Here's why the body may reject lung transplants

A study led by researchers at Washington University School of Medicine in St. Louis, has identified, in mice, a process that may prevent antibody-mediated rejection in lung transplants and lead to the development of therapies to treat this form of rejection.

The risk of organ failure and death following a lung transplant is high, particularly compared with the outcomes of transplant patients who receive new hearts, kidneys or livers.

This often happens due to lung rejection, which occurs when cells in the patient's immune system perceive the donor as a foreign threat.

One particularly deadly form of rejection -- called antibody-mediated rejection -- remains difficult to diagnose after a lung transplant and is mostly unreceptive to available treatments.

 

This process has been observed in more than 10 per cent of lung transplant recipients and occurs when a type of white blood cell, called B cells, from the recipient produces antibodies against the donor lung.

The study is published February 1 in The Journal of Clinical Investigation.

Speaking about the study, senior author Daniel Kreisel said, "Antibody-mediated rejection is a vexing problem that is increasingly being acknowledged as an important cause of lung failure after transplantation."

Kreisel added, "Unfortunately, this complication can be fast-moving and hard to detect before it's too late. Even when we do recognise it, current treatments have had limited success. Lung transplant centers -- not just ours, but across the world -- are losing too many patients to the condition."

According to the 2018 International Society of Heart and Lung Transplantation Registry Report, more than 4,200 lung transplants were performed in 2016.

Five years after lung transplantation, about half of the transplanted lungs are still functioning, according to the US Organ Procurement and Transplantation Network. However, this compares with five-year organ survival rates of about 70 to 80 per cent for liver, heart and kidney transplants.

The study's first author, WenJun Li, developed a method for re-transplanting pea-sized mouse lungs. A re-transplant procedure involves the placement of a previously transplanted lung into a new host in order to assess immune networks that are established in the transplanted lung.

Speaking about it, Li said, "This mouse lung re-transplant model is extremely delicate and technically challenging."

Using genetic tools, Li manipulated interactions involving immune cells within re-transplanted lung grafts.

The researchers found that giving mice immunosuppressive drugs at the time of transplant helped the lungs to survive and induced the growth of lymph node-like structures within the lung grafts.

They discovered that these newly induced structures contained Foxp3-expressing T cells, a cell population that can dampen immune responses. The researchers noted that antibody-mediated rejection after lung transplantation occurs when B cells mingle with T cells in the donor lung. This co-mingling between B and T cells is prevented by Foxp3-expressing T cells. This suggests a treatment may be developed that interrupts the interaction so the two cell types cannot find each other.

"We thought these Foxp3 T-cells would inhibit activation of T cells after lung transplantation and prevent cellular rejection," said Kreisel, who is also the G. Alexander Patterson, MD/Mid-America Transplant Endowed Distinguished Chair in Lung Transplantation. "Instead, we were surprised to find that it was the antibody-producing B cells that sparked lung rejection when Foxp3 T cells were absent."

Kreisel added, "Future research needs to show whether these findings will translate into human lung transplant recipients, and possibly to other organ transplant patients who develop antibody-mediated rejection.