Chronic Lung Allograft Dysfunction: Clinical Manifestations and Immunologic Mechanisms.

The term "chronic lung allograft dysfunction" has emerged to describe the clinical syndrome of progressive, largely irreversible dysfunction of pulmonary allografts. This umbrella term comprises 2 major clinical phenotypes: bronchiolitis obliterans syndrome and restrictive allograft syndrome. Here, we discuss the clinical manifestations, diagnostic challenges, and potential therapeutic avenues to address this major barrier to improved long-term outcomes. In addition, we review the immunologic mechanisms thought to propagate each phenotype of chronic lung allograft dysfunction, discuss the various models used to study this process, describe potential therapeutic targets, and identify key unknowns that must be evaluated by future research strategies.

Safety of pulsed field ablation in more than 17,000 patients with atrial fibrillation in the MANIFEST-17K study.

Pulsed field ablation (PFA) is an emerging technology for the treatment of atrial fibrillation (AF), for which pre-clinical and early-stage clinical data are suggestive of some degree of preferentiality to myocardial tissue ablation without damage to adjacent structures. Here in the MANIFEST-17K study we assessed the safety of PFA by studying the post-approval use of this treatment modality. Of the 116 centers performing post-approval PFA with a pentaspline catheter, data were received from 106 centers (91.4% participation) regarding 17,642 patients undergoing PFA (mean age 64, 34.7% female, 57.8% paroxysmal AF and 35.2% persistent AF). No esophageal complications, pulmonary vein stenosis or persistent phrenic palsy was reported (transient palsy was reported in 0.06% of patients; 11 of 17,642). Major complications, reported for ~1% of patients (173 of 17,642), were pericardial tamponade (0.36%; 63 of 17,642) and vascular events (0.30%; 53 of 17,642). Stroke was rare (0.12%; 22 of 17,642) and death was even rarer (0.03%; 5 of 17,642). Unexpected complications of PFA were coronary arterial spasm in 0.14% of patients (25 of 17,642) and hemolysis-related acute renal failure necessitating hemodialysis in 0.03% of patients (5 of 17,642). Taken together, these data indicate that PFA demonstrates a favorable safety profile by avoiding much of the collateral damage seen with conventional thermal ablation. PFA has the potential to be transformative for the management of patients with AF.

Deciphering Unexpected Vascular Locations of Scedosporium spp. and Lomentospora prolificans Fungal Infections, France.

Scedosporium spp. and Lomentospora prolificans are emerging non-Aspergillus filamentous fungi. The Scedosporiosis/lomentosporiosis Observational Study we previously conducted reported frequent fungal vascular involvement, including aortitis and peripheral arteritis. For this article, we reviewed 7 cases of Scedosporium spp. and L. prolificans arteritis from the Scedosporiosis/lomentosporiosis Observational Study and 13 cases from published literature. Underlying immunosuppression was reported in 70% (14/20) of case-patients, mainly those who had solid organ transplants (10/14). Osteoarticular localization of infection was observed in 50% (10/20) of cases; infections were frequently (7/10) contiguous with vascular infection sites. Scedosporium spp./Lomentospora prolificans infections were diagnosed in 9 of 20 patients ≈3 months after completing treatment for nonvascular scedosporiosis/lomentosporiosis. Aneurysms were found in 8/11 aortitis and 6/10 peripheral arteritis cases. Invasive fungal disease--related deaths were high (12/18 [67%]). The vascular tropism of Scedosporium spp. and L. prolificans indicates vascular imaging, such as computed tomography angiography, is needed to manage infections, especially for osteoarticular locations.

Prolonged dialysis during ex vivo lung perfusion promotes inflammatory responses.

