The success of lung transplantation in patients with end-stage lung disease has been limited by a high incidence of chronic rejection, which has only been partially ameliorated by the use of immunosuppressive drugs. However, in many preclinical studies, we have observed that the induction of transplant tolerance prevents acute and chronic rejection, and eliminates the need for long-term immunosuppression, which in patients often leads to opportunistic infection, toxicity, and malignancy. Our center has demonstrated the ability to induce tolerance in swine receiving fully mismatched lung allografts, when transplanted under ideal laboratory conditions (healthy anesthetized donors with minimal ischemic times). However, when the same lungs are procured from a brain-dead lung donor (which is the common clinical scenario), tolerance is abrogated. We hypothesize that the inflammatory state associated with donor brain death prevents the induction of tolerance in this preclinical model. Our long-term objective is to develop strategies to minimize the negative impact of pro-inflammatory states on the donor graft. In this proposal, we will determine whether 1) the blockade of specific inflammatory pathways or 2) ex vivo treatment of the donor graft prior to implantation will restore tolerogenicity to grafts procured from a brain-dead donor. Specifically, we will use antibodies to block the inflammatory cytokines IL-6 and IL1, and perfuse the donor graft ex vivo with a stabilizing perfusate. Our results will uncover potential strategies to maximize tolerance induction that will be clinically applicable to patients undergoing lung transplantation for end- stage lung disease. The research training program at our center is ideally suited to developing young investigators into independent scientists. This is accomplished through a comprehensive training curriculum including supervised experimental work, didactic instruction, and technical training. Fellows at our center participate in all aspect of research, including experimental planning and design and data analysis and interpretation. Our fellows also have ample opportunities to present to and interact with many world-class faculties in the field of transplant immunology.

Public Health Relevance

The life expectancy of lung transplant recipients is unfortunately limited by high incidences of graft loss, opportunistic infection, and malignancy. The induction of transplant tolerance has been shown experimentally and clinically to eliminate rejection and the deleterious sequelae of long-term immunosuppression, but data from our laboratory have shown that donor brain death yields inflamed grafts which are difficult to tolerize. We are proposing two strategies to ameliorate the deleterious effects of donor brain death in a swine model of lung transplantation, so that techniques successful in the laboratory can be moved into clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL117540-02
Application #
8724980
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Colombini-Hatch, Sandra
Project Start
2013-08-06
Project End
2015-08-05
Budget Start
2014-08-06
Budget End
2015-08-05
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Madariaga, M L L; Spencer, P J; Michel, S G et al. (2016) Effects of Lung Cotransplantation on Cardiac Allograft Tolerance Across a Full Major Histocompatibility Complex Barrier in Miniature Swine. Am J Transplant 16:979-86
Madariaga, Maria Lucia L; Spencer, Philip J; Shanmugarajah, Kumaran et al. (2016) Effect of tolerance versus chronic immunosuppression protocols on the quality of life of kidney transplant recipients. JCI Insight 1:
Madariaga, M L; Michel, S G; La Muraglia 2nd, G M et al. (2015) Kidney-induced cardiac allograft tolerance in miniature swine is dependent on MHC-matching of donor cardiac and renal parenchyma. Am J Transplant 15:1580-90
Madariaga, Maria Lucia L; Kreisel, Daniel; Madsen, Joren C (2015) Organ-specific differences in achieving tolerance. Curr Opin Organ Transplant 20:392-9
La Muraglia 2nd, G M; O'Neil, M J; Madariaga, M L et al. (2015) A novel approach to measuring cell-mediated lympholysis using quantitative flow and imaging cytometry. J Immunol Methods 427:85-93
Madariaga, Maria Lucia L; Shanmugarajah, Kumaran; Michel, Sebastian G et al. (2015) Immunomodulatory Strategies Directed Toward Tolerance of Vascularized Composite Allografts. Transplantation 99:1590-7
Madariaga, Maria Lucia L; Michel, Sebastian G; La Muraglia 2nd, Glenn M et al. (2015) Recipient-matching of Passenger Leukocytes Prolongs Survival of Donor Lung Allografts in Miniature Swine. Transplantation 99:1372-8
Madariaga, Maria Lucia L; Ott, Harald C (2014) Bioengineering kidneys for transplantation. Semin Nephrol 34:384-93
Madariaga, M L; Michel, S G; Tasaki, M et al. (2013) Induction of cardiac allograft tolerance across a full MHC barrier in miniature swine by donor kidney cotransplantation. Am J Transplant 13:2558-66