Despite advances in surgical techniques and peri-operative care overall survival rates after lung transplantation remain disappointing, lagging significantly behind long-term success rates achieved for other solid organ transplants. This may be in large part related to unique immunologic factors associated with the pulmonary alloimmune response leading to higher rates of graft rejection. The overriding hypothesis for this Program Project is that higher success rates after pulmonary transplantation can be achieved if proper treatment strategies are developed, which are tailored to specifically address the unique immunological characteristics of lungs. Project 1 will examine the role of intragraft lymphoid neogenesis in inducing and maintaining lung transplant tolerance. This project is based on published data demonstrating that tolerant lung allografts harbor organized lymphoid structures that are rich in regulatory cell populations. This sets the lung apart from other organ and tissue grafts where lymphoid neogenesis has been associated with poor outcomes. This project will be led by Dr. Kreisel. Project 2 will build upon recently published data that, unlike the case for othr organs, memory CD8+ T cells play a critical role in inducing tolerance after lung transplantation. Project 2 will be directed by Dr. Krupnick. Project 3 will be led by Dr. Gelman. This project will focus on the unique and dichotomous role of neutrophils in regulating lung transplant tolerance. This project will build upon novel observations on how neutrophils regulate adaptive immune responses that control lung transplant tolerance. All three projects will utilize mouse models of lung transplantation and intravital imaging of lung grafts. These procedures will be coordinated by a Microsurgery Core, which will be directed by Dr. Li, an experienced and pioneering microsurgeon. An Administrative Core, which will be directed by Dr. Gelman, will provide the framework for the communication between project leaders and the microsurgical core leader as well as provide fiscal oversight and organize scientific guidance to optimize program project scientific productivity. Taken together, this Program Project will provide novel and fundamental information with regard to requirements to induce and maintain tolerance after pulmonary transplantation, laying the foundation for new and much needed therapeutic strategies for lung transplant patients.
This program project proposes to conduct mechanistic investigations that elucidate cellular and molecular cues that regulate lung transplant tolerance. It is composed of three synergistic projects, a microsurgery core and an administrative core. Insights gained from this program project will lay the foundation for the development of new therapies that will improve outcomes after lung transplantation. Project-001: The Role of Lymphoid Neogenesis in Lung Transplant Tolerance Project Leader: Daniel Kreisel DESCRIPTION (as provided by applicant): Lung transplantation remains the only available treatment for many patients, who suffer from pulmonary failure. However, outcomes after lung transplantation continue to lag behind those after transplantation of other organs. Current immunosuppressive strategies for lung transplant patients are based on protocols that have been successfully used for recipients of other organs. However, such approaches do not take into account that immune responses to lung grafts differ from other commonly transplanted organs. Utilizing new mouse models of lung transplantation we have uncovered that tolerance to pulmonary grafts is regulated locally through interactions of immune cells within lymphoid aggregates that are newly formed in the graft. This application proposes to study mechanisms how tolerance is regulated after pulmonary transplantation and will allow for the development of new therapeutic strategies for lung transplant patients. PROJECT NARRATIVE: Lung transplantation is the only available therapy for numerous patients who suffer from end stage pulmonary disease. Outcomes after lung transplantation are markedly worse compared to transplantation of other organs. Identifying pathways that regulate alloimmune responses after lung transplantation is of critical importance. Our work has identified unique immune responses that set lung transplants apart from other organs. This application will utilize mouse models of lung transplantation to examine how local immune pathways that are established within newly formed lymphoid aggregates in tolerant lungs protect grafts from immunological destruction by the recipient. The proposed experiments will yield novel information that could lead to new therapies to improve outcomes after lung transplantation.
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