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Acute rejection (AR), common during the first year after lung transplantation (LuTx), can trigger chronic rejection (CR), the leading cause of late morbidity and mortality of LuTx. Extracorporeal photopheresis (ECP) has emerged as a promising treatment for chronic rejection. Only few studies are focus on ECP as prophylactic therapy of AR and CR. This study aims to verify, in recipients affected by cystic fibrosis (CF), whether the induction therapy with ECP can decrease the rate of AR, in order to impact positively on CR (primary end point: survival, AR). The expected results are the reduction of AR episodes in its clinical and histopathological manifestations. This is a pilot clinical trial on 20 CF lung-transplanted patients, randomize, 2 parallel arms: standard immunosuppressive therapy and ECP (ECP) vs standard immunosuppressive therapy alone (CTR). We investigated the effect of ECP by the evaluation of lymphocyte immunophenotype by multiplex essay (CD4 + and CD25 +), the cytokine profile, the leukocytes subsets (by flow cytometry) in blood and BAL at different time points. AR episodes and infections were recorded, as far as ECP-related adverse events. No differences were detected in terms of AR episodes. Treg cells were significantly increased in the ECP group at 3 weeks post LuTx, and this difference was more evident 1 year post LuTx. Th17 cells were diminished in the ECP group. The anti-inflammatory IL10-producing NKs were significantly increased in the ECP group. Cytokine profile, both in BAL and plasma obtained at defined time points shows that in ECP group pro-inflammatory cytokines were early reduced and anti-inflammatory cytokines were upregulated. In FC lung transplanted patients ECP was well tolerated without increasing in opportunistic infections. Its tolerogenic effect was not pointed out in terms of AR episodes, but has been confirmed in the immunological setting of ECP patients vs control: it prevents decline in Treg and NK observed with standard immunosuppressive drugs, with higher expression of anti-inflammatory cytokines (Il10, Il1RA) and less pro-inflammatory ones (Il1beta, Il6). Its effect is more evident months after the end of ECP treatment. The schedule of ECP prophylactic treatment has to be tested in an ampler cohort in order to reach its best immunomodulatory effect. [ABSTRACT FROM AUTHOR]

Transbronchial biopsy (TBB) using forceps is the standard procedure to establish the presence of allograft rejection after lung transplantation. However, inadequate tissue samples, high degree of interobservers variability and possible complications seems to prevent many centers in scheduling TBB in lung transplant follow-up.We aimed to compare histological quality of cryobiopsy (CB) and conventional forceps biopsy (FB) for sampling lung tissue in transplants recipients. Eligible for inclusion were adults subjected to scheduled transbronchial biopsy at 3, 6 and 12 months after lung transplantation. A single pathologist classified the biopsy according to ISHLT scale.From January 2019 to August 2020, 54 consecutive transbronchial lung biopsies procedures were included in the study. All patients underwent at least 6 biopsies with forceps and 3 with cryoprobe in the same lung lobe. Clinical, functional data and histological findings were collected. The diagnostic yield of acute rejection using cryobiopsy is 100% compared to 79% using biopsy forceps. The difference in proportion is 0.20 [95% C.I: 0,11-0,29, p<0,001]. The diagnostic yield of airway inflammation is 64.2% using cryoprobe compared to 42.6% using transbronchial forceps biopsies. In this case, the difference in proportion is 0.22 (95% C.I: 0,11-0,32, p<0,001; OR 7.0 C.I 2,4-27,5). The diagnostic yield of chronic rejection is 90.6% using cryobiopsy compared to 68.5% using transbronchial biopsy forceps. The difference in proportion is 0.22 (95% C.I: 0,13-0,31, p<0,001). Overall the major complication rate was 11%: there were 5 cases of pneumothorax, of which 4 required chest tube and 1 case treated conservatively. There were no cases of bleeding that required invasive treatment in the patient cohort. Transbronchial cryobiopsy is effective for diagnosis of lung allograft rejection because it provides larger and more diagnostic lung parenchyma specimens than traditional forceps biopsies. [ABSTRACT FROM AUTHOR]

Extracorporeal photopheresis has emerged as a promising treatment for chronic rejection. To date, there are no data on extracorporeal photopheresis as induction therapy. We are implementing a single-center, single blind, randomized controlled trial enrolling 24 recipients with cystic fibrosis (CF) who undergo lung transplantation (LTx) randomly allocated in 2 parallel arms: induction with extracorporeal photopheresis plus standard immunosuppressive therapy (ECP) vs. standard immunosuppressive therapy (CTR). We present the interim analysis focused on safety and immunomodulation effectiveness. We recorded every adverse event, including acute rejection (AR), which occurred in the first year after lung transplantation. Immune parameters (activated T cells, Treg, Th17, Th1, NK, PD-1 and PD-L1 expression, IL-10, TNFα, IL-1β, and IFNγ production) were evaluated at different time points in the first year after LTx. Preliminary data on the first ten patients (6 ECP and 4 CTR) are reported. No AR episodes were observed and no adverse events due to extracorporeal photopheresis were recorded. In the control arm, one patient died of post-operative infection on 20th postoperative day. In ECP compared to CTR patients: 1) regulatory T cells (Treg) as well as IL10 production by Treg were increased; 2) IL17-secreting Th17 as well as Th1 T cells were reduced; 3) CD107+/CD8+ (perforin-releasing CTL) T lymphocytes were reduced, 4) IL10-producing NK cells were increased; 5) LPS-stimulated IL-10 production was augmented whereas that of TNFα and IL-1β was reduced. In the setting of LTx for CF, extracorporeal photopheresis is well tolerated and it results in an overall modulation of immune responses. The positive result of this interim analysis led to the decision of continuing to enroll patients in this randomized trial with the aim of probing the possible positive effect of extracorporeal photopheresis as induction therapy in AR prevention. [ABSTRACT FROM AUTHOR]

Acute rejection (AR) is common during the first year after lung transplantation (LuTx) and can trigger chronic rejection (CR), the leading cause of late morbidity and mortality of LuTx. Extracorporeal photopheresis (ECP) is a promising treatment for chronic rejection. Few studies focus on ECP as prophylactic therapy of AR and CR. Microvesicles and exosomes (i.e.extracellular vesicles EV) are released into the blood and in bronchoalveolar lavage (BAL) and their role in cell-to-cell communication has been assessed in several studies; EV have been proposed as non-invasive biomarkers to assess lung injury and monitor clinical outcome. We conduct a pilot clinical trial on 24 cystic fibrosis patients undergoing LuTx, randomly allocated in 2 parallel arms: standard immunosuppressive therapy and ECP (ECP) vs standard immunosuppressive therapy alone (CTR). EV concentration was assessed at different time points in blood and BAL in the first year after LuTx (analyzed by nanoparticle tracking analysis Nanosight NS300, Malvern). EV were analyzed for antigen expression with MACSplex bead-based assay. AR episodes and infections were recorded, as far as ECP-related adverse events. Preliminary data on the first 18 patients (9 ECP and 9 CTR) are reported ECP was well tollerated and no adverse events or AR occurred in either groups. EV presented highly polydispersed size distributions in a 50-1000 nm range. The expression of EV-associated markers CD63, CD9 and CD81 was detected. Upregulation of platelets (CD62p; p<0.05 by t-test), lymphocytes (CD3, CD24) markers and integrins (CD29, CD49e) was observed in ECP-treated patient compared to the control group. The underlying mechanism of ECP remains unresolved. The identification of specific EV antigen signatures may represent a promising approach to better understand the immunomodulatory effects of ECP, both at molecular and cellular level. [ABSTRACT FROM AUTHOR]