Exploring central tolerance in lung transplantation

The survival rate after single lung transplantation has improved over time but is still the lowest of all solid organ transplants. One of the main contributors is the development of chronic rejection, diagnosed as chronic lung allograft dysfunction (CLAD). CLAD is defined as declined forced expiratory volume in 1 second (FEV1), compared to the average of the two best post-operative FEV1’s, for at least 3 weeks. Unfortunately, at the time of diagnosis is the loss of function and tissue damage most often already irreversible. Also, the underlying mechanisms during the onset and progression of rejection are still unknown. Life-long immunosuppression is used to prevent and treat chronic rejection. However, this medication has many adverse effects including an increased risk to develop infections, cancer, etc. A murine orthotopic left lung transplantation model is used to mimic the human situation. The immune system of the recipient recognizes the allograft as foreign and tries to attack it. So, we hypothesize that altering the immune system of the recipient, it no longer recognizes the graft as foreign, and could stop or decrease the rejection. In this project we want to investigate if inducing central tolerance in this murine model is possible through removing the recipients bone marrow, thymus, and local lymph nodes followed by transplanting the donors’ thymus and bone marrow. So, we can investigate if this indeed affects the onset/progression of rejection (microCT imaging, histology, etc.). Our second aim is to explore the effect of chimerism on rejection. Chimerism would be achieved by transplanting the thymus and bone marrow of the donor, without removing the bone marrow and thymus of the recipient. We hypothesize that when both the immune system of donor and recipient are present, this could also decrease rejection.