A New Lining for Lung Transplants Might Let Us Breathe Easy

Pekka Hammainen
Department of Cardiothoracic Surgery
Stanford School of Medicine
December 2001

Lung transplantation has become a good option to treat end stage lung diseases. However, in the long run, the majority of lung transplant patients suffer from problems due to rejection. My research is aimed at clarifying the role of intact airway linings in the process of ongoing rejection.

The linings of the lung airways consist of respiratory epithelial cells, which in the long term, may play a key role in lung transplant acceptance. Unlike others who study methods of preserving the health of donor epithelium in the transplanted lung, we are learning whether it is possible to replace it with a host's own epithelium. We hope that this research will yield improved transplant acceptance and long-term benefits for patients.

Lung transplantation has become a generally accepted method of treating patients suffering from chronic life threatening lung diseases. Due to refined methods, the one-year survival rate has steadily improved and is over 70-80% in most transplantation centers. However, in long run, over one half of the transplants are affected by irreversible narrowing of the small airways, which is considered to be manifestation of ongoing transplant rejection. This condition, termed obliterative
bronchiolitis (OB), leads to deterioration of the patients' respiratory function and ultimately to death. Although OB progression can often be delayed, and occasionally stopped, it cannot be cured with the use of current immunosuppressive therapy.

There are several theoretical methods of increasing transplant acceptance in the recipient, and thereby improve the prognosis of lung transplant patients. In the case of cadaveric (brain dead) donors, better immunological matching of the donor and recipient does not appear possible. Long term results in the recently started program of living related donor transplantations, where only a single lobe of the lung is transplanted from a living donor, is interesting, but this option clearly possesses additional risks to involved living donors. Alternative methods of reducing the immunogenicity of transplant include genetic manipulation of transplantation antigens by using
transgenic donors (donor animals like pigs, for xenotransplantation from one species to another). This is a tempting possibility for solving also the shortage of donor organs. The occurrence of immediate rejection has been eliminated in xenotransplantation by removal of certain sugars from the donor endothelial cell surface structures, but no long term results exist. There also exists the possibility of transfering unknown pathogens into immunosuppressed humans, but with consequences no one is able to forecast.

To elaborate, pathogenesis of OB includes infiltration of the linings of the airways by inflammatory cells causing epithelial damage and sloughing. Reparative process follow the initial damage, but instead of healing the lesions, the excess scar tissue formation results an obliteration of small airways and thereby loss of respiratory function. As mentioned, intact respiratory epithelium plays a key role in preventing OB. It has been experimentally shown that after a short segment of trachea has been transplanted, recipient respiratory epithelium migrates into it to cover the transplant, and interior narrowing is thereby prevented. However, nobody knows what happens in real lung transplants, except that proximal airways are spared from obliteration. If recipient epithelial cells are capable of providing shelter against OB, their migration across the airway connection could explain the distribution pathological alterations seen in human lung
transplants.

We have chosen another way of inspecting the prevention of OB. If recipient cells could gradually replace the respiratory epithelium in the transplant, it would not serve as a target for rejection. We have started our program by doing experimental lung transplants. One to two months follow-up time after the operation is needed. In our model, we are able to differentiate host epithelial cells in the transplant. We estimate the extent and magnitude of epithelial cell migration preserving proximal to peripheral orientation of sequential horizontally cut specimen of the airways of the transplant. Different immunosuppressive regimens are used in order to see whether the levels of immunosuppression and rejection affect this process. It is known that lung transplantation between these strains results in a variable degree of acute rejection, but unlike in
humans, no convincing OB can usually be detected. Thus we expect that extensive epithelial cell migration occurs in our rat lung transplant model, and this could explain the scarce chronic rejection related damages in this model.

Further studies could illuminate the factors contributing to recipient epithelial cell migration, its clinical significance and the chances of artificially replacing epithelial cells.