Chest
Volume 117, Issue 3, March 2000, Pages 834-840
Journal home page for Chest

Laboratory and Animal Investigations
Radionuclide Imaging of Acute Lung Transplant Rejection With Annexin V

https://doi.org/10.1378/chest.117.3.834Get rights and content

Study objectives

Early detection and treatment of lung transplant rejection is critical for preservation of pulmonary graft function. Damage to pulmonary allografts is mediated by apoptotic cell death induced by the alloreactive T lymphocytes that infiltrate lung grafts. Previous studies demonstrate that acute cardiac allograft rejection can be visualized using radiolabeled annexin V. This study was done to determine whether this technique could visualize acute rejection in a rodent model of unilateral orthotopic lung transplantation.

Design

Eighteen Sprague-Dawley ACI rats underwent removal of their left lung followed by orthotopic transplant of either an allogeneic (PVG, immunologically mismatched; N = 10) or a syngeneic (ACI, immunologically matched) pulmonary graft (N = 8). Animals were imaged 1 h after IV injection of 1 mCi (37.0 MBq) of 99mTc-annexin V 1 to 7 days after transplantation.

Results

Lungs receiving the allograft demonstrated moderate to marked mononuclear infiltration of the perivascular, interstitial, and peribronchial tissues. No mononuclear infiltrates were noted in the native right lungs nor in the syngeneic transplants. Region of interest image analysis revealed significant (p < 0.0005) increases of transplant to normal lung activity ratios 3 to 7 days after allograft surgery. The increased annexin V uptake in these lungs was confirmed at biodistribution assay (allograft 151% greater than isograft activity, p < 0.005).

Conclusions

Acute experimental lung transplant rejection can be noninvasively identified using 99mTc-annexin V. Radiolabeled annexin V may be a clinically useful noninvasive screening tool for acute rejection.

Section snippets

Rodent Model

Young adult male ACI (RT1a) and PVG (RT1c) Sprague-Dawley rats (Harlan; Indianapolis, IN), weighing between 200 and 250 g, underwent orthotopic left lung transplantation using the technique first described by Marck and Wildevuur.24 Animals were maintained at the animal care facilities of the Department of Cardiothoracic Surgery under standard temperature, humidity, and time-regulated light conditions. Water and food were provided ad libitum. Animals were treated in a humane manner, conforming

Histopathology and TUNEL Staining in Situ

The right and left (grafted) lungs of 18 transplanted animals were studied. None of the syngeneic (ACI to ACI) transplants (N = 7) demonstrated histologic evidence of rejection (ie, all were grade 0) or apoptotic nuclei as seen by in situ TUNEL staining (Table 1 ) for up to 7 days after surgery. The histology of all native lungs (N = 18) was also normal.

Ten of 11 allograft (PVG to ACI) transplants demonstrated grade 2 (moderate) or greater grades of acute rejection. The one allograft on day 3

Discussion

The frequency and severity of acute rejection episodes after lung transplantation, particularly in the first 4 months, is the most significant risk factor for the development of chronic rejection. Of particular concern to pulmonary transplant clinicians is that only 40% of the cases of histologically confirmed grades 2 through 4 acute rejection are associated with clinical signs or symptoms.1 However, noninvasive methods to diagnose acute rejection, including high-resolution CT and pulmonary

References (28)

  • LS Medina et al.

    Pediatric lung transplantation: radiographic–histopathologic correlation

    Radiology

    (1993)
  • A Montoya et al.

    Survival and functional outcome after single and bilateral lung transplantation

    Surgery

    (1994)
  • P Loubeyre et al.

    Bronchiectasis detected with thin-section CT as a predictor of chronic lung allograft rejection

    Radiology

    (1995)
  • H Shennib et al.

    Altered nonspecific lymphocyte cytotoxicity in bronchoalveolar lavage of lung transplant recipients

    Transplantation

    (1996)
  • Cited by (46)

    • Pediatric Interstitial (Diffuse) Lung Disease

      2019, Imaging in Pediatric Pulmonology, Second Edition
    View all citing articles on Scopus

    Presented at the Scientific Session of the 29th Annual Fleischner Society Meeting Tucson, AZ, April 18, 1999.

    Supported by National Institutes of Health grant 1RO1 HL61717-01A1 and HL-47151.

    View full text