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Background: The presence of neutrophils in the lung was identified as a factor associated with CLAD but requires invasive samples. The aim of this study was to assess the kinetics of peripheral blood neutrophils after lung transplantation as early predictor of CLAD., Methods: We retrospectively included all recipients transplanted in our center between 2009 and 2014. Kinetics of blood neutrophils were evaluated to predict early CLAD by mathematical modeling using unadjusted and adjusted analyses., Results: 103 patients were included, 80 in the stable group and 23 in the CLAD group. Bacterial infections at 1 year were associated with CLAD occurrence. Neutrophils demonstrated a high increase postoperatively and then a progressive decrease until normal range. Recipients with CLAD had higher neutrophil counts (mixed effect coefficient beta over 3 years = +1.36 G/L, 95% Confidence Interval [0.99-1.92], p < .001). A coefficient of celerity (S for speed) was calculated to model the kinetics of return to the norm before CLAD occurrence. After adjustment, lower values of S (slower decrease of neutrophils) were associated with CLAD (Odds Ratio = 0.26, 95% Confidence Interval [0.08-0.66], p = .01)., Conclusion: A slower return to the normal range of blood neutrophils was early associated with CLAD occurrence., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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 hi CD38 hi 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 hi CD38 hi 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 hi CD38 hi 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., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Fc gamma receptors (FcγRs) play a major role in the regulation of humoral immune responses. Single-nucleotide polymorphisms (SNPs) of FCGR2A and FCGR3A can impact the expression level, IgG affinity and function of the CD32 and CD16 FcγRs in response to their engagement by the Fc fragment of IgG. The CD16 isoform encoded by FCGR3A [158V/V] controls the intensity of antibody-dependent cytotoxic alloimmune responses of natural killer cells (NK) and has been identified as a susceptibility marker predisposing patients to cardiac allograft vasculopathy after heart transplant. This study aimed to investigate whether FCGR2A and FCGR3A polymorphisms can also be associated with the clinical outcome of lung transplant recipients (LTRs). The SNPs of FCGR2A ([131R/H], rs1801274) and FCGR3A ([158V/F], rs396991) were identified in 158 LTRs and 184 Controls (CTL). The corresponding distribution of genotypic and allelic combinations was analyzed for potential links with the development of circulating donor-specific anti-HLA alloantibodies (DSA) detected at months 1 and 3 after lung transplant (LTx), the occurrence of acute rejection (AR) and chronic lung allograft dysfunction (CLAD), and the overall survival of LTRs. The FCGR3A [158V/V] genotype was identified as an independent susceptibility factor associated with higher rates of AR during the first trimester after LTx (HR 4.8, p < 0.0001, 95% CI 2.37-9.61), but it could not be associated with the level of CD16- mediated NK cell activation in response to the LTR's DSA, whatever the MFI intensity and C1q binding profiles of the DSA evaluated. The FCGR2A [131R/R] genotype was associated with lower CLAD-free survival of LTRs, independently of the presence of DSA at 3 months (HR 1.8, p = 0.024, 95% CI 1.08-3.03). Our data indicate that FCGR SNPs differentially affect the clinical outcome of LTRs and may be of use to stratify patients at higher risk of experiencing graft rejection. Furthermore, these data suggest that in the LTx setting, specific mechanisms of humoral alloreactivity, which cannot be solely explained by the complement and CD16-mediated pathogenic effects of DSA, may be involved in the development of acute and chronic lung allograft rejection.

