This proposal is designed to address the issue of innate immune responses to allografts following transplantation, an area that is poorly studied and ill characterized. The focus of this project is on reciprocal interactions between host alloreactive NK cells and donor allogeneic dendritic cells, and the mechanisms and consequence of such interactions on the activation of T effector cells and Tregs in transplant models. This is based on our recent discovery that the innate NK cells play a critical regulatory role in the induction of allograft survival by costimulatory blockade treatment. We found that NK cells appear to control survival and dissemination of graft-derived donor cells in transplant recipients, thereby regulating a critical process in T cell priming, and eventually the fate of an allograft. We have provided convincing preliminary data showing that both NK cells and DCs are extremely heterogeneous. In addition, they are also highly responsive to cytokines and inflammatory stimulations, and therefore, the reciprocal interactions between host alloreactive NK cells and donor allogeneic DCs are likely to be complex, and the impact of such interactions on the nature of the allograft response (rejection vs. tolerance) is likely to be significant. The hypothesis proposed in this proposal is that NK cells play a critical role in the induction of an effector type (rejection) or a regulatory type (tolerance) of immune responses by regulating life and death of different donor DC subsets in transplant recipients. The novelty of this project is the examination of new mechanisms of tolerance induction, new roles of alloreactive NK cells in the allograft response, and new subsets of NK cells in transplant models. The implication of this study is that, besides T cells, the alloreactive NK cells should also be therapeutically manipulated for the induction of transplant tolerance. The proposed studies may lead to the development of new therapeutic protocols in tolerance induction in the clinic. These studies may also lead to the rational design of DST protocols or tailored immunosuppressive protocols based on the composition of DCs in a particular graft in tolerance induction in the clinic. We have invested considerable time and efforts in the development of better animal models and cells selection/identification techniques, which makes execution of these studies feasible. We are confident that new advances in our understanding of innate immune responses to allografts will be made after accomplishment of this project.

Public Health Relevance

Transplantation is often the only choice of treatment for end-stage organ failure, but transplant patients must take immunosuppressive drugs for life. The unwanted side effects frequently seen with current immunosuppressive drugs and our inability to control chronic graft loss despite maximal immunosuppression are the compelling reasons for the development of better and more specific tolerance- inducing strategies. Our project is designed to specifically study how innate immune cells react to allotransplants and the impact of such reactivity in graft rejection and tolerance induction. This line of research will open new opportunities for the development of tolerance-induction strategies. Moreover, knowledge gained from those studies will have a broad impact on therapeutic interventions of other conditions including autoimmune disorders, bone marrow transplantation, and cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI080779-02
Application #
8307648
Study Section
Special Emphasis Panel (ZRG1-IMM-J (02))
Program Officer
Nabavi, Nasrin N
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2011-07-15
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$223,571
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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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