This project addresses a new and emerging area- allospecificity and memory of innate immune cells with a specific focus on macrophages and how such cells impact transplant outcomes. The recent reports that graft loss under broad immunosuppression therapies or after aggressive T cell depletion is dominated by macrophages, plus the strong evidence that macrophages can discriminate self from allogeneic non-self in selected transplant models, place macrophages right under the limelight of graft damage. We believe that induction of transplant tolerance requires comprehensive strategies that target both the innate and adaptive immune cells, and this approach demands a detailed understanding of how innate immune cells respond to alloantigens. We provide the first evidence that macrophages may use a very different mechanism to discriminate self from allogeneic non-self. We showed that macrophages potently rejected allogeneic non-self in an antigen- specific manner. One outstanding feature of our findings is that this allospecificity is induced, and requires stimulation by alloantigens and CD40 engagement. We generated new data that the ligands for allospecific macrophages are donor MHC class I molecules, and macrophages most likely use the paired Ig-like receptors (PIRs) to respond to allogeneic non-self. In this project the central hypothesis is that macrophages use paired Ig-like receptors (PIR) to sense allogeneic cells, and that rejection of target cells requires further acquisition cytolytic M1 features. We put together 3 Aims ito test this hypothesis.
Aim 1 addresses the allospecificity PIR-A isoforms and signaling apparatus, and its relationships with PIR-B.
Aim 2 examines the molecular pathways leading to the induction of PIR and cytolytic activities in macrophages, investigating whether these two processes are regulated by different mechanisms.
Aim 3 determines whether allospecific macrophages could be redirected by modulating either their allospecificity or cytolytic pathways to favor graft survival in vivo. We have all the tools to study the PIR system, including PIR-A/B deficient mice and FcR gamma deficient mice. These models and tools put us in a unique position in resolving the questions proposed in this application. This line of inquiry will lead to major advance in our understanding of innate immune cells in transplant tolerance.

Public Health Relevance

The potential of organ transplantation as a life saving procedure is limited by drug-associated toxicities and chronic progressive graft loss. Our project is designed to uncover the new cell types and new mechanisms that hinder transplant survival. The studies of new features of innate immune cells will open new therapeutic opportunities in the development of greatly improved therapies for patients with organ transplants as well as treatment of other immune mediated diseases including bone marrow transplantation, autoimmune diseases, and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI080779-07
Application #
9232642
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Nabavi, Nasrin N
Project Start
2011-03-01
Project End
2021-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030
Liu, Yianzhu; Chen, Wenhao; Wu, Chenglin et al. (2017) Macrophage/monocyte-specific deletion of Ras homolog gene family member A (RhoA) downregulates fractalkine receptor and inhibits chronic rejection of mouse cardiac allografts. J Heart Lung Transplant 36:340-354
Lan, Peixiang; Fan, Yihui; Zhao, Yue et al. (2017) TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury. J Clin Invest 127:2222-2234
Xing, Junji; Zhang, Ao; Zhang, Hua et al. (2017) TRIM29 promotes DNA virus infections by inhibiting innate immune response. Nat Commun 8:945
Zhao, Yue; Chen, Song; Lan, Peixiang et al. (2017) Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model. Am J Transplant :
Lakkis, F G; Li, X C (2017) Innate allorecognition by monocytic cells and its role in graft rejection. Am J Transplant :
Xing, Junji; Weng, Leiyun; Yuan, Bin et al. (2016) Identification of a role for TRIM29 in the control of innate immunity in the respiratory tract. Nat Immunol 17:1373-1380
Liu, Yianzhu; Kloc, Malgorzata; Li, Xian C (2016) Macrophages as Effectors of Acute and Chronic Allograft Injury. Curr Transplant Rep 3:303-312
Wu, C; Zhao, Y; Xiao, X et al. (2016) Graft-Infiltrating Macrophages Adopt an M2 Phenotype and Are Inhibited by Purinergic Receptor P2X7 Antagonist in Chronic Rejection. Am J Transplant 16:2563-73
Xiao, Xiang; Shi, Xiaomin; Fan, Yihui et al. (2016) The Costimulatory Receptor OX40 Inhibits Interleukin-17 Expression through Activation of Repressive Chromatin Remodeling Pathways. Immunity 44:1271-83
Xiao, Xiang; Shi, Xiaomin; Fan, Yihui et al. (2015) GITR subverts Foxp3(+) Tregs to boost Th9 immunity through regulation of histone acetylation. Nat Commun 6:8266

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