The innate immune system is responsible for the early non-self recognition events that lead to adaptive immunity. Although the mechanisms by which the innate immune system recognizes microbial non-self have been well defined, it is not known how the innate immune system senses allogeneic non-self. We have discovered that monocytes mount a specific response to allogeneic non-self independent of T, B, and NK cels. This response leads to persistent monocyte differentiation to mature dendritic cells (DC) after transplantation and is responsible for indirect alloantigen presentation. In this grant application we propose to define (1) the role of innate allorecognition by monocytes in acute and chronic rejection, and (2) the mechanisms by which monocytes sense allogeneic non-self. To accomplish these aims we will utilize transgenic and gene-knockout mice in which specific cell types and molecular pathways can be tracked or deleted. Genetic tools to identify mechanisms of innate allorecognition will also be employed. The proposed studies are innovative and significant because they represent a shift in our thinking about the innate immune response to transplanted organs and could yield novel targets for interrupting innate immune activation in a specific and safe manner.

Public Health Relevance

Despite significant improvement in short-term survival of organ transplants, attrition of transplanted organs over time remains a significant clinical problem. Identifying the mechanisms by which the immune system recognizes transplanted organs as foreign and continues to reject them could lead to novel therapies that enhance long-term graft and patient survival after transplantation. !

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI099465-03
Application #
8704104
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Rice, Jeffrey S
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Oberbarnscheidt, Martin H; Lakkis, Fadi G (2014) Innate allorecognition. Immunol Rev 258:145-9
Oberbarnscheidt, Martin H; Zeng, Qiang; Li, Qi et al. (2014) Non-self recognition by monocytes initiates allograft rejection. J Clin Invest 124:3579-89