Ex-vivo lung perfusion (EVLP) has extended the number of transplantable lungs by reconditioning marginal organs. However, EVLP is performed at 37°C without homeostatic regulation leading to metabolic wastes' accumulation in the perfusate and, as a corrective measure, the costly perfusate is repeatedly replaced during the standard of care procedure. As an interesting alternative, a hemodialyzer could be placed on the EVLP circuit, which was previously shown to rebalance the perfusate composition and to maintain lung function and viability without appearing to impact the global gene expression in the lung. Here, we assessed the biological effects of a hemodialyzer during EVLP by performing biochemical and refined functional genomic analyses over a 12h procedure in a pig model. We found that dialysis stabilized electrolytic and metabolic parameters of the perfusate but enhanced the gene expression and protein accumulation of several inflammatory cytokines and promoted a genomic profile predicting higher endothelial activation already at 6h and higher immune cytokine signaling at 12h. Therefore, epuration of EVLP with a dialyzer, while correcting features of the perfusate composition and maintaining the respiratory function, promotes inflammatory responses in the tissue. This finding suggests that modifying the metabolite composition of the perfusate by dialysis during EVLP can have detrimental effects on the tissue response and that this strategy should not be transferred as such to the clinic.

Phenotypes and outcome of diffuse pulmonary non-amyloid light chain deposition disease.

BACKGROUND: Light chain deposition disease (LCDD) is a very rare entity. Clinical manifestations of LCDD vary according to the organs involved. Data on pulmonary LCDD are scarce and limited to small series or case reports. This study aimed to describe the characteristics and outcome of diffuse pulmonary non-amyloid LCDD localized to the lungs. STUDY DESIGN AND METHODS: A multicenter retrospective cohort study was conducted. Clinical characteristics were collected, and chest CTs were centrally reviewed. The diagnosis of pulmonary non-amyloid LCDD was confirmed by immunohistochemistry. RESULTS: Thirty-one cases were identified (68% female), with a median age at diagnosis of 50 years (IQR 20). Baseline FEV1/FVC was < 0.70 in 45% of patients. Mean (± SD) FEV1 and DLCO were 86% ± 26.2 and 52% ± 23.9, respectively. CT revealed peculiar patterns of thin-walled cysts (58%) and thin-walled cystic bronchiectases (27%). Increased serum kappa light chain was found in 87% of patients. Histological analysis showed kappa light chain deposits in all patients, except one with lambda chain deposits. Median annual FEV1 decline was 127 ml (IQR 178) and median DLCO decline was 4.3% (IQR 4.3). Sixteen patients received immunomodulatory treatment or chemotherapy; serum light chain levels decreased in 9 cases (75%), without significant improvement in FEV1 (p = 0.173). Overall, 48% of patients underwent bilateral lung transplantation. Transplant-free survival at 5 and 10 years were 70% and 30%, respectively. An annual FEV1 decline greater than 127 ml/year was associated with increased risk of death or transplantation (p = 0.005). CONCLUSIONS: Diffuse pulmonary LCDD is characterised by female predominance, a peculiar imaging pattern with bronchiectasis and/or cysts, progressive airway obstruction and severe DLCO impairment, and poor outcome. Lung transplantation is a treatment of choice.

Blood MMP-9 measured at 2 years after lung transplantation as a prognostic biomarker of chronic lung allograft dysfunction.

BACKGROUND: Long-term outcomes of lung transplantation (LTx) remain hampered by chronic lung allograft dysfunction (CLAD). Matrix metalloproteinase 9 (MMP-9) is a secretory endopeptidase identified as a key mediator in fibrosis processes associated with CLAD. The objective of this study was to investigate whether plasma MMP9 levels may be prognostic of CLAD development. METHODS: Participants were selected from the Cohort in Lung Transplantation (COLT) for which a biocollection was associated. We considered two time points, year 1 (Y1) and year 2 (Y2) post-transplantation, for plasma MMP-9 measurements. We analysed stable recipients at those time points, comparing those who would develop a CLAD within the 2 years following the measurement to those who would remain stable 2 years after. RESULTS: MMP-9 levels at Y1 were not significantly different between the CLAD and stable groups (230 ng/ml vs. 160 ng/ml, p = 0.4). For the Y2 analysis, 129 recipients were included, of whom 50 developed CLAD within 2 years and 79 remained stable within 2 years. MMP-9 plasma median concentrations were higher in recipients who then developed CLAD than in the stable group (230 ng/ml vs. 118 ng/ml, p = 0.003). In the multivariate analysis, the Y2 MMP-9 level was independently associated with CLAD, with an average increase of 150 ng/ml (95% CI [0-253], p = 0.05) compared to that in the stable group. The Y2 ROC curve revealed a discriminating capacity of blood MMP-9 with an area under the curve of 66%. CONCLUSION: Plasmatic MMP-9 levels measured 2 years after lung transplantation have prognostic value for CLAD.

