Immunological ignorance occurs if an antigen remains outside secondary lymphoid tissues, the site where? mature antigen presenting cells (ARC) activate naive T and B lymphocytes. Although ignorance is an? important mechanism by which autoreactive T cells avoid self-antigens, ignorance of transplanted organs is? seldom observed. Even allografts that are allowed to recover from the surgical procedure continue to? present antigen in the draining lymphoid tissue and undergo either acute or chronic rejection when? immunosuppression is withdrawn or upon the transfer of exogenous naive or effector/memory T cells. This? suggests that transplantation poses a barrier to immunologic ignorance even after long periods of stable? allograft function. Exploring these barriers could provide new strategies that facilitate allograft acceptance? and prevent chronic rejection. Therefore, we propose in this component of the PPG to investigate why the? immune system does not ignore a 'healed' allograft.
The specific aims will focus on two hypotheses that? integrate with Projects 1 and 2 of the PPG, respectively: (1) Innate immune activation persists in a """"""""healed""""""""? allograft leading to APC maturation, naive T cell activation, and enhanced entry of effector/memory T cells? into the graft; and (2) lymphodepletion that often accompanies tolerance-inducing regimens is responsible for? continuous recognition of the graft by naive T cells that undergo lymphopenia-induced proliferation (LIP) and? transform into memory-like lymphocytes.
In specific aim 1, we will investigate what perpetuates the innate? immune response to a 'healed' allograft, with emphasis on innate lymphocytes (NK and iNKT cells),? neutrophils, the complement system, and direct activation of APCs via TLR-signaling pathways. In specific? aim 2, we will investigate the mechanisms responsible for regulating lymphophenia-induced proliferation of? naTve T cells, with emphasis on CTLA-4 and TGFb. Understanding these mechanisms would allow us to? develop ignorance-based strategies that facilitate allograft acceptance and prevent chronic rejection. This? Project is critically dependent on the Histopathology Core for processing and analysis of cardiac? allograft samples, quantitating allograft vasculopathy, and phenotyping dendritic cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI064343-02
Application #
7485137
Study Section
Allergy & Clinical Immunology-1 (AITC)
Project Start
Project End
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$396,667
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Oberbarnscheidt, Martin H; Zeng, Qiang; Li, Qi et al. (2014) Non-self recognition by monocytes initiates allograft rejection. J Clin Invest 124:3579-89
Walch, Jeffrey M; Zeng, Qiang; Li, Qi et al. (2013) Cognate antigen directs CD8+ T cell migration to vascularized transplants. J Clin Invest 123:2663-71
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Isse, Kumiko; Lesniak, Andrew; Grama, Kedar et al. (2013) Preexisting epithelial diversity in normal human livers: a tissue-tethered cytometric analysis in portal/periportal epithelial cells. Hepatology 57:1632-43
Isse, K; Lesniak, A; Grama, K et al. (2012) Digital transplantation pathology: combining whole slide imaging, multiplex staining and automated image analysis. Am J Transplant 12:27-37
Zecher, Daniel; Li, Qi; Williams, Amanda L et al. (2012) Innate immunity alone is not sufficient for chronic rejection but predisposes healed allografts to T cell-mediated pathology. Transpl Immunol 26:113-8
Li, Hongmei; Demetris, Anthony J; McNiff, Jennifer et al. (2012) Profound depletion of host conventional dendritic cells, plasmacytoid dendritic cells, and B cells does not prevent graft-versus-host disease induction. J Immunol 188:3804-11

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