The induction of tolerance in transplantation and autoimmunity remains an elusive clinical goal. A more thorough understanding of the fundamental mechanisms of immunologic tolerance is therefore necessary. We propose here a multidisciplinary approach to investigate peripheral mechanisms of immunologic tolerance by studying murine models of solid organ transplantation, bone marrow transplantation, and autoimmunity. A multidisciplinary approach is proposed because the mechanisms responsible for tolerance to self and foreign antigens overlap, and because significant cross-talk among the three clinical disciplines exists: bone marrow transplantation is increasingly employed to induce tolerance to solid organ allografts, and therapeutic agents used in transplantation are applicable to patients with autoimmunity (and vice versa). ? The PPG consists of three integrated projects and a core: histopathology. Integration among the projects is based on commonality of immunologic concepts, ongoing and future collaborations between the investigators, and the sharing of methods and resources. Project 1 will explore the mechanisms of dendritic cell maturation that lead to graft-versus-host disease (GVHD) following bone marrow transplantation. Project 2 will investigate tolerance induction via the generation of regulatory T cells (Treg) in a mouse model of inflammatory bowel disease. Project 3 will explore the phenomenon of immunologic ignorance by studying the innate and adaptive mechanisms that are responsible for continued recognition of a transplanted organ by the host's immune system. The Histopathology Core will provide tissue processing, staining, immunohistochemistry, in situ hybridization, imaging, and interpretation services to all three projects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI064343-03
Application #
7485139
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Kehn, Patricia J
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$1,334,207
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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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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