GRAfT 2.0. A Multimodal Prospective Approach to Define the Mechanisms and Clinical Features of Acute and Chronic Rejection in Lung Transplantation

Background:

Lung transplants can save lives, but the procedure has risks. Some people develop donor-specific antibodies (DSA) after the procedure-that is, their bodies create proteins that treat the new lungs as foreign and mount an immune response against them. This is called rejection. But not everyone who has a transplant develops DSA, and not everyone who has DSA develops rejection. Researchers want to understand why.

Objective:

To collect data to try to find out why some people develop rejection after lung transplants while others do not.

Eligibility:

People aged 18 to 75 years who have undergone or may undergo a lung transplant.

Design:

Participants will have clinic visits every 3 to 6 months for up to 4 years. Some visits might require an overnight stay.

Each visit will include multiple tests and procedures:

Physical exam with blood and urine tests. Some blood will be used for genetic testing.

Imaging scans. Participants will have 2 types of scan to get images of their lungs. For one, they will have a contrast agent given through a tube inserted into a vein.

Six-minute walk test. Participants will walk back and forth in a hallway at their own pace. Researchers will check on how their body responds.

Lung function test. Participants will breathe into a tube connected to a machine.

Two other tests are optional:

Bronchoscopy with washings (lavage). A long tube with a light will be threaded down through the participant s nose or mouth and into their lungs.

Endomicroscopy. During the bronchoscopy a tiny camera may be used to take pictures inside the lungs.

...

Study Overview

• Status: Recruiting
• Conditions: Rejection; Lung Transplant; End Stage Lung Disease

Detailed Description

Study Description:

Our hypothesis is that lung transplant recipients with donor-specific antibodies (DSA) who develop AMR (DSA+/AMR+) exhibit distinct molecular mechanisms compared to DSA+/AMR- and DSA-recipients.

This study will recruit lung transplant patients to the NIH Clinical Center to investigate these differences. Participants will undergo blood draws, bronchoscopy with bronchoalveolar lavage, imaging and other diagnostic testing. After the initial visit, participants will continue routine care in their transplant programs with multiple planned NIH follow-up visits for blood draw and testing/sampling. The primary goal of this proposal is to profile the molecular changes from DSA detection to the development of acute rejection (AR) and subsequent development of chronic lung allograft dysfunction (CLAD).

Secondary goals of the study are to profile changes in pulmonary function testing, pulmonary imaging, surveillance bronchoscopy, and advanced bronchoscopy measures that coincide with the molecular changes. The dynamic assessment is poised to identify actionable timing and molecular targets to preemptively treat patients before AMR develops and to halt progression to CLAD.

Objectives:

Primary Objective:

-To identify molecular pathways associated with development of AMR from DSA

Secondary Objectives:

• To identify clinical subtypes (endotypes) of AMR
• To identify molecular and clinical pathways associated with development of CLAD from AMR

Endpoints:

Primary Endpoint:

-Multi-omic molecular differences between DSA+ participants who progress to AMR (DSA+/AMR+), DSA+ participants who do not progress to AMR (DSA+/AMR-), and DSA- participants.

Secondary Endpoints:

• Multi-omic molecular differences between participants who progress to CLAD (CLAD+), and no CLAD (CLAD-)
• Physiological changes (PFT, 6MWT) between (DSA+/AMR+), (DSA+/AMR-), and DSA- groups.
• Physiological changes (PFT, 6MWT): Between CLAD+, and CLAD- participants
• Imaging findings differences (low dose CT, MRI, Confocal Microscopy) between (DSA+/AMR+), (DSA+/AMR-), and DSAgroups.
• Imaging findings differences (CT, MRI, Confocal Microscopy): Between CLAD+, and CLAD- participants

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Andrew G Keel, C.R.N.P.; Phone Number: (301) 648-5674; Email: andrew.keel@nih.gov
• Study Contact Backup: Name: Muhtadi H Alnababteh, M.D.; Phone Number: (301) 827-3272; Email: muhtadi.alnababteh@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults with lung transplantation, progressive lung disease, or undergoing evaluation for lung transplantation. The population includes: (1) lung transplant recipients across the post-transplant spectrum (stable maintenance, acute rejection, infection, chronic allograft dysfunction), (2) patients with advanced lung disease being evaluated as transplant candidates, and (3) patients with progressive pulmonary disorders that may warrant lung transplant