The 2022 Banff Meeting Lung Report.

The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: (1) recognition of limitations in current standard of care assessment of lung allograft dysfunction; (2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and (3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes.

Assessing the role of phosphorylated S6 ribosomal protein in the pathological diagnosis of pulmonary antibody-mediated rejection.

BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients. METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed. RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%. CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.

Center variability in the prognostic value of a cumulative acute cellular rejection "A-score" for long-term lung transplant outcomes.

The acute rejection score (A-score) in lung transplant recipients, calculated as the average of acute cellular rejection A-grades across transbronchial biopsies, summarizes the cumulative burden of rejection over time. We assessed the association between A-score and transplant outcomes in 2 geographically distinct cohorts. The primary cohort included 772 double lung transplant recipients. The analysis was repeated in 300 patients from an independent comparison cohort. Time-dependent multivariable Cox models were constructed to evaluate the association between A-score and chronic lung allograft dysfunction or graft failure. Landmark analyses were performed with A-score calculated at 6 and 12 months posttransplant. In the primary cohort, no association was found between A-score and graft outcome. However, in the comparison cohort, time-dependent A-score was associated with chronic lung allograft dysfunction both as a time-dependent variable (hazard ratio, 1.51; P < .01) and when calculated at 6 months posttransplant (hazard ratio, 1.355; P = .031). The A-score can be a useful predictor of lung transplant outcomes in some settings but is not generalizable across all centers; its utility as a prognostication tool is therefore limited.

Chronic lung allograft dysfunction is associated with an increased number of non-HLA antibodies.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the major cause of adverse outcomes in lung transplant recipients. Multiple factors, such as infection, alloimmunity, and autoimmunity, may lead to CLAD. Here, we aim to examine the role of non-human leukocytes antigen (HLA) antibodies in CLAD in a large retrospective cohort. METHODS: We analyzed non-HLA antibodies in the pre- and post-transplant sera of 226 (100 CLAD, 126 stable) lung transplant recipients from 5 centers, and we used a separate cohort to confirm our findings. RESULTS: A panel of 18 non-HLA antibodies was selected for analysis based on their significantly higher positive rates in CLAD vs stable groups. The panel-18 non-HLA antibodies (n > 3) may be positive pre- or post-transplant; the risk for CLAD is higher in the latter. The presence of both non-HLA antibody and HLA donor-specific antibody (DSA) was associated with an augmented risk of CLAD (HR=25.09 [5.52-14.04], p < 0.001), which was higher than that for single-positive patients. In the independent confirmatory cohort of 61 (20 CLAD, 41 stable) lung transplant recipients, the risk for CLAD remained elevated in double-positive patients (HR=10.67 [0.98-115.68], p = 0.052). After adjusting for nonstandard immunosuppression, patients with double-positive DSA/Non-HLA antibodies had an elevated risk for graft loss (HR=2.53 [1.29-4.96], p = 0.007). CONCLUSIONS: Circulating non-HLA antibodies (n > 3) were independently associated with a higher risk for CLAD. Furthermore, when non-HLA antibodies and DSA were detected concomitantly, the risk for CLAD and graft loss was significantly increased. These results show that humoral immunity to HLA and non-HLA antigens may contribute to CLAD development.

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation.

