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 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL083983-04
Application #
7589687
Study Section
Special Emphasis Panel (ZHL1-CSR-O (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$120,960
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Krupnick, Alexander Sasha; Lin, Xue; Li, Wenjun et al. (2014) Central memory CD8+ T lymphocytes mediate lung allograft acceptance. J Clin Invest 124:1130-43
Kreisel, Daniel; Lai, Jiaming; Richardson, Steven B et al. (2011) Polarized alloantigen presentation by airway epithelial cells contributes to direct CD8+ T cell activation in the airway. Am J Respir Cell Mol Biol 44:749-54
Gelman, A E; Okazaki, M; Sugimoto, S et al. (2010) CCR2 regulates monocyte recruitment as well as CD4 T1 allorecognition after lung transplantation. Am J Transplant 10:1189-99
Kreisel, Daniel; Richardson, Steven B; Li, Wenjun et al. (2010) Cutting edge: MHC class II expression by pulmonary nonhematopoietic cells plays a critical role in controlling local inflammatory responses. J Immunol 185:3809-13
Li, Wenjun; Sugimoto, Seiichiro; Lai, Jiaming et al. (2010) Orthotopic vascularized right lung transplantation in the mouse. J Thorac Cardiovasc Surg 139:1637-43
Kreisel, Daniel; Nava, Ruben G; Li, Wenjun et al. (2010) In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc Natl Acad Sci U S A 107:18073-8
Krupnick, Alexander S; Lin, Xue; Li, Wenjun et al. (2009) Orthotopic mouse lung transplantation as experimental methodology to study transplant and tumor biology. Nat Protoc 4:86-93
Okazaki, M; Sugimoto, S; Lai, J et al. (2009) Costimulatory blockade-mediated lung allograft acceptance is abrogated by overexpression of Bcl-2 in the recipient. Transplant Proc 41:385-7
Gelman, Andrew E; Li, Wenjun; Richardson, Steven B et al. (2009) Cutting edge: Acute lung allograft rejection is independent of secondary lymphoid organs. J Immunol 182:3969-73
Gelman, Andrew E; Okazaki, Mikio; Lai, Jiaming et al. (2008) CD4+ T lymphocytes are not necessary for the acute rejection of vascularized mouse lung transplants. J Immunol 180:4754-62

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