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Introduction: Extracorporeal Photopheresis (ECP) may be considered the unique large-scale cell therapy currently available. It is currently employed mainly as second-line treatment, especially in steroid-resistant or steroid-dependent Graft versus Host Disease (GvHD) with good results and very few limitations., Areas Covered: Many points need to be clarified regarding the ECP mechanism of action, that conditions the lack of uniqueness among the different centers, essentially cycle frequency, treatment duration, and the number of cells to be treated to obtain a response, according to the organs involved. Moreover, reliable biomarkers for prediction of response are lacking, as well as the best pharmacological combination. We will focus on the recent advances concerning ECP for GvHD treatment. We performed a systematic literature research in Pubmed and Embase as of September 2023., Expert Opinion: The recent studies on ECP mechanism of action along with the promising biomarkers of response, and the synergistic benefit of ECP in association with the new drugs render this therapy an important weapon for GvHD resistant to conventional treatment and can be proposed as a valid first-line therapy option with promising results. We believe that it should be used early in all categories of patients, considering its high safety profile.

Background: CLAD (Chronic Lung Allograft Dysfunction) remains a serious complication following lung transplantation. Some evidence shows that portions of Extracorporeal Photopheresis (ECP)-treated patients improve/stabilize their graft function. In spite of that, data concerning molecular mechanisms are still lacking. Aims of our study were to assess whether ECP effects are mediated by Mononuclear Cells (MNCs) modulation in term of microRNAs (miRNAs) expression and growth factors release., Methods: Cells from leukapheresis of 16 CLAD patients, at time 0 and 6-months (10 cycles), were cultured for 48h ± PHA (10 ug/ml) or LPS (2 ug/ml). Expression levels of miR-146a-5p, miR-155-5p, miR-31-5p, miR181a-5p, miR-142-3p, miR-16-5p and miR-23b-5p in MNCs-exosomes were evaluated by qRT-PCR, while ELISA assessed different growth factors levels on culture supernatants., Results: Our result showed miR-142-3p down-regulation (p = 0.02) in MNCs of ECP-patients after the 10 cycles and after LPS stimulation (p = 0.005). We also find miR-146a-5p up-regulation in cells after the 10 cycles stimulated with LPS (p = 0.03). Connective tissue growth factor (CTGF) levels significantly decreased in MNCs supernatant (p = 0.04). The effect of ECP is translated into frequency changes of Dendritic Cell (DC) subpopulations and a slight increase in T regulatory cells (Treg) number and a significant decrease in CTGF release., Conclusions: ECP might affect regulatory T cell functions, since both miR-142 and miR-146a have been shown to be involved in the regulation of suppressor regulatory T cell functions and DCs. On the other side ECP, possibly by regulating macrophage activation, is able to significantly down modulate CTGF release., (© 2024. The Author(s).)

Extracorporeal photopheresis (ECP) is a cell therapy originally employed for cutaneous T cell lymphoma and later for GvHD, solid organ rejection and other immunological diseases demonstrating an excellent safety profile. Mononuclear cell (MNCs) apoptosis triggered by UV-A light irradiation in the presence of 8-methoxypsoralene has a key role in priming the cells, ultimately leading to immunomodulation. We report preliminary data about an evaluation of the new automated irradiator device LUMILIGHT (Pelham Crescent srl) for off-line ECP. Fifteen MNCs samples collected by apheresis from 15 adult patients undergoing ECP at our Center were cultured immediately after irradiation along with untreated samples and evaluated at 24, 48 and 72 h timepoints for T cell apoptosis and viability by flow cytometry with Annexin V and Propide Iodidum staining. Post irradiation Hematocrit (HCT), calculated by the device, was compared with that of the automated cell counter. Bacterial contamination was also tested. In irradiated samples after 24-48 and 72 h, the average total apoptosis was 47 %, 70 % and 82 %, respectively, showing a significant difference from untreated samples; residual viable lymphocytes at 72 h were, on average, 18 %. The greatest initiation of apoptosis occurred from 48 h of irradiation onwards. Average early apoptosis of irradiated samples decreased over time (26 %, 17 % and 10 % at 24, 48 and 72 h, respectively). HCT measured by LUMILIGHT was over-estimated, possibly due to the low pre irradiation red blood cell contamination. Bacterial tests resulted negative. Our study showed the LUMILIGHT device to be a valid instrument for MNCs irradiation with good handling and no major technical problems as well as no adverse events in the patients. Our data need to be confirmed in larger studies., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Clinical evidence suggests an improvement or stabilization of lung function in a fraction of patients with bronchiolitis obliterans syndrome (BOS) treated by extracorporeal photopheresis (ECP); however, few studies have explored the epigenetic and molecular regulation of this therapy. The aim of present study was to evaluate whether a specific set of miRNAs were significantly regulated by ECP. Total RNA was isolated from serum of patients with established BOS grade 1-2 prior to the start and after 6 months of ECP treatment. We observed a significant downregulation of circulating hsa-miR-155-5p, hsa-miR-146a-5p and hsa-miR-31-5p in BOS patients at the start of ECP when compared to healthy subjects. In responders, increased miR-155-5p and decreased miR-23b-3p expression levels at 6 months were found. SMAD4 mRNA was found to be a common target of these two miRNAs in prediction pathways analysis, and a significant downregulation was found at 6 months in PBMCs of a subgroup of ECP-treated patients. According to previous evidence, the upregulation of miR-155 might be correlated with a pro-tolerogenic modulation of the immune system. Our analysis also suggests that SMAD4 might be a possible target for miR-155-5p. Further longitudinal studies are needed to address the possible role of miR-155 and its downstream targets.