Introduction: Lung transplantation often results in primary and/or chronic dysfunctions that are related to early perioperative innate allo-responses where myeloid subsets play a major role. Corticosteroids are administered upon surgery as a standard-of-care but their action on the different myeloid cell subsets in that context is not known. Methods: To address this issue, we used a cross-circulatory platform perfusing an extracorporeal lung coupled to cell mapping in the pig model, that enabled us to study the recruited cells in the allogeneic lung over 10 hours. Results: Myeloid cells, i.e. granulocytes and monocytic cells including classical CD14pos and non-classical/intermediate CD16pos cells, were the dominantly recruited subsets, with the latter upregulating the membrane expression of MHC class II and CD80/86 molecules. Whereas corticosteroids did not reduce the different cell subset recruitment, they potently dampened the MHC class II and CD80/86 expression on monocytic cells and not on alveolar macrophages. Besides, corticosteroids induced a temporary and partial anti-inflammatory gene profile depending on cytokines and monocyte/macrophage subsets. Discussion: This work documents the baseline effects of the standard-of-care corticosteroid treatment for early innate allo-responses. These insights will enable further optimization and improvement of lung transplantation outcomes.

Outcome of lung transplantation for adults with interstitial lung disease associated with genetic disorders of the surfactant system.

Background: Interstitial lung disease associated with genetic disorders of the surfactant system is a rare entity in adults that can lead to lung transplantation. Our objective was to describe the outcome of these patients after lung transplantation. Methods: We conducted a retrospective, multicentre study, on adults who underwent lung transplantation for such disease in the French lung transplant centres network, from 1997 to 2018. Results: 20 patients carrying mutations in SFTPA1 (n=5), SFTPA2 (n=7) or SFTPC (n=8) were included. Median interquartile range (IQR) age at diagnosis was 45 (40-48) years, and median (IQR) age at lung transplantation was 51 (45-54) years. Median overall survival after transplantation was 8.6 years. Two patients had a pre-transplant history of lung cancer, and two developed post-transplant lung cancer. Female gender and a body mass index <25 kg·m-2 were significantly associated with a better prognosis, whereas transplantation in high emergency was associated with a worst prognosis. Conclusions: Lung transplantation in adults with interstitial lung disease associated with genetic disorders of surfactant system may be a valid therapeutic option. Our data suggest that these patients may have a good prognosis. Immunosuppressive protocol was not changed for these patients, and close lung cancer screening is needed before and after transplantation.

Donor/recipient origin of lung cancer after lung transplantation by DNA short tandem repeat analysis.

Background: Lung cancer is more common in posttransplant recipients than in the general population. The objective of this study was to examine the chimerism donor/recipient cell origin of graft cancer in recipients of lung transplant. Methods: A retrospective chart review was conducted at Foch Hospital for all lung transplantations from 1989 to 2020. Short tandem repeat PCR (STR-PCR) analysis, the gold standard technique for chimerism quantification, was used to determine the donor/recipient cell origin of lung cancers in transplant patients. Results: Fourteen (1.4%) of the 1,026 patients were found to have graft lung cancer after lung transplantation, and one developed two different lung tumors in the same lobe. Among the 15 lung tumors, 10 (67%) presented with adenocarcinoma, four (27%) with squamous cell carcinoma and one with small cell lung cancer. STR analysis showed that the origin of the cancer was the donor in 10 patients (71%), the recipient in three patients (21%), and was undetermined in one patient. Median time to diagnosis was 62 months. Conclusion: The prevalence of lung cancer in lung transplant recipients is very low. However, the results of our study showed heterogeneity of genetic alterations, with 21% being of recipient origin. Our results highlight the importance of donor selection and medical supervision after lung transplantation.

Individual cell types in C. elegans age differently and activate distinct cell-protective responses.

Aging is characterized by a global decline in physiological function. However, by constructing a complete single-cell gene expression atlas, we find that Caenorhabditis elegans aging is not random in nature but instead is characterized by coordinated changes in functionally related metabolic, proteostasis, and stress-response genes in a cell-type-specific fashion, with downregulation of energy metabolism being the only nearly universal change. Similarly, the rates at which cells age differ significantly between cell types. In some cell types, aging is characterized by an increase in cell-to-cell variance, whereas in others, variance actually decreases. Remarkably, multiple resilience-enhancing transcription factors known to extend lifespan are activated across many cell types with age; we discovered new longevity candidates, such as GEI-3, among these. Together, our findings suggest that cells do not age passively but instead react strongly, and individualistically, to events that occur during aging. This atlas can be queried through a public interface.

