Despite significant reduction in acute rejection rates, long-term allograft survival remains stagnant, hovering at around a half-life of 10 years for most transplanted organs. A principal cause of poor long-term graft outcomes is persistent host immune activation leading to chronic rejection. We propose here that persistent immune activation is driven by the innate immune system, specifically by monocytes which recognize allogeneic non-self and acquire memory to it. Monocytes sense non-MHC and MHC polymorphisms on allogeneic tissues and acquire the ability to mount an enhanced recall response specific to donor MHC. This response results in sustained graft infiltration by mature, IL-12+, monocyte-derived DCs that maintain an inflammatory Th1 response and are critical for allograft rejection. The goal of this grant application is to investigate in Aim 1 the molecular and cellular mechanisms of monocyte memory generation and specificity to allogeneic MHC, and to determine in Aim 2 the contribution of monocyte memory to chronic allograft rejection. Completion of the proposed studies is likely to have a significant impact on organ transplantation by uncovering novel innate immune system targets to prevent or treat rejection.

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 innate immune system recognizes transplanted organs as foreign and generates memory to them could lead to novel therapies that enhance long-term graft and patient survival after transplantation. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI099465-08
Application #
9942365
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bridges, Nancy D
Project Start
2012-09-27
Project End
2023-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260
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Zhuang, Quan; Liu, Quan; Divito, Sherrie J et al. (2016) Graft-infiltrating host dendritic cells play a key role in organ transplant rejection. Nat Commun 7:12623
Tieu, Roger; Lakkis, Fadi G; Oberbarnscheidt, Martin H (2016) Getting Down and Dirty: Germ-Exposed Laboratory Mice as a Model of the Adult Human Immune System. Transplantation 100:2490-2491
Alegre, Maria-Luisa; Lakkis, Fadi G; Morelli, Adrian E (2016) Antigen Presentation in Transplantation. Trends Immunol 37:831-843
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Zhuang, Quan; Lakkis, Fadi G (2015) Dendritic cells and innate immunity in kidney transplantation. Kidney Int 87:712-8
Oberbarnscheidt, Martin H; Zeng, Qiang; Li, Qi et al. (2014) Non-self recognition by monocytes initiates allograft rejection. J Clin Invest 124:3579-89
Oberbarnscheidt, Martin H; Lakkis, Fadi G (2014) Innate allorecognition. Immunol Rev 258:145-9