The Transplantation Immunology Program is dedicated to a greater understanding of the basic biology of transplantation of the lung allograft. This multidisciplinary program incorporates surgical, immunologic, and medical expertise in the care and research of patients with end-stage lung disease who undergo lung transplantation. Our program also takes great pride in hypothesis testing through novel laboratory study of human samples, and randomized, placebo-controlled clinical trials.
Dr. Steven Duncan has pioneered techniques in inducing immunologic tolerance using a novel methodology of intravenous infusion of donor-derived thymic medullary dendritic cells. He has also identified populations of T cells involved in allograft rejection. He demonstrated that oligoclonal T cell expansions were associated with rejection. He has described a unique T lymphocyte population, CD4+CD28null T-cells, which demonstrate potentially pathogenic functions and are a marker for allograft dysfunction.
He has also developed a humanized murine model of bronchiolitis obliterans, further expanding our capabilities for testing treatments and ultimately finding a cure for chronic lung rejection.
Dr. Bruce Johnson has been a leader in clinical therapeutic studies in drugs to prevent rejection. He helped develop the first inhaled anti-rejection medication, inhaled cyclosporine, a drug taken from the bench to the bedside at the University of Pittsburgh (See The Cyclosporine Story), and is co-principal investigator on the current Phase III Multicenter randomized control trial entitled “A Multi-Center, Randomized, Controlled Study to Demonstrate the Efficacy and Safety of Cyclosporine Inhalation Solution (CIS) in Improving Bronchiolitis Obliterans Syndrome-Free Survival Following Lung Transplantation.” Dr. Johnson also performed a phase IV trial examining mycophenolic sodium (Myfortic) versus mycophenolate mofetil (Cellcept), and found that Myfortic was associated with a decreased incidence of nausea and upper GI distress. Dr. Johnson started his transplant clinical research career assisting Dr. Duncan in the first prospective, randomized controlled drug treatment trial ever in the history of lung transplantation. Finally, Drs. Johnson and Duncan were the first to report recurrence of a pre-transplant disease in lung allografts and the first to report an association between statin use and improved survival in lung transplant recipients.
Dr. Timothy Corcoran's research focuses on the effective delivery of inhaled medications for the treatment of a variety of lung diseases. This includes a longstanding commitment to the development of inhaled immunosuppressants and anti-infective medications for lung transplant recipients. He has performed a series of studies using radiolabels to study the deposition of inhaled cyclosporine in lung transplant recipients. Dr. Corcoran has also been involved in the development of new technologies to improve the performance of inhaled medications for cystic fibrosis patients. He has developed new nuclear-medicine based imaging techniques for determining the efficacy of medications for the treatment of cystic fibrosis. He has also helped to develop new inhaled medications for use by the United States Army.
Dr. Maria Crespo’s work focuses on the application of interventional bronchoscopy to improve outcomes post transplantation. Dr. Crespo pioneered the use of endobronchial valves in reducing native lung hyperinflation in a single lung transplant recipient, and now utilizes endobronchial ultrasound and super Dimenson bronchoscopy in the management of lung transplant patients. Dr. Crespo participates in multiple multicenter collaborative studies. Her current research focuses on primary graft dysfunction, and as a co-investigator in the multicenter Lung Transplant Outcomes Group (Jason Christie, PI) she has contributed more subjects and specimens to the study than all other centers combined. In addition, she is the site director recruiting for the Alnylam Phase 2b study of ALN-RSV01 in lung transplant patients infected with respiratory syncytial virus (RSV). She is also interested in studying clinical outcomes post lung transplantation.
Dr. Cynthia Gries focuses on developing statistical modeling to predict short term and long term outcomes post transplant. She performed one of the first studies looking at the impact of the lung allocation score on disease severity and survival, and subsequently has been working on modeling in post-transplant survival. She also examines the impact of health literacy, depression and Post Traumatic Stress Disorder (PTSD) on quality of life in patients and care-givers as well as post-transplant survival.
Dr. Joseph Pilewski’s research centers of Cystic Fibrosis and other suppurative lung diseases, both pre- and post-transplant. He works towards improving post-transplant outcomes particularly in this patient population, including in patients who are colonized with drug resistant organisms. He also serves as principal investigator of a lung tissue bank that makes explanted lung samples available to investigators studying Cystic Fibrosis and other end stage lung diseases. Lastly, he is collaborating with Dr. Andrej Petrov on studies of hypogammaglobulinemia in lung transplant recipients.
Dr. Matthew Morrell's research has been focused mainly on clinical outcomes in lung transplant recipients. He recently published the largest case series to date of lung transplant patients treated with extracorporeal photopheresis for bronchiolitis obliterans. His interests also include clinical outcomes related to the production of donor specific antibodies after lung transplantation, including antibody mediated rejection. He also is involved in a prospective trial evaluating the efficacy of nitrite in preventing the development of primary graft dysfunction in lung transplantation.
The Inhaled Cyclosporine Story
The University of Pittsburgh takes pride in its bench-to-bedside development of inhaled cyclosporine in the prevention of chronic rejection. This idea originated with Dr. Bartley Griffith, previous director of heart and lung transplantation who performed the first lung transplant at UPMC. While preclinical work was done in his lab at the University of Pittsburgh in a rat model, ultimately this drug was carried forth in collaboration with Dr. Aldo Iocono, Bruce Johnson, James Dauber, Tim Corcoran, Steve Duncan, Ken McCurry, and others. These investigators have hypothesized that higher concentrations of the drug will enter the transplanted lung by aerosol inhalation than could be achieved by the more traditional oral route, thereby facilitating better control of rejection while minimizing drug toxicity.
Deposition of a radiolabeled aerosol medication in a double lung transplant recipient
Early data from a randomized, placebo-controlled trial at the University of Pittsburgh showed that inhaled cyclosporine improved chronic rejection free survival five years after lung transplant from 50% to 89%. The trial (Iacono AT et al, NEJM 2006) was and remains the only one that has ever improved survival after lung transplantation. The investigators are currently completing a multicenter Phase III randomized clinical trial, with 278 subjects enrolled from 20 transplant centers in North America. Late phase trials are underway using aerosol cyclosporine as rescue to treat patients with refractory acute rejection that failed to respond to all forms of conventional immunosuppression.
At the University of Pittsburgh, we hope to lead the transplant community in developing and practicing evidence based medicine, and the aerosolized cyclosporine story is an important example of that. With continued leadership and participation in clinical trials, we aim to continue to advance the field of lung transplantation and improve future outcomes.