Description

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Stated willingness to comply with study procedures and availability for the duration of the study.
2. Male or female, aged 18 - 75 years of age.
3. Have undergone or being evaluated for lung transplantation.
4. Ability of subjects to understand the informed consent document.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Pregnancy or lactation

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
DSA-; Lung transplant patients who didn't develop donor specific antibodies
DSA+; Lung transplant patients who developed donor specific antibodies

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Multi-omic molecular differences between DSA+ participants who progress to AMR (DSA+/AMR+), and DSA+ participants who do not progress to AMR (DSA+/AMR-), and DSA- participants	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Multi-omic molecular differences between participants who progress to CLAD (CLAD+), and no CLAD (CLAD-)	3 years
Imaging findings differences (low dose CT, MRI, Confocal Microscopy) between (DSA+/AMR+), (DSA+/AMR-), and DSA- groups.	3 years
Imaging findings differences (CT, MRI, Confocal Microscopy): Between CLAD+, and CLAD- participants	3 years

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: National Institutes of Health Clinical Center (CC)
• Investigators: Principal Investigator: Muhtadi H Alnababteh, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Agbor-Enoh S, Jackson AM, Tunc I, Berry GJ, Cochrane A, Grimm D, Davis A, Shah P, Brown AW, Wang Y, Timofte I, Shah P, Gorham S, Wylie J, Goodwin N, Jang MK, Marishta A, Bhatti K, Fideli U, Yang Y, Luikart H, Cao Z, Pirooznia M, Zhu J, Marboe C, Iacono A, Nathan SD, Orens J, Valantine HA, Khush K. Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis. J Heart Lung Transplant. 2018 Jul;37(7):925-932. doi: 10.1016/j.healun.2018.01.1305. Epub 2018 Jan 31.
• Alnababteh M, Sun J, Meda R, Ponor L, Shah P, Mathew J, Kong H, Charya A, Helen Luikart RN, Aryal S, Nathan SD, Orens JB, Khush KK, Jang M, Agbor-Enoh S, Keller MB. Impact of donor specific antibodies on longitudinal lung function and baseline lung allograft dysfunction. J Heart Lung Transplant. 2025 Nov;44(11):1766-1773. doi: 10.1016/j.healun.2025.06.012. Epub 2025 Jun 26.
• Keller MB, Newman D, Alnababteh M, Bon A, Ponor L, Shah P, Mathew J, Kong H, Andargie T, Park W, Charya A, Luikart H, Intrieri T, Aryal S, Nathan SD, Orens JB, Khush KK, Jang M, Agbor-Enoh S. Molecular criteria for pulmonary antibody-mediated rejection are associated with an increased risk of allograft failure. J Heart Lung Transplant. 2025 Oct;44(10):1535-1542. doi: 10.1016/j.healun.2025.03.015. Epub 2025 Mar 20.
• Alnababteh M, Keller MB, Kong H, Phipps K, Namian J, Ponor L, Shah P, Mathews J, Andargie T, Park W, Orens JB, Aryal S, Nathan SD, Bush E, Redekar N, Hill T, Jang M, Tian X, Agbor-Enoh S. Early post-transplant recipient tissue injury predicts allograft function, rejection and survival in lung transplant recipients: evidence from cell-free DNA. Eur Respir J. 2026 Apr 16;67(4):2402537. doi: 10.1183/13993003.02537-2024. Print 2026 Apr.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2026
• Primary Completion (Estimated): March 27, 2032
• Study Completion (Estimated): March 27, 2032

Study Registration Dates

• First Submitted: April 6, 2026
• First Submitted That Met QC Criteria: April 7, 2026
• First Posted (Actual): April 8, 2026

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 4, 2026

More Information

Terms related to this study

• Keywords: Rejection; Lung Transplant
• Additional Relevant MeSH Terms: Behavior; Social Behavior; Rejection, Psychology
• Other Study ID Numbers: 10002352; 002352-H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: IPD sharing plan will be determined upon study completion, contingent on appropriate de-identification methods for longitudinal transplant data and compliance with NIH data sharing policy.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No