Background and Objectives: Very recently, Fresenius Kabi, improved the software (autoMNC lymphocytes, SW 04.03.08) for mononuclear cells (MNCs) collection with the aim to ameliorate the quality of harvest, employing the automated autoMNC lymphocytes software SW 04.03.09. Herein, we report the results of an observational study evaluating the feasibility of MNCs collection in patients undergoing extracorporeal photopheresis (ECP) at our centre, using the new COM.TEC software 04.03.08c for MNC collection, afterwards integrated in the software 04.03.09, available on the market since November 2018., Materials and Methods: Thirty adult patients (21 males and 9 females) with GvHD, Chronic Lung Allograft Dysfunction or renal rejection, were consecutively enrolled to undergo 1 ECP procedure by the offline technique, according to our internal protocol, processing 1·5 blood volumes. Feasibility of collection was defined as: Hct in collection bag ≤5%, MNCs purity (percentage of MNCs/bag) ≥80%, MNCs collection efficiency (CE2) ≥60%, patient's platelet depletion ≤50%., Results: Thirty ECP procedures were evaluated. Feasibility (defined by the four parameters previously described) of MNCs collection was observed in 1 out of the 30 harvests analysed. Median Hct in the product was 3·45% (IQR: 2·6-5·0), and median MNCs purity was 97·2% (IQR 89·1-98·6). Median CE2 for MNCs was 21·4% (IQR: 11·9-41·2), and median patient's platelet depletion was 36·2% (IQR 21·9-51·4)., Conclusion: The autoMNC lymphocytes software SW 04.03.08c for MNCs collection in ECP setting demonstrated to collect a good quality product in terms of purity and RBC contamination even if the collection efficiency and platelet contamination must be improved., (© 2019 International Society of Blood Transfusion.)

Renal rejection clinically represents a major cause of graft dysfunction and sadly the loss of the renal transplant. This is despite the considerable progress in immunosuppressive therapy. It is strongly believed that the complex immunologic network underlying the response against major histocompatibility molecules (MHC) is responsible for rejection, an unresolved issue that is, in part, not inhibited by the current prophylactic and therapeutic strategies. Extracorporeal photopheresis (ECP) is an effective cell therapy approach that was successfully used in immunomodulating heart rejection, acute and chronic GvHD, lung rejection and some selected autoimmune diseases. In this concise report we provide a brief review on the mechanisms of action and the use of ECP in acute and chronic renal allograft rejection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Bronchiolitis obliterans syndrome (BOS) is the main manifestation of pulmonary GVHD. It has often a dramatic and fast evolution and current treatment (change or increase in immunosuppression, macrolides and inhaled therapy) is poor with high mortality rates. In this scenario, extracorporeal photopheresis (ECP) bursts as a new immunomodulatory approach with a different philosophical purpose. In fact, available data show that ECP treatment is intended to delay the inflammatory process and consequently respiratory lung function decline, rather than reverse the damage itself. Preliminary results reported in literature show that ECP may effectively improve/slow lung function decline in cGVHD patients with BOS after standard treatment failure. Further studies are needed to confirm the efficacy of ECP, assess the optimal schedule and consider it for early treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Extracorporeal photopheresis (ECP) is an effective cell therapy employed in several diseases, including graft versus host disease (GVHD) and organ rejection. When ECP is performed using an off-line technique, mononuclear cell (MNC) collection by leukapheresis is necessary for further manipulation (addition of 8-methoxypsoralen and ultraviolet A irradiation before reinfusion to the patient). We report the results of the first crossover equivalence study on yield and purity of MNCs collected from patients undergoing ECP with two different automated systems: MNC and CMNC (working with intermittent and continuous-flow collection, respectively), released by Terumo BCT., Study Design and Methods: Fifty-one patients (15 males and 36 females) with GVHD or chronic lung allograft dysfunction were consecutively enrolled and randomly assigned to MNC collection alternatively by the CMNC or MNC system within each ECP cycle (two procedures) in two consecutive cycles. ECP procedures were performed using the off-line technique, according to our internal protocol, processing 1.5 blood volumes., Results: A total of 204 ECP procedures were evaluated. The MNC system showed a higher MNC concentration capacity than the CMNC (mean difference, -13.46; 95% confidence interval, -21.05 to -5.47; p < 0.001). Collection efficiency was higher with the CMNC system as well as total MNC bag content, while MNC bag purity was equivalent for both systems. Platelet loss was higher with the CMNC. Equivalence was shown for MNC purity and anticoagulant infused to the patient., Conclusion: CMNC and MNC systems offer different advantages in different clinical conditions, and both are safe and efficient in collecting MNCs for ECP., (© 2016 AABB.)

