2006 — 2010 |
Kreisel, Daniel |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Vascular Endothelium Directs the Development of Regulatory T Cells
[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Candidate Goals and Career Development Plan: The candidate is a cardiothoracic surgeon with the long term goal of becoming an independent investigator in an academic medical center. The candidate has learned skills in basic immunological research with a special focus on transplantation immunology. This award will provide support needed to develop the foundation of knowledge and skills required for successful long-term investigation. This foundation will be built over the proposed five years of the award by (1) understanding how vascular endothelial cells induce allogeneic regulatory CD4+ T cells, (2) understanding how activation of innate immune responses influences this process, (3) acquiring detailed knowledge about immune regulation and innate immunity and (4) gathering data for the development of an independent project in developing strategies to induce immunological tolerance to solid organ grafts with a particular focus on lung transplantation. Environment: The environment at Washington University in St. Louis is rich in the availability of expertise in immunology in general. The candidate's sponsor is a nationally and internationally recognized independent investigator with expertise in innate immunity and antigen presentation. The applicant's co-sponsor is a world-renowned lung transplant surgeon, who is also well recognized as an independent investigator in ischemia-reperfusion injury of lung allografts. The candidate has a well-equipped laboratory and a full-time research technician whose salary is supported by the Department. Research Proposal: The primary aim of this grant proposal is to investigate the immunological consequences of interactions between vascular endothelium and allogeneic CD4+ T lymphocytes. Preliminary data indicate that CD4+ T lymphocytes acquire strain-specific regulatory function after co-culture with allogeneic vascular endothelial cells. We plan to identify the mechanism underlying this induction of CD4+ T lymphocytes with regulatory properties. Furthermore, we will examine their generation and their regulatory properties in vivo models that have been well described in our laboratory. Finally, preliminary data suggest that activation of the innate immune system may disrupt the induction of CD4* T cells with regulatory properties by vascular endothelial cells. We plan to study the impact of innate immune system activation on this process. (End of Abstract) [unreadable] [unreadable] [unreadable]
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2009 — 2021 |
Gelman, Andrew Eric (co-PI) [⬀] Kreisel, Daniel |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Ischemia Reperfusion Injury in Lung Allograft Rejection
? DESCRIPTION (provided by applicant): Outcomes after lung transplantation remain markedly worse compared to other grafts. Ischemia-reperfusion injury is a neutrophilic form of inflammation that inhibits both short and long-term survival of lung transplant recipients. These observations have led our group to focus on molecular signals that promote neutrophil trafficking into lung grafts following transplantation. In our previous funding period we developed methods to employ intravital 2-photon microscopy to analyze real-time neutrophil trafficking dynamics within ventilated mouse orthotopic lung grafts. This technical innovation allowed us to reveal the critical role that monocytes play in the neutrophil transendothelial migration into reperfused lung grafts and to uncover interactions between neutrophils and other lung graft cells that promote alloimmunity. In this application we propose to examine innate immune signaling pathways that regulate neutrophil trafficking behavior within lung grafts to better understand how these cells prevent tolerance. To this end in Aim 1 we will analyze the role of recipients monocytes and donor Dap12, an adaptor molecule that controls innate immune signaling, in lung graft injury through regulating neutrophil recruitment. We will specifically determine if Dap12 regulates neutrophil transendothelial trafficking and tolerance through controlling the production of cytokines and chemokines in macrophages. In Aim 2 we propose to define the role of necrotaxis in lung transplants, a specialized form of neutrophil chemotaxis towards dying cells. To execute this aim we will analyze the role of FPR1, a chemokine receptor recently shown to control necrotaxis, to determine if this specific type of neutrophil migratory behavior controls transepithelial trafficking and in turn promotes inflammatory signals that regulate CD4+ T cell polarization and lung transplant rejection.
