Developing Hyperpolarized Gas MRI Signatures to Detect and Manage Acute Cellular Rejection

Advanced Immunoclinical Phenotyping of Rejection in Lung Transplant

Lung transplantation (LT) is the only definitive therapy for many patients with end-stage lung diseases. The supply of donors' lungs is the biggest bottleneck to performing a lung transplant, and many patients die while waiting. Acute Cellular Rejection (ACR) is a significant risk factor for developing chronic allograft failure, a primary reason for death in this patient population. These observations highlight the importance of early diagnosis and management of ACR to prevent chronic graft failure. The preliminary results support the idea that Hyperpolarized Gas Magnetic Resonance Imaging has excellent potential to address this clinical gap. This study hypothesizes that optimized hyperpolarized gas magnetic resonance imaging (HGMRI) signatures can detect early pathophysiologic derangements in lung allografts consistent with ACR. This study also hypothesizes that the optimized HGMRI signatures will correlate with single-cell transcriptomic signatures that reflect dysregulated immune responses associated with ACR.

Lung transplantation (LT) is the only definitive therapy for subjects with end-stage lung diseases. The supply of donors' lungs is the biggest bottleneck to performing a lung transplant, and many patients die while waiting. Many lung transplant recipients experience at least one acute rejection episode after transplantation. Acute Cellular Rejection (ACR) is a significant risk factor for developing chronic allograft failure, a primary reason for death in this patient population. These observations highlight the importance of early diagnosis and management of ACR to prevent chronic graft failure. The preliminary results support the idea that Hyperpolarized Gas Magnetic Resonance Imaging (HGMRI) signatures have excellent potential to address this clinical gap. In lung transplant patients without suspicion of ACR, HGMRI detected subtle, regional abnormalities in pulmonary physiology that were not detected by pulmonary function tests (PFTs) or high-resolution chest computer tomography (HRCT). Biopsy-proven regions of ACR in these subjects exhibited worse airflow and gas exchange HGMRI signatures, which corroborated well with the tissue pathology diagnosis of ACR. This data demonstrates the potential of HGMRI signatures to detect ACR even when existing clinical tools cannot. By merging anatomic CT and physiologic HGMRI readouts, the previous study developed a method to identify the airways that led to the allograft segments with abnormal HGMRI signatures. Then, a method to sample these areas of allografts is enabled during routine surveillance bronchoscopy by mapping the airways leading to dysfunctional allograft regions to enhance the diagnostic accuracy of clinical bronchoscopy. The primary molecular driver of ACR is the exaggerated host immune response to the donor's lungs. The anticipated results are that within the same subject, the single-cell transcriptome of cells from lung regions with abnormal HGMRI signatures would be more immunologically abnormal than those with normal HGMRI signatures. The hypothesis is that optimized HGMRI signatures can detect early pathophysiologic derangements in lung allografts consistent with ACR. The second hypothesis is that the optimized HGMRI signatures correlate with single-cell transcriptomic signatures reflecting the dysregulated immune responses underlying ACR. This study proposes: Aim 1: Determine the optimized HGMRI signatures to detect early regional allograft dysfunction consistent with ACR in lung allografts at the baseline Visit 1 (V1); Aim 2: Determine how the within-subject longitudinal changes in regional HGMRI signatures over a 1-year follow-up Visit 2 (V2) correlate with a clinical diagnosis of ACR.

Inclusion Criteria:

• All subjects must be willing to participate and undergo the procedure, and be managed as outpatients

• HXe MRI-specific Inclusion

• All patients who successfully underwent a lung transplant at the University of Virginia

• Followed by the medical lung transplant team for the post-lung transplant rejection surveillance program at the University of Virginia

• a clinical diagnosis of lung transplant within the past 12 months

• absence of any significant allograft dysfunction/rejection at the time of the 12-month surveillance bronchoscopy

• the ability to understand a written informed consent form and comply with the requirements of the study.

• have an acceptable pre-bronchoscopy pulmonary function test: FEV1>45% before use of any bronchodilator

• Must have acceptable pre-procedural screening studies.

• Complete Blood Count: normal WBC, Hgb, and PLT

• PT: Normal < 1.2

• Basic Metabolic Panel: Normal

  1. Scenario 1 (two visits): Standard bronchoscopy with Normal MRI results and without a diagnosis of acute rejection after bronchoscopy.

  2. Scenario 2 (two visits): Navigational bronchoscopy with abnormal MRI result but without a diagnosis of acute rejection after bronchoscopy by clinical pathology.

  3. Scenario 3 (three or four visits): Navigational bronchoscopy with abnormal MRI result and a diagnosis of acute rejection after bronchoscopy by clinical pathology at the first visit, the second visit, or both visits.

  4. Scenario 4 (one visit): Subjects who previously signed Part 2 Substudy corresponding to the First HXe MRI visit of the Part 3 Substudy (6 or 12 month evaluation). They will be asked to join the Part 3 Substudy to undergo a 24-month follow-up evaluation, including MRI and bronchoscopy, as described for Scenarios 1, 2, or 3.

     Exclusion Criteria:

  1. Unable to Consent

  2. Continuous oxygen use at home.

  3. Blood oxygen saturation of less than 92% as measured by pulse oximetry on the day of imaging.

  4. FEV1 percent predicted less than 25%.

  5. Pregnancy or lactation.

  6. Claustrophobia, inner ear implants, aneurysms or other surgical clips, metal foreign bodies in the eye, pacemakers, or other contraindications to MR scanning. Subjects with any implanted device that cannot be verified as MRI compliant will be excluded.

  7. Chest circumference greater than that of the xenon MR and/or helium coil. The circumference of the coil is approximately 42 inches.

  8. History of congenital cardiac disease, chronic renal failure, or cirrhosis.

  9. Inability to understand simple instructions or to hold still for approximately 10 seconds.

  10. History of respiratory infection within 2 weeks prior to the MR scan

  11. History of MI, stroke, and/or poorly controlled hypertension.

  12. Failure to complete study-related procedures

  13. Unavailability of a reliable communication network and contacts for follow-up with the second in-house backup contact

  14. Patient actively smokes.

  15. Before 48 hours, any event being considered to be too risky to preclude surveillance bronchoscopy: SaO2 <90%, >16 puffs/24 hours of short-acting β-agonist (SABA), worsening symptoms prompting the use of any inhalers, FEV1 < 45% before using a bronchodilator.

  16. acute or chronic renal failure

  17. uncontrolled coronary artery disease or congestive heart failure; uncontrolled diabetes mellitus; uncontrolled hypertension, liver disease; history of neurologic diseases, including stroke, any disease concerning fibrotic processes.

  18. Pregnant females will be excluded

  19. Claustrophobic or too large to fit into the available MR chest RF coils.

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