Currently, more than 1080 peer-reviewed papers are displayed on PubMed when initiating a search for therapeutic indications and mechanisms of action of extracorporeal photochemotherapy (ECP). This concise review focuses mainly on some prevalent and traditional treatment-resistant disorders with an emphasis on immunologic complications emerging from stem cell and solid organ transplantation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Extracorporeal photochemotherapy (ECP) for chronic lung allograft dysfunction (CLAD) has been reported as beneficial in a few short-term studies., Objectives: In this retrospective cohort study on 48 CLAD patients treated by ECP (off-line technique) for a period of >8 years (compared to 58 controls), we explored potential predictors of survival and response., Methods: Failures were defined as a decrease in forced expiratory volume in 1 s (FEV1) of >10% from ECP initiation., Results: ECP patients were enrolled between February 2003 and December 2013; 14 (29.2%) with restrictive allograft syndrome (RAS) and 34 with bronchiolitis obliterans syndrome. Grade 1 severity was indicated in 58.3%, grade 2 in 20.8%, and grade 3 in 20.8% of patients. The median follow-up was 65 months (cumulative 2,284.4 person-months). Twenty (41.7%) patients died, including 17 (85%) CLAD-related deaths. Among the controls, there were 42 deaths (72.4%), of which 32 (76.2%) were CLAD related, over a median of 51 months (cumulative 3,066.5 person-months; p = 0.09). Among ECP patients, the FEV1 slope flattened out after a decline in the initial months (slope -19 ml/month in months 0-6, +4 in months 36-48 and later; p = 0.001). RAS was associated with poorer survival, whereas a 'rapid decline in the previous 6 months' was not. No ECP side effects or complications were observed., Conclusion: Long-term ECP for CLAD is safe and reduces FEV1 decline over time; the RAS phenotype might show a poorer response. ECP deserves to be evaluated in a randomized controlled trial., (© 2015 S. Karger AG, Basel.)

Background: Extracorporeal photopheresis (ECP) is an effective treatment for both acute and chronic graft-versus-host disease (GVHD) in children and adults. Despite the large use of this treatment, a large heterogeneity in current application of ECP has been reported so far and recent evidence brought novel issues into some specific topics. Consensus-based recommendations ameliorate the appropriateness in daily clinical practice and, in turn, optimize the use of health care resources., Study Design and Methods: Two Italian scientific societies, the Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and the Italian Group for Bone Marrow Transplantation (GITMO), joined to develop and disseminate recommendations on appropriate application of ECP treatment in patients with GVHD. Accordingly, SIdEM and GITMO named an expert panel that first selected 16 questions that were considered relevant for clinical practice: the questions were subsequently addressed through a revision of the available literature and in consensus meetings. The whole group discussed the proposed recommendations according to the nominal group technique., Results: The above-described approach in turn allowed the panel to agree on 47 practice recommendations. SIdEM and GITMO will disseminate such recommendations to the national transplant centers., Conclusion: In conclusion, SIdEM and GITMO have made a scientific effort to provide a useful tool to physicians involved in the field, thus supporting daily clinical practice, as well as strategic decisions in the setting of ECP treatment of GVHD., (© 2013 American Association of Blood Banks.)