Background: Immunosuppressive strategy targets mainly adaptive immunity after solid organ transplantation. We assessed the influence of early post-operative sepsis on T cell and monocyte reconstitution in anti-thymocyte globulin (ATG)-treated lung transplant recipients., Methods: We retrospectively included recipients who underwent a first lung transplant at our Lung Transplant Center (Marseille, France) between July 2011 and February 2013. Peripheral blood T-lymphocyte subset counts and monocyte HLA-DR (mHLA-DR) expression routinely performed by flow cytometry within 60 days post-transplant were analyzed. We compared the immune kinetics of patients who did or did not develop sepsis during the post-operative intensive care unit stay., Results: Among the 37 recipients included, 19 patients (51%) developed at least one episode of sepsis. At the ICU admission, septic recipients had higher SOFA score (9 [7.5-9] versus 6 [4-7]), p = .01), higher primary graft dysfunction score (1.4 ± 1.4 versus 0.3 ± 0.7, p = .008) and more frequent use of ECMO (47% versus 0%, p = .003). Whereas both groups had similar T-lymphocytes reconstitution in the post-operative period, mHLA-DR reconstitution was dramatically affected in septic patients after day 14, median mHLA-DR expression at 2.3 MFI [1.3-3.5] in the septic versus 8.0 MFI [5.1-10.5] in the non-septic group, p = .02., Conclusion: We found that sepsis is negatively correlated with the mHLA-DR expression but not adaptive T cell immune reconstitution. This finding highlights the importance of immunomonitoring after lung transplantation and questions the strategy of a lower immunosuppression therapy in context of sepsis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-β. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-β-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Lung transplantation (LTx) is a valid therapeutic option for selected patients with end-stage lung disease. Soluble HLA-G (sHLA-G) has been associated with increased graft survival and decreased rejection episodes in solid organ transplantation. HLA-G haplotypes named UTRs, defined by SNPs from both the 5'URR and 3'UTR, have been reported to reliably predict sHLA-G level. The aim of this retrospective study was to determine the impact of HLA-G alleles and UTR polymorphism from LTx recipients on anti-HLA allo-immunization risk, overall survival and chronic rejection (CLAD). HLA-G SNPs were genotyped in 124 recipients who underwent LTx from 1996 to 2010 in Marseille, 123 healthy individuals and 26 cystic fibrosis patients not requiring LTx. sHLA-G levels were measured for 38 LTx patients at D0, M3 and M12 and for 123 healthy donors. HLA-G*01:06∼UTR2 was associated with a worse evolution of cystic fibrosis (p = 0.005) but not of long-term survival post-LTx. HLA-G*01:04∼UTR3 haplotype was associated with lower levels of sHLA-G at D0 and M3 (p = 0.03), impaired long-term survival (p = 0.001), increased CLAD occurrence (p = 0.03) and the production of de novo donor-specific antibodies (DSA) at M3 (p = 0.01). This study is the first to show the deleterious association of different HLA-G alleles and UTRs in LTx., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Therapeutic drug monitoring of tacrolimus is a major support to patient management and could help improve the outcome of lung transplant recipients, by minimizing the risk of rejections and infections. However, despite the wide use of tacrolimus as part of maintenance immunosuppressive regimens after lung transplantation, little is known about its pharmacokinetics in this population. Better knowledge of the pharmacokinetics of tacrolimus in lung transplant recipients, and the development of tools dedicated to its therapeutic drug monitoring, could thus help improve their outcome., Objectives: The aims of this study were (i) to characterize the population pharmacokinetics of tacrolimus in lung transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator of the tacrolimus area under the blood concentration-time curve from time zero to 12 hours (AUC(12)) for its therapeutic drug monitoring in lung transplant recipients., Methods: A population pharmacokinetic model was developed by nonlinear mixed-effects modelling using NONMEM® version VI, from 182 tacrolimus full concentration-time profiles collected in 78 lung transplant recipients within the first year post-transplantation. Patient genotypes for the cytochrome P450 3A5 (CYP3A5) A6986G single nucleotide polymorphism (SNP) were characterized by TaqMan allelic discrimination. Patients were divided into an index dataset (n = 125 profiles) and a validation dataset (n = 57 profiles). A Bayesian estimator was derived from the final model using the index dataset, in order to determine the tacrolimus AUC(12) on the basis of a limited number of samples. The predictive performance of the Bayesian estimator was evaluated in the validation dataset by comparing the estimated AUC(12) with the trapezoidal AUC(12)., Results: Tacrolimus pharmacokinetics were described using a two-compartment model with Erlang absorption and first-order elimination. The model included cystic fibrosis (CF) and CYP3A5 polymorphism as covariates. The relative bioavailability in patients with CF was approximately 60% of the relative bioavailability observed in patients without CF, and the transfer rate constant between the transit compartments was 2-fold smaller in patients with CF than in those without CF (3.32 vs 7.06 h-1). The apparent clearance was 40% faster in CYP3A5 expressers than in non-expressers (24.5 vs 17.5 L/h). Good predictive performance was obtained with the Bayesian estimator developed using the final model and concentrations measured at 40 minutes and at 2 and 4 hours post-dose, as shown by the mean bias (1.1%, 95% CI -1.4, 3.7) and imprecision (9.8%) between the estimated and the trapezoidal AUC(12). The bias was >20% in 1.8% of patients., Conclusion: Population pharmacokinetic analysis showed that lung transplant patients with CF displayed lower bioavailability and a smaller transfer rate constant between transit compartments than those without CF, while the apparent clearance was faster in CYP3A5 expressers than in non-expressers. The Bayesian estimator developed in this study provides an accurate prediction of tacrolimus exposure in lung transplant patients, with and without CF, throughout the first year post-transplantation. This tool may allow routine tacrolimus dose individualization and may be used to conduct clinical trials on therapeutic drug monitoring of tacrolimus after lung transplantation.

