532DOI Listing
November 2019

Elicited and pre-existing anti-Neu5Gc antibodies differentially affect human endothelial cells transcriptome.

Xenotransplantation 2019 11 10;26(6):e12535. Epub 2019 Jul 10.

Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.

Humans cannot synthesize N-glycolylneuraminic acid (Neu5Gc) but dietary Neu5Gc can be absorbed and deposited on endothelial cells (ECs) and diet-induced anti-Neu5Gc antibodies (Abs) develop early in human life. While the interaction of Neu5Gc and diet-induced anti-Neu5Gc Abs occurs in all normal individuals, endothelium activation by elicited anti-Neu5Gc Abs following a challenge with animal-derived materials, such as following xenotransplantation, had been postulated. Ten primary human EC preparations were cultured with affinity-purified anti-Neu5Gc Abs from human sera obtained before or after exposure to Neu5Gc-glycosylated rabbit IgGs (elicited Abs). RNAs of each EC preparation stimulated in various conditions by purified Abs were exhaustively sequenced. EC transcriptomic patterns induced by elicited anti-Neu5Gc Abs, compared with pre-existing ones, were analyzed. qPCR, cytokines/chemokines release, and apoptosis were tested on some EC preparations. The data showed that anti-Neu5Gc Abs induced 967 differentially expressed (DE) genes. Most DE genes are shared following EC activation by pre-existing or anti-human T-cell globulin (ATG)-elicited anti-Neu5Gc Abs. Compared with pre-existing anti-Neu5Gc Abs, which are normal component of ECs environment, elicited anti-Neu5Gc Abs down-regulated 66 genes, including master genes of EC function. Furthermore, elicited anti-Neu5Gc Abs combined with complement-containing serum down-regulated most transcripts mobilized by serum alone. Both types of anti-Neu5Gc Abs-induced a dose- and complement-dependent release of selected cytokines and chemokines. Altogether, these data show that, compared with pre-existing anti-Neu5Gc Abs, ATG-elicited anti-Neu5Gc Abs specifically modulate genes related to cytokine responses, MAPkinase cascades, chemotaxis, and integrins and do not skew the EC transcriptome toward a pro-inflammatory profile in vitro.
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http://dx.doi.org/10.1111/xen.12535DOI Listing
November 2019

Role of JAK inhibitors and immune cells in transplantation.

Cytokine Growth Factor Rev 2019 06 11;47:62-73. Epub 2019 May 11.

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France. Electronic address:

Immunosuppressive challenge after transplantation has dual objectives, namely, to efficiently inhibit immune populations involved in acute, chronic, humoral or cellular transplant rejection while minimizing the effect on immune integrity toward pathogens. The current immunosuppressive strategies show limited efficacy and remain associated with strong side effects, and thus, it is essential to develop new strategies. The use of Janus kinase (JAK) inhibitors is one of the new strategies focusing on cytokine pathways. Specifically, the first-generation JAK inhibitors (JAKis) showed low specificity toward the four known JAK molecules and did not exhibit better effects than calcineurin inhibitors, which constitute the standard treatment posttransplantation. However, because the new generation of JAKis present higher specificity, we are gaining further insights on the response of cells to these inhibitions. This review focuses on the impact of JAKis on different immune cell subsets, focusing on their role in transplantation.
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http://dx.doi.org/10.1016/j.cytogfr.2019.05.002DOI Listing
June 2019