Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model

Martins, Saulo; Perrot, Marc de; Imai, Yumiko; Yamane, Masaomi; Quadri, S. M.; Segall, Lorne; Dutly, André; Shoji, Shuichi; Chaparro, Adriana; Bl, Davidson; Waddell, T.K.; Liu, Mingyao; Keshavjee, Shaf

doi:10.1038/sj.gt.3302357

Cited by 66 publications

(44 citation statements)

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“…13 Other animal models of lung transplantation have demonstrated that adenoviral gene therapy to upregulate expression of the anti-inflammatory cytokine IL-10 in the donor lung downregulates inflammation and improves function in the recipient animal after transplant. [14][15][16][17] These observations suggest that attenuating the donor lungs' inflammatory response before implantation may improve early outcome after lung transplantation, and help to safely maximise lung use from the existing donor pool.…”

Section: Impact Of Donor Lung Injurymentioning

confidence: 98%

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK

Fisher

Andreasson

Chrysos

et al. 2016

Health Technol Assess

111

115

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BackgroundMany patients awaiting lung transplantation die before a donor organ becomes available. Ex vivo lung perfusion (EVLP) allows initially unusable donor lungs to be assessed and reconditioned for clinical use.ObjectiveThe objective of the Donor Ex Vivo Lung Perfusion in UK lung transplantation study was to evaluate the clinical effectiveness and cost-effectiveness of EVLP in increasing UK lung transplant activity.DesignA multicentre, unblinded, non-randomised, non-inferiority observational study to compare transplant outcomes between EVLP-assessed and standard donor lungs.SettingMulticentre study involving all five UK officially designated NHS adult lung transplant centres.ParticipantsPatients aged ≥ 18 years with advanced lung disease accepted onto the lung transplant waiting list.InterventionThe study intervention was EVLP assessment of donor lungs before determining suitability for transplantation.Main outcome measuresThe primary outcome measure was survival during the first 12 months following lung transplantation. Secondary outcome measures were patient-centred outcomes that are influenced by the effectiveness of lung transplantation and that contribute to the health-care costs.ResultsLungs from 53 donors unsuitable for standard transplant were assessed with EVLP, of which 18 (34%) were subsequently transplanted. A total of 184 participants received standard donor lungs. Owing to the early closure of the study, a non-inferiority analysis was not conducted. The Kaplan–Meier estimate of survival at 12 months was 0.67 [95% confidence interval (CI) 0.40 to 0.83] for the EVLP arm and 0.80 (95% CI 0.74 to 0.85) for the standard arm. The hazard ratio for overall 12-month survival in the EVLP arm relative to the standard arm was 1.96 (95% CI 0.83 to 4.67). Patients in the EVLP arm required ventilation for a longer period and stayed longer in an intensive therapy unit (ITU) than patients in the standard arm, but duration of overall hospital stay was similar in both groups. There was a higher rate of very early grade 3 primary graft dysfunction (PGD) in the EVLP arm, but rates of PGD did not differ between groups after 72 hours. The requirement for extracorporeal membrane oxygenation (ECMO) support was higher in the EVLP arm (7/18, 38.8%) than in the standard arm (6/184, 3.2%). There were no major differences in rates of chest radiograph abnormalities, infection, lung function or rejection by 12 months. The cost of EVLP transplants is approximately £35,000 higher than the cost of standard transplants, as a result of the cost of the EVLP procedure, and the increased ECMO use and ITU stay. Predictors of cost were quality of life on joining the waiting list, type of transplant and number of lungs transplanted. An exploratory model comparing a NHS lung transplant service that includes EVLP and standard lung transplants with one including only standard lung transplants resulted in an incremental cost-effectiveness ratio of £73,000. Interviews showed that patients had a good understanding of the need for, and the processes of, EVLP. If EVLP can increase the number of usable donor lungs and reduce waiting, it is likely to be acceptable to those waiting for lung transplantation. Study limitations include small numbers in the EVLP arm, limiting analysis to descriptive statistics and the EVLP protocol change during the study.ConclusionsOverall, one-third of donor lungs subjected to EVLP were deemed suitable for transplant. Estimated survival over 12 months was lower than in the standard group, but the data were also consistent with no difference in survival between groups. Patients receiving these additional transplants experience a higher rate of early graft injury and need for unplanned ECMO support, at increased cost. The small number of participants in the EVLP arm because of early study termination limits the robustness of these conclusions. The reason for the increased PGD rates, high ECMO requirement and possible differences in lung injury between EVLP protocols needs evaluation.Trial registrationCurrent Controlled Trials ISRCTN44922411.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 85. See the NIHR Journals Library website for further project information.

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Section: Impact Of Donor Lung Injurymentioning

confidence: 98%

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK

Fisher

Andreasson

Chrysos

et al. 2016

Health Technol Assess

111

115

View full text Add to dashboard Cite

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“…Conversely, rapid expression of high levels of target gene is a major advantage of adenovirus-mediated gene therapy in a setting of lung transplantation (36,37). Thus, one could envision that these gene therapeutic strategies could even be combined to be complementary to each other in effectively protecting lung allografts using IL-10 as a therapeutic target gene-with rapid production of IL-10 early on to attenuate the inflammatory burst related to ischemiareperfusion injury, and sustained low level intra-graft IL-10 production to modulate the more chronic IL-17 allograft response (38) without needing excessive levels of systemic immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Lentivirus IL-10 Gene Therapy Down-Regulates IL-17 and Attenuates Mouse Orthotopic Lung Allograft Rejection

Hirayama

Sato

Loisel-Meyer

et al. 2013

American Journal of Transplantation

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contributed equally to this work.The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 AE 0.6 vs. 2.0 AE 0.6 (mean AE SD); p ¼ 0.025; n ¼ 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-gt without affecting levels of IL-12 and interferon-g (IFNg). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation.

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“…Recent evidence has demonstrated a crucial role of IL-17 produced by iNKT cells in the initiation of lung IR injury via modulation of neutrophil infiltration and activation in an in vivo mouse model . On the other hand, a potent role for IL-10 as an antiinflammatory molecule, promoting the abrogation of lung IR injury, has been shown in experimental lung IR models (Boehler, et al, 1998;Martins, et al, 2004;McRae, et al, 2001). The cytotoxic and immunomodulatory effects of cytokines and chemokines are critical in the progression of lung IR injury.…”

Section: Cytokines and Chemokinesmentioning

confidence: 99%

Pulmonary Transplantation and Ischemia-Reperfusion Injury

Sharma¹,

Stone²,

Lau³

et al. 2012

Topics in Thoracic Surgery

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Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model

Cited by 66 publications

References 40 publications

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK

An observational study of Donor Ex Vivo Lung Perfusion in UK lung transplantation: DEVELOP-UK

Lentivirus IL-10 Gene Therapy Down-Regulates IL-17 and Attenuates Mouse Orthotopic Lung Allograft Rejection

Pulmonary Transplantation and Ischemia-Reperfusion Injury

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