The Role of Immune Checkpoints in Lung Transplant (ILTRA) (ILTRA)

March 6, 2024 updated by: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

The Role of Immune Checkpoints in Lung Transplant: the Pathways of Rejection and the Immunomodulatory Therapeutic Perspectives

The goal of this observational study is to learn about rejection in lung transplantation.

The main question it aims to answer is:

• what is the role of immune checkpoints in lung transplantation? Participants will describe pathways of rejection in lung transplantation analyzing the immune checkpoints on explanted lungs as well as trans-bronchial biopsies.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Lung transplantation is the less common solid organ transplant performed; it is the treatment of choice for end stage lung disease. Lung transplantation is "problematic" for a number of reasons: low graft availability, high waitlist mortality and unsatisfactory survival. Acute rejection, occurring days to months after surgery, has been identified as one of the main risk factors for the development of chronic rejection: in the first five years after lung transplantation, chronic rejection is the major cause of graft failure, morbidity and mortality. A deep knowledge of the immunological scenarios associated with lung graft tolerance could allow selectively switch-off T-cells involved in the rejection process. The researches, preliminary demonstrated the central role of immunological checkpoints in the development of acute rejection and its evolution towards chronic rejection. The aim of this study is the identification of markers that could be associated with the establishment of lung graft tolerance.

The project is articulated into two parts: a retrospective and a prospective section. The retrospective section is constituted by a cross-sectional study of immune checkpoints on lungs explanted during lung re-transplantation for chronic rejection (cohort 1). In addition, the retrospective section includes a retrospective cohort study of immune checkpoints on specimens from transbronchial lung biopsies of participants who received lung transplantation and have 3 years of follow-up (cohort 2). The prospective section is a cohort study of immune checkpoints on specimens from transbronchial lung biopsies and gene expression analysis on immune cells purified from bronchoalveolar lavage; participants will be subjects receiving the lung transplantation during the first year of recruitment and followed for one year (cohort 3).

Study Type

Observational

Enrollment (Estimated)

280

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Milan, Italy, 20122
        • Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico
        • Contact:
        • Contact:
        • Principal Investigator:
          • Mario Nosotti, Medicine
        • Sub-Investigator:
          • Ilaria Righi, Medicine
        • Sub-Investigator:
          • Lorenzo Rosso, Medicine
        • Sub-Investigator:
          • Valentina Vaira, Biology
        • Sub-Investigator:
          • Mario Clerici, Medicine
        • Sub-Investigator:
          • Daria Trabattoni, Biology
      • Modena, Italy, 41121
        • University of Modena and Reggio Emilia
        • Contact:
      • Padova, Italy, 35131
        • University of Padua
        • Contact:
      • Torino, Italy, 10124

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Cohort 1: Participants who received lung re-transplantation for chronic lung allograft dysfunction.

Cohort 2 and 3: Participants who received first lung transplantation for end stage respiratory insufficiency.

Description

Inclusion Criteria:

  • Lung transplant patients

Exclusion Criteria:

  • Hyperimmunized patients
  • History of auto-immune disorders

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Lung re-transplant cohort
This cohort includes consecutive participants who underwent lung re-transplantation for chronic lung allograft dysfunction from 2010 to 2020; the immune checkpoints analyses will be conducted on stored specimens from lungs explanted during re-transplantation.
Diagnostic test: Immune checkpoints analysis
The researcher will analyze immune checkpoint molecules, which will include the lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA), besides the canonical PD1 and ligands L1 and L2, T cell immunoglobulin and ITIM domain (TIGIT) and CTLA-4. In addition, Foxp3, GATA3 and TOX will be analyzed as specific lineage markers.
Previous lung transplant cohort
This cohort includes participants who received first bilateral lung transplantation from 2017 to 2020. The immune checkpoints analyses will be conducted on stored specimens from postoperative transbronchial biopsy performed for clinical suspicious of rejection.
Diagnostic test: Immune checkpoints analysis
The researcher will analyze immune checkpoint molecules, which will include the lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA), besides the canonical PD1 and ligands L1 and L2, T cell immunoglobulin and ITIM domain (TIGIT) and CTLA-4. In addition, Foxp3, GATA3 and TOX will be analyzed as specific lineage markers.
Prospective lung transplant cohort
This cohort includes participants who will have their first bilateral lung transplant from April 2024 to April 2025. Immunopathological characterization of bronchoalveolar leukocytes and analysis of immuno checkpoints will be performed on leftover material of bronchoalveolar lavage and transbronchial lung biopsy samples performed for clinical suspicious of rejection.
Diagnostic test: Immune checkpoints analysis
The researcher will analyze immune checkpoint molecules, which will include the lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA), besides the canonical PD1 and ligands L1 and L2, T cell immunoglobulin and ITIM domain (TIGIT) and CTLA-4. In addition, Foxp3, GATA3 and TOX will be analyzed as specific lineage markers.
Diagnostic test: Gene expression analysis
Immune cells will be purified from bronchoalveolar lavage; total RNA will be purified and subjected to gene expression analysis by Quantigene multiplex 80-plex Assay, which allows to evaluate simultaneously the follow mRNA targets: CCL2, CCL3, CCL5, CXCL10, CSF2, CSF3, IL1A, IL1B, IL1RN, IL6, IL6R, IL8, IL10, IL12B, IL17A, IL18, IL22, IL28A, TNF, TNFRSF4, IFNA2, IFNB1, IFNG, IFI16, IFITM1, IFITM3, MX1, TLR3, TLR4, TLR7, TLR8, NOD1, NOD2, CASP1, NLRP3, PYCARD, CD44, CLEC4M, CD209, ITGA4, ITGB7, CH25H, ABCA1, HMGCS1, NR1H3, ACAT1, PDCD1, PTGS2, CD274, CD69, MPO, HAVCR2, TAP1, ERAP1, ERAP2, AGTR2, AGTR1, PPARG, CRP, IL7, IL12A, ACE2, ELOVL6, CD38, NOS2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Lung-tissue immune-checkpoint profile and bronchoalveolar immune-cells mRNA signature in acute rejection after lung transplantation.
Time Frame: Twelve months after lung transplantation (prospective data)
Prevalence of immune checkpoint markers and gene-expression on leukocytes from transbronchial biopsies and bronchoalveolar lavage. Participants: cohort number 3.
Twelve months after lung transplantation (prospective data)
Lung-tissue immune-checkpoint profile in chronic rejection after lung transplantation.
Time Frame: Cohort 1: at re-transplantation for chronic lung allograft dysfunction (cross-sectional data). Cohort 2: from one to 36 months after lung transplantation (retrospective data)
Prevalence of immune checkpoint markers on leukocytes from explanted lung grafts and transbronchial biopsies. Participants: cohort number 1 and 2.
Cohort 1: at re-transplantation for chronic lung allograft dysfunction (cross-sectional data). Cohort 2: from one to 36 months after lung transplantation (retrospective data)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Collaborators

University of Padova
University of Turin, Italy
University of Milan

Investigators

  • Principal Investigator: Mario Nosotti, Medicine, University of Milan, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2024

Primary Completion (Estimated)

January 1, 2026

Study Completion (Estimated)

February 1, 2026

Study Registration Dates

First Submitted

February 28, 2024

First Submitted That Met QC Criteria

March 6, 2024

First Posted (Actual)

March 8, 2024

Study Record Updates

Last Update Posted (Actual)

March 8, 2024

Last Update Submitted That Met QC Criteria

March 6, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • 2022XJ9W4F
  • G53D2300526 0006 (Other Grant/Funding Number: Ministry of University and Research. NextGenetationUE)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The anonymized data collected will be recorded on a database available online by other researchers upon request

IPD Sharing Time Frame

Data requests can be submitted starting 9 months after closing of recruitment and the data will be made accessible for up to 36 months. Extensions will be considered on a case-by-case basis.

IPD Sharing Access Criteria

Access to IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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