Background: Chronic lung rejection is characterized by obliterative bronchiolitis (OB) diagnosed based on spirometric criteria reflecting an already advanced process. Biologic markers such as bronchoalveolar lavage (BAL) neutrophilia or increased levels of chemokines (interleukin-8, RANTES [regulated on activation: normal T cell expressed and secreted]) have been proposed as early diagnosis tools. However, BAL is too invasive to be used as a routine strategy. Induced sputum (IS), however, is a non-invasive method of recovering bronchial cells., Methods: The aim of this study was to compare BAL and IS differential cellular counts as well as IL-8 and RANTES levels between patients with bronchiolitis obliterans syndrome (BOS), recipients with good outcome and well-preserved lung function (non-BOS) and non-transplanted controls. We compared 34 BAL and IS findings obtained consecutively from 34 lung transplant recipients (LTRs), including 22 non-BOS and 12 BOS patients., Results: IS results were compared with 19 samples from non-transplanted controls. IS was well tolerated. There was no correlation between BAL and sputum cell populations. BAL neutrophils and IL-8 levels were increased in BOS, and these parameters were positively correlated. Moreover, BAL neutrophils and IL-8 levels were both negatively correlated with respiratory function. Sputum evaluation allows discrimination of BOS from non-BOS by the presence of higher neutrophil and eosinophil counts. Moreover, IS neutrophils and eosinophils were both correlated with lung function parameters. In contrast to BAL, IL-8 level in sputum was not a useful predictive marker of BOS development. IS RANTES levels were higher in BOS than in healthy recipients and correlated significantly with IS eosinophils., Conclusions: IS and BAL provide different but complementary data. In this study, IS appeared to be a useful, non-invasive tool for LTR monitoring. Furthermore, IS provides new insights into BOS pathogenesis, especially with regard to implication of eosinophils and its chemokine, RANTES, at the bronchial level.

Introduction: The major obstacle to long-term survival after lung transplantation is chronic graft rejection (CR) which is defined histologically by obliterative bronchiolitis (OB)., State of the Art: The causes of post-transplant OB are not fully understood, but there is evidence that this chronic process is influenced by both immunologically mediated injury directed against endothelial and specifically epithelial cells, and alloantigen-independent events, such as cytomegalovirus infection, ischaemic-reperfusion injury and biophysical alterations. The generation of an allogenic immune response seems to be the central event involved in the subsequent development of OB, and prior acute rejection is the strongest risk factor for CR. Whatever the role of each of the factors, injury to the bronchiolar structure is the primary event which triggers an invasion of various inflammatory cells and an increase in pro-inflammatory and chemotactic mediators within the bronchiolar wall. As the process evolves, an uncontrolled repair process, with sub-mucosal fibrous tissue proliferation leading to obstructive airway scarring involving mesenchymal cell and fibroblast replication, and connective-tissue deposition in response to profibrotic cytokines and growth factors released by local tissue. We review here the risk factors and the mechanisms, which are currently recognized in the development of OB., Perspectives and Conclusions: A better understanding of the pathogenesis of CR by combining several techniques should allow detection of OB at a preclinical stage and may ultimately lead to novel preventive and therapeutic strategies for the condition.

The aim of this study was to evaluate the incidence of postoperative lymphocytotoxic antibodies (LA) formation and to assess their potential utility in immunologic monitoring after lung transplantation. We determined prospectively the percentage LA against a reference panel reactive antibody in a complement-dependent microlymphocytotoxicity test in 137 sequential serum samples obtained from 14 consecutive lung transplant recipients who survived over the first postoperative year. Four patients developed high titers of LA (greater than 10% panel reactive antibody reactivity in at least 3 consecutive samples) by 2 to 24 months after surgery. Antibodies were mostly immunoglobulin M isotype, without any specificity against the donor's human leukocyte antigen and were correlated with the development of bronchiolitis obliterans syndrome (p=.01) and with chronic bronchial infectious colonization (p=.03). In conclusion, a polyclonal immunoglobulin M antibody production can be detected in serum samples from lung transplant recipients and seems to be involved in the progression of chronic rejection process. These preliminary results incline to carry on the cytotoxicity screening of a panel of lymphocytes to better understand the significance of such reactivity.

Limited published data exist on outcomes related to lung transplantation (LTx) in human immunodeficiency virus (HIV)-infected individuals. We conducted a multicenter retrospective study of LTx in HIV- infected patients and describe key transplant- and HIV-related outcomes. We identified 22 HIV-infected LTx recipients across 25 transplant centers from 2007 through 2021. At transplantation, mean age was 53 [46 - 59] years, 55% were male. Two (9%) patients had an history of previous opportunistic infection and AIDS status. Pretransplant CD4 T cell count was 514 [351 - 670] cell/mm3 and RNA viral load was negative in all patients and their values did not change significantly post operatively. Due to calcineurin inhibitor interactions, 3 (15%) patients required an antiretroviral regimen change before LTx. Main indications for LTx were pulmonary arterial hypertension in 7 (32%), fibrosis in 5 (23%) and cystic fibrosis in 3 (14%). LTx procedure was predominantly bilateral-lung transplantation (91%). Immunosupression was giving according to local protocols including induction in 7 (32%) patients. During first post-LTx year, acute cellular rejection, antibody-mediated rejection, and infections requiring hospitalization occurred in 7 (37%), 2 (11%) and 8 (40%), respectively. During the median [range] follow-up of 25 [0.1-172] months, 26% and 14% of patients developed chronic lung allograft dysfunction and malignancy, respectively. Posttransplant survival rates after 1, 3, and 5 years were 79%, 79%, and 79%, respectively. At last news evaluation, 59% of the patients were fully active and independent. Apart from early infection rates, survival rates and post-operative outcome were similar to their HIV-uninfected LTx recipients. At last follow-up, more than half of the patients had near-normal functional status. [ABSTRACT FROM AUTHOR]