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2012 — 2015 |
Kreisel, Daniel Krupnick, Alexander S (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Lung Allograft Acceptance
DESCRIPTION (provided by applicant): It is well established that various organ allografts differ in their immunogenicity and susceptibility to immunosuppression-mediated acceptance. Lungs are among the most immunogenic organs with particularly high rates of graft rejection leading to poor long-term outcomes. Immunologic requirements for lung allograft rejection and acceptance remain poorly understood. Our laboratory has made the surprising observation that, in stark contrast to other organs, the presence of CD8+ (specifically CD8+PD-1+) rather than CD4+ T cells, is critical for co-stimulatory blockade-mediated acceptance of lung allografts. The overall goal of this application is to perform mechanistic studies in the mouse vascularized orthotopic lung transplantation model to investigate the role of CD8+ T cells in down-regulating alloimmune responses deleterious to graft survival. In the first aim we will define mechanisms of regulatory CD8+ T cell generation. In the second aim we will investigate the role of antigen presenting cells in CD8+ T cell-mediated lung allograft acceptance. In the third aim we will characterize how clinically relevant innate immune stimulation through Toll-like receptor 2 (TLR2) prevents CD8+ T cell-mediated lung allograft acceptance.
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2015 — 2019 |
Kreisel, Daniel |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Pathways Regulating Lung Transplant Tolerance
? DESCRIPTION (provided by applicant): 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.
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2015 — 2019 |
Kreisel, Daniel |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
The Role of Lymphoid Neogenesis in Lung Transplant Tolerance
PROJECT SUMMARY 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.
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2020 — 2021 |
Kreisel, Daniel |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Pathways Regulating Lung Transplant Tolerance.
PROJECT SUMMARY/ABSTRACT Lung transplantation remains the only available treatment for many patients, who suffer from end- stage pulmonary disease. Outcomes after lung transplantation, however, continue to be far worse compared to those after transplantation of other organs. Current immunosuppression for lung transplant patients are based on protocols that have been developed for patients receiving other organs. However, such approaches do not take unique immunological features of lungs into consideration that differ substantially from other commonly transplanted organs. Utilizing new clinically relevant mouse models of lung transplantation we have uncovered that induction and maintenance of tolerance to pulmonary grafts is regulated locally through interactions of immune cells within the graft. Tolerant lung grafts develop tertiary lymphoid organs that are enriched in immunoregulatory cell populations that maintain a quiescent state. This proposal explores mechanisms how tolerance is regulated after pulmonary transplantation. We examine pathways that result in graft failure when the tolerant state is disrupted. Insights gained from this application will allow for the development of new therapeutic strategies for lung transplant patients.
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2020 — 2021 |
Kreisel, Daniel Lavine, Kory J. (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Donor Innate Immune Responses in Regulating Alloimmunity After Heart Transplantation
PROJECT SUMMARY/ABSTRACT The success of heart transplantation is limited by ischemia reperfusion injury-mediated primary graft dysfunction and allograft rejection, two processes that may be immunologically linked. Current strategies to reduce graft rejection and improve survival are mostly based on ablation of recipient immune cell populations. These approaches are only modestly effective and carry high risks of life-threatening infections. An alternative and potentially safer approach is to target immune pathways and cell populations within the donor graft that initiate inflammatory responses and resultant alloreactivity. The ability to precisely control the initial immune response following heart transplantation represents a promising approach to increase allograft tolerance and improve clinical outcomes. Our recent work has identified that ferroptosis, a non-apoptotic form of inflammatory cell death mediates the early inflammatory response after reperfusion of heart grafts. We have discovered that graft endothelial cells and tissue-resident CCR2+ macrophages play important and complementary roles in promoting the recruitment of inflammatory immune cells to the transplanted heart. In this proposal, we will use state-of-the- art techniques, including intravital microscopy, single cell RNA sequencing and novel mouse strains to perform studies that will 1) define mechanisms of cell death (Aim1), 2) evaluate the role of cell-specific inflammatory cytokine signaling (Aim 2) and 3) examine the role of cardiac macrophage heterogeneity (Aim 3) in driving innate inflammatory and alloimmune responses after heart transplantation. Our studies will lay the foundation for novel therapy that will improve outcomes after cardiac transplantation.
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2020 — 2021 |
Kreisel, Daniel |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
The Role of Lymphoid Neogenesis in the Maintece of Lung Transplant Tolerance
PROJECT SUMMARY / ABSTRACT Pulmonary transplantation remains the only available treatment for numerous patients, who suffer from end-stage lung disease. However, outcomes after lung transplantation continue to be substantially worse than 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 account for fundamental differences between immune responses to lung grafts and other commonly transplanted solid 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. We have reported that disruption of immunoregulatory circuits in tolerant grafts results in the local activation of graft-infiltrating lymphocytes, which triggers rejection. This application proposes to study mechanisms how tolerance is maintained at the level of the graft microenvironment after pulmonary transplantation and will allow for the development of new therapies for lung transplant recipients.
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