Background: Extracorporeal photochemotherapy (ECP) is an effective cell therapy employed in several diseases, including graft-versus-host disease (GVHD) and organ rejection after transplantation. When ECP is performed using the off-line technique, mononuclear cell (MNC) collection by leukapheresis is necessary for further manipulation. Semiautomated apheresis systems require experienced personnel to obtain a good MNC collection; an automated device, able to efficiently collect MNCs with high purity, is desirable. We compared the semiautomated COBE Spectra MNC and the new automated Spectra Optia v.5.0 MNC (Terumo BCT) devices in terms of efficacy and safety., Study Design and Methods: Adult patients with GVHD or bronchiolitis obliterans syndrome (BOS) after lung transplant undergoing ECP at our center were alternatively assigned, within the same ECP cycle (composed by two procedures each), to MNC collection with either device. Patients' characteristics, procedure, and product-related variables were compared., Results: Thirty-nine patients (24 with GVHD and 15 with BOS) underwent a total of 126 ECP procedures, with good compliance to both devices. Product volume and platelet (PLT) and red blood cell contamination were significantly lower with the Spectra Optia. MNC collection efficiency (CE), purity, and PLT loss were similar between the two devices, while white blood cells CE was in favor of the COBE Spectra., Conclusion: The Spectra Optia device proved to be a good option for MNC collection in the difficult ECP setting, since it ensures high-quality MNC collection, while at the same time saving personnel's time, guaranteeing optimal monitoring and care to this frail patient population., (© 2013 American Association of Blood Banks.)

Background: Chronic graft-versus-host disease (cGVHD) classification has recently been improved by the National Institutes of Health (NIH); patients' stratification with those new criteria has implications for patients' prognosis., Study Design and Methods: To assess whether the NIH consensus classification (NCC) better predicts survival and response to extracorporeal photochemotherapy (ECP), and to identify variables associated with response and survival, we retrospectively analyzed 102 patients with cGVHD reclassified according to NCC treated with ECP (1997-2010) at our center. Cox regression was used in univariate and multivariate models., Results: Of the 102 patients, 64 (62.7%) had classic cGVHD, 24 (23.5%) had overlap cGVHD, and seven (6.9%) patients each had late and persistent acute GVHD. The cumulative ECP-specific follow-up was 2333.3 person-years. Response was complete in 16 (15.7%), partial in 38 (37.3%), minimal in 28 (27.5%), and absent in 20 (19.6%). Of the 22 deaths, 15 (68.2%) occurred among patients with minimal or no response (p = 0.031). The only variables associated with response were nonmyeloablative transplant (hazard ratio, 3.5; 95% confidence interval [CI], 1.36-9.08; p = 0.009), donor lymphocyte infusion (hazard ratio, 2.58; 95% CI, 1.2-5.56; p = 0.015), and lung involvement (hazard ratio, 0.34; 95% CI, 0.12-0.94; p = 0.038)., Conclusion: ECP is a safe and effective treatment for cGVHD and response to ECP is the only variable that influences survival. We found no correlation between response and NCC clinical subtype, number, or degree of organ involvement, except for lung, or the variables mentioned above. Prospective studies are needed to identify subsets of patients with higher probability of response., (© 2012 American Association of Blood Banks.)

Background: Extracorporeal photochemotherapy (ECP) is a valid therapeutic option in the treatment of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively). No standard clinical and laboratory criteria of response to ECP treatment are available at the moment., Study Design and Methods: Clinical and laboratory variables on 73 pediatric patients with aGVHD (n = 50) and cGVHD (n = 23) were correlated with response to ECP and survival., Results: An overall response (OR) was obtained in 34 of 50 (68%) aGVHD and in 16 of 23 (69.5%) cGVHD patients. Steroid tapering within 30 days of 1.3 mg/kg in OR (p = 0.004) was the sole highly significant correlation with response found in aGVHD while no correlation emerged for cGVHD (p = 0.28). Among aGVHD patients, response to ECP was inversely associated with death: among OR, deaths were 13 of 34 (38.2%), while among nonresponders, deaths were 15 of 16 (93.8%; p < 0.001). On the other hand, decrease of steroid dose at 30 days was associated with survival: for each 1 mg/kg reduction, the hazard ratio was 2.2, and the 95% confidence interval was 1.5 to 3.2 (p < 0.001). No other clinical or laboratory variables statistically associated with survival were found., Conclusions: Our results demonstrate that steroid tapering within the first 30 days of ECP treatment in aGVHD and response to ECP in acute and chronic GVHD are the only variables influencing response and survival, respectively.

This study aimed to ascertain whether extracorporeal photochemotherapy (ECP) is an effective treatment for paediatric patients with refractory graft-versus-host disease (GVHD). From January 1992 to December 2000, 77 children (median age 8.6 years) with either acute (n = 33) or chronic (n = 44) GVHD, resistant to conventional immunosuppressive therapy, were treated with ECP in four Italian paediatric hospitals. After ECP, acute GVHD involving skin, liver and gut responded completely in 76%, 60% and 75% of patients respectively. The 5-year overall survival was 69% for responding patients vs 12% for non-responders (P = 0.001). Among the 44 children with chronic GVHD, 15 (44%) showed a complete response and 10 (29%) a significant improvement after ECP. The 5-year overall survival was 96% for responders vs 58% for non-responders (P = 0.04). Our results suggest that ECP is an effective treatment that may be useful in paediatric patients with either acute or chronic GVHD who have failed to respond to standard immunosuppressive therapy.