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 immunosuppression is withdrawn or upon the transfer of exogenous naive or effector/memory T cells.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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Allergy & Clinical Immunology-1 (AITC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
New Haven
United States
Zip Code
Rothstein, David M; Camirand, Geoffrey (2015) New insights into the mechanisms of Treg function. Curr Opin Organ Transplant 20:376-84
Walch, Jeffrey M; Lakkis, Fadi G (2014) T-cell migration to vascularized organ allografts. Curr Opin Organ Transplant 19:28-32
Camirand, Geoffrey; Wang, Ying; Lu, Yuning et al. (2014) CD45 ligation expands Tregs by promoting interactions with DCs. J Clin Invest 124:4603-13
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
Reichenbach, D K; Li, Q; Hoffman, R A et al. (2013) Allograft outcomes in outbred mice. Am J Transplant 13:580-8
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

Showing the most recent 10 out of 23 publications