Cell type- and time-dependent biological responses in ex vivo perfused lung grafts.

In response to the increasing demand for lung transplantation, ex vivo lung perfusion (EVLP) has extended the number of suitable donor lungs by rehabilitating marginal organs. However despite an expanding use in clinical practice, the responses of the different lung cell types to EVLP are not known. In order to advance our mechanistic understanding and establish a refine tool for improvement of EVLP, we conducted a pioneer study involving single cell RNA-seq on human lungs declined for transplantation. Functional enrichment analyses were performed upon integration of data sets generated at 4 h (clinical duration) and 10 h (prolonged duration) from two human lungs processed to EVLP. Pathways related to inflammation were predicted activated in epithelial and blood endothelial cells, in monocyte-derived macrophages and temporally at 4 h in alveolar macrophages. Pathways related to cytoskeleton signaling/organization were predicted reduced in most cell types mainly at 10 h. We identified a division of labor between cell types for the selected expression of cytokine and chemokine genes that varied according to time. Immune cells including CD4+ and CD8+ T cells, NK cells, mast cells and conventional dendritic cells displayed gene expression patterns indicating blunted activation, already at 4 h in several instances and further more at 10 h. Therefore despite inducing inflammatory responses, EVLP appears to dampen the activation of major lung immune cell types, what may be beneficial to the outcome of transplantation. Our results also support that therapeutics approaches aiming at reducing inflammation upon EVLP should target both the alveolar and vascular compartments.

Results of Lung Transplantation for Cystic Fibrosis With Selected Donors Over 65 Years Old.

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

Rarely Encountered Gram-Negative Rods and Lung Transplant Recipients: A Narrative Review.

The respiratory tract of lung transplant recipients (LTR) is likely to be colonized with non-fermentative Gram-negative rods. As a consequence of the improvements in molecular sequencing and taxonomy, an increasing number of bacterial species have been described. We performed a review of the literature of bacterial infections in LTR involving non-fermentative Gram-negative rods with exclusion of Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter spp. and Burkholderia spp. Overall, non-fermenting GNR were recovered from 17 LTR involving the following genera: Acetobacter, Bordetella, Chryseobacterium, Elizabethkinga, Inquilinus, and Pandoraea. We then discuss the issues raised by these bacteria, including detection and identification, antimicrobial resistance, pathogenesis, and cross-transmission.

A cross-circulatory platform for monitoring innate allo-responses in lung grafts.

Lung transplantation is the only curative option for end-stage chronic respiratory diseases. However the survival rate is only about 50% at 5 years. Although experimental evidences have shown that innate allo-responses impact on the clinical outcome, the knowledge of the involved mechanisms involved is limited. We established a cross-circulatory platform to monitor the early recruitment and activation of immune cells in an extracorporeal donor lung by coupling blood perfusion to cell mapping with a fluorescent marker in the pig, a commonly-used species for lung transplantation. The perfusing pig cells were easily detectable in lung cell suspensions, in broncho-alveolar lavages and in different areas of lung sections, indicating infiltration of the organ. Myeloid cells (granulocytes and monocytic cells) were the dominant recruited subsets. Between 6 and 10 h of perfusion, recruited monocytic cells presented a strong upregulation of MHC class II and CD80/86 expression, whereas alveolar macrophages and donor monocytic cells showed no significant modulation of expression. This cross-circulation model allowed us to monitor the initial encounter between perfusing cells and the lung graft, in an easy, rapid, and controllable manner, to generate robust information on innate response and test targeted therapies for improvement of lung transplantation outcome.

Changes in HCMV immune cell frequency and phenotype are associated with chronic lung allograft dysfunction.

