Solid organ and bone marrow transplantation (BMT) represent the last hope for many patients with terminal organ failure, and non-malignant as well as malignant bone marrow disease. Significant barriers to these procedures exist, which limit the clinical applicability. One of the most substantial barriers is the fact that true immunologic tolerance to either a solid organ or bone marrow allograft is not yet achievable in the clinical setting. Patients, therefore, are at constant risk of acute and chronic rejection, and in the case of BMT, of graft-versus-host disease. To treat or prevent these complications, transplant patients require long-term non-specific immunosuppression, which plagues patients with infectious, cardiovascular and malignant sequelae. Thus, strategies to promote the acceptance of allogeneic tissues without the need for chronic immunosuppression will reduce the risk of these life- and graft-threatening complications and expand the application of transplantation. Much work has focused on the role that T cells play in transplantation tolerance, and strategies have been devised to down-regulate T cell activity by inhibiting T cell costimulation. However, these strategies have not yet been clinically successful, which has promted a search for mediators of T cell costimulation blockade-resistant rejection'. It is increasingly recognized that Natural Killer (NK) cells impact transplantation success, and may represent a potent barrier to costimulation blockade-induced tolerance. The mechanisms by which they do this are currently unknown. This research proposal is designed to elucidate the mechanisms underlying NK alloreactivity through the following Specific Aims: 1) To define the molecular mechanisms of NK cell-mediated rejection of allo-BMT in the presence and absence of T cell costimulation blockade. 2) To determine the effect of specific inhibition of NK-mediated adhesion and activation on rejection of allo-BMT during costimulation blockade transplantation. The research proposed is part of a customized 4-year training and career development plan for the PI. The proposal includes active mentoring by experienced scientists, access to diverse resources, and an environment uniquely suited to help the PI develop as an independent clinician-scientist. Relevance: Each year in the US more than 35,000 children and adults receive bone marrow and solid organ transplants, and over 10,000 people die while awaiting a suitable donor. Thus, complications of transplantation represent a major public health issue. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI065822-02
Application #
7189932
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2006-03-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$121,716
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Singh, K; Kozyr, N; Stempora, L et al. (2012) Regulatory T cells exhibit decreased proliferation but enhanced suppression after pulsing with sirolimus. Am J Transplant 12:1441-57
Johnson, Z P; Eady, R D; Ahmad, S F et al. (2012) Immunogenetic Management Software: a new tool for visualization and analysis of complex immunogenetic datasets. Immunogenetics 64:329-36
Kean, L S; Singh, K; Blazar, B R et al. (2012) Nonhuman primate transplant models finally evolve: detailed immunogenetic analysis creates new models and strengthens the old. Am J Transplant 12:812-9
Page, A; Srinivasan, S; Singh, K et al. (2012) CD40 blockade combines with CTLA4Ig and sirolimus to produce mixed chimerism in an MHC-defined rhesus macaque transplant model. Am J Transplant 12:115-25
Ramakrishnan, S K; Page, A; Farris 3rd, A B et al. (2012) Evidence for kidney rejection after combined bone marrow and renal transplantation despite ongoing whole-blood chimerism in rhesus macaques. Am J Transplant 12:1755-64
Larsen, C P; Page, A; Linzie, K H et al. (2010) An MHC-defined primate model reveals significant rejection of bone marrow after mixed chimerism induction despite full MHC matching. Am J Transplant 10:2396-409
Miller, Weston P; Srinivasan, Swetha; Panoskaltsis-Mortari, Angela et al. (2010) GVHD after haploidentical transplantation: a novel, MHC-defined rhesus macaque model identifies CD28- CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression. Blood 116:5403-18
Anderson, A; Martens, C L; Hendrix, R et al. (2008) Expanded nonhuman primate tregs exhibit a unique gene expression signature and potently downregulate alloimmune responses. Am J Transplant 8:2252-64
Hamby, K; Trexler, A; Pearson, T C et al. (2007) NK cells rapidly reject allogeneic bone marrow in the spleen through a perforin- and Ly49D-dependent, but NKG2D-independent mechanism. Am J Transplant 7:1884-96

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