Anti-rejection Nanotherapy Shows Promise In Rodent Lung Transplant Model

Just as some lung transplant patients celebrate the ability to breathe again, their immune systems begin to attack their new organ.

This inflammatory autoimmune activity, called rejection, can lead to failure of the transplanted lungs. Of the people who receive new lungs each year, 30 percent to 40 percent will suffer an episode of rejection within a year of transplant.

A multidisciplinary team from The University of Texas Health Science Center at San Antonio, in collaboration with The University of Texas at Austin, is testing a novel nanoparticle aerosol therapy to prevent post-transplant rejection. The UT Health Science Center is home to one of the few research groups in the country studying solutions for this problem in a rodent model of lung transplant (rodent donor and recipient).

Conventional treatment of rejection includes high doses of prednisone and other anti-inflammatory medications that can harm the kidneys. “It is thought that if the therapy is inhaled, most will go to the lung, alleviating rejection and protecting the kidneys,” said Scott B. Johnson, M.D., associate professor of surgery in the UT Health Science Center Division of Cardiothoracic Surgery and principal investigator of the rodent lung transplant program.

Going beyond existing therapeutic aerosols, the UT Austin College of Pharmacy developed a formulation in which the aerosol particles are the size of nanometers (one billionth of a meter). This may help the 80 percent of patients who cannot inhale existing aerosols, Dr. Johnson said.

The chief collaborator from UT Austin is Robert O. Williams III, Ph.D., the Johnson & Johnson Centennial Professor of Pharmaceutics in the College of Pharmacy.

UT Health Science Center personnel have performed more than 200 rodent lung transplants, with 80 percent of the recipients surviving two weeks post-operatively, considered long-term survival in this rodent model.

The inch-wide surgical field is visualized using a high-strength microscope.

“Studies such as this are very difficult to perform in human subjects, in part because only a few thousand lung transplants are done in the U.S. annually,” said Clinton E. Baisden, M.D., professor and research director in the Division of Cardiothoracic Surgery.

Post-treatment analysis shows the nanoparticle aerosol concentration is very high in the lungs while concentrations elsewhere are much lower, Dr. Johnson said. The therapy will soon be tested in strains of rats bred to experience reproducible rejection at one week after transplant.

The Department of Medicine/Division of Pulmonary Diseases and the Department of Pathology at the UT Health Science Center provide key expertise toward the rodent lung transplant program, which is funded entirely through contributions from private benefactors.

“Several donors have made generous gifts to advance this important scientific effort,” said Jay I. Peters, M.D., professor of medicine/pulmonary diseases at the UT Health Science Center and a key collaborator on the project. “More than one of the donors has received a second chance at life through our lung transplant program, which is offered in conjunction with University Hospital (one of the UT Health Science Center's teaching hospitals). Now these wonderful individuals have joined forces with the Health Science Center to make lives better for future transplant patients.”

Dr. Johnson gives much of the credit for establishing the rodent lung transplant lab and perfecting the technique to Adam M. Cline, M.D., a research resident. Adham R. Saad, M.D., a third-year general surgery resident, works with Dr. Cline in the rodent lung transplant laboratory.

“Dr. Saad and I design the research under the division’s tutelage,” Dr. Cline said. “We enjoy performing these intricate surgeries in the hope that we can help lung transplant patients throughout the world.”