Background: Human cytomegalovirus (HCMV) infection is common and often severe in lung transplant recipients (LTRs), and it is a risk factor associated with chronic lung allograft dysfunction (CLAD). The complex interplay between HCMV and allograft rejection is still unclear. Currently, no treatment is available to reverse CLAD after diagnosis, and the identification of reliable biomarkers that can predict the early development of CLAD is needed. This study investigated the HCMV immunity in LTRs who will develop CLAD. Methods: This study quantified and phenotyped conventional (HLA-A2pp65) and HLA-E-restricted (HLA-EUL40) anti-HCMV CD8+ T (CD8 T) cell responses induced by infection in LTRs developing CLAD or maintaining a stable allograft. The homeostasis of immune subsets (B, CD4T, CD8 T, NK, and γδT cells) post-primary infection associated with CLAD was also investigated. Results: At M18 post-transplantation, HLA-EUL40 CD8 T responses were less frequently found in HCMV+ LTRs (21.7%) developing CLAD (CLAD) than in LTRs (55%) keeping a functional graft (STABLE). In contrast, HLA-A2pp65 CD8 T was equally detected in 45% of STABLE and 47.8% of CLAD LTRs. The frequency of HLA-EUL40 and HLA-A2pp65 CD8 T among blood CD8 T cells shows lower median values in CLAD LTRs. Immunophenotype reveals an altered expression profile for HLA-EUL40 CD8 T in CLAD patients with a decreased expression for CD56 and the acquisition of PD-1. In STABLE LTRs, HCMV primary infection causes a decrease in B cells and inflation of CD8 T, CD57+/NKG2C+ NK, and δ2-γδT cells. In CLAD LTRs, the regulation of B, total CD8 T, and δ2+γδT cells is maintained, but total NK, CD57+/NKG2C+ NK, and δ2-γδT subsets are markedly reduced, while CD57 is overexpressed across T lymphocytes. Conclusions: CLAD is associated with significant changes in anti-HCMV immune cell responses. Our findings propose that the presence of dysfunctional HCMV-specific HLA-E-restricted CD8 T cells together with post-infection changes in the immune cell distribution affecting NK and γδT cells defines an early immune signature for CLAD in HCMV+ LTRs. Such a signature may be of interest for the monitoring of LTRs and may allow an early stratification of LTRs at risk of CLAD.

Conversion to belatacept after lung transplantation: Report of 10 cases.

BACKGROUND: Calcineurin inhibitors (CNIs) remain the cornerstone of maintenance immunosuppression (IS) after lung transplantation (LTx), although CNI-related life-threatening toxic effects may occur. Belatacept, a novel immunosuppressant that blocks a T-cell co-stimulation pathway, is a non-nephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, there are only a few reports of belatacept conversion as a CNI-free or CNI-sparing IS treatment. METHODS: We reviewed a series of 10 LTx recipients with conversion to a CNI-free belatacept IS regimen within the first year post-LTx (n = 7) or a belatacept/low-dose CNI combination after the first year (n = 3). RESULTS: Use of belatacept was triggered by severe renal failure in 9 patients and under-IS with previous other IS-related toxicities in 1 patient. Mean estimated glomerular filtration rate after starting belatacept significantly improved at 6 months after initiation and at the last-follow-up (p = 0.006, and p = 0.002 respectively). The incidence of recurrent and/or severe acute cellular rejection (ACR) episodes was high in patients with CNI-free belatacept-based IS (n = 4/7). Chronic graft allograft dysfunction developed in 2 of 9 recipients under belatacept IS. Belatacept was stopped in 6 patients because of recurrent/severe ACR (n = 3), recurrent opportunistic infections (n = 1), center modified policy (n = 1), or other cause (n = 1). CONCLUSION: Early conversion to CNI-free belatacept-based IS improved renal function in this series but was counterbalanced by a high incidence of recurrent ACR, including life-threatening episodes. Other studies are needed to better determine the indications for its use after LTx, possibly with lower immunological risk IS regimens, such as CNI-sparing belatacept.