The long-term goal of this project is to use mouse models of transplantation to address focused and mechanistic questions about requirements for, and barriers to, tolerance, and to use this knowledge to develop new approaches to induce reproducible and durable graft acceptance. In this renewal application, we are continuing to focus on novel mechanisms of resistance to transplantation tolerance. We are particularly interested in two pathways, CD28 and the IL-17/T17 pathway, each of which have critical roles in alloreactivity and in ultimately dictating the phenotype of the alloimmune response, and thus the fate of the allograft. Using both wild-type and T cell receptor transgenic mice in combination with fluorochrome-reporter and gene-targeted mice, we will study how manipulations of these pathways influence the generation and homeostatic maintenance of effector/memory and regulatory T cells. These experiments particularly will address our central concept, which is that our understanding of how to manipulate the CD28 and T17 pathways to minimize effector responses, and optimize regulation, is incomplete. Thus, our goal is to better understand these pathways in order to develop novel approaches to more effectively target them and induce tolerance. To accomplish these goals we propose three aims:
In Specific Aim #1, we will test the hypothesis that blockade of CD28 costimulation has differential effects on allograft responses depending upon whether the effector arm or the regulatory arm predominates. Using combinations of physiologic MHC mismatched models, foxp3 reporter mice, and TCR transgenic mice which allow for cell fate tracking, we will test differential requirements for CD28 signals in effector and regulatory-dependent responses.
In Specific Aim #2, we will use conditional targeting of CD28 to study its role in effector and regulatory T cells. We have just completed the "construction" of CD28-floxed mice, which have now gone germline. Through the use these CD28-floxed mice we will delete CD28 in all T cells, Tregs (using foxp3-Cre mice) under temporal control with tamoxifen (using CreT2 mice). We will specifically test hypotheses regarding the roles of CD28 in Tregs, and at different time points in the allograft response. Lastly, in Specific Aim #3, we will study two aspects of T17 biology relevant to transplantation. First, we will test the hypothesis that T17 cells participate in allograft rejection by promoting Tc and Th1 responses, and second, we will investigate the role of CD28 (using CD28-conditional mice) and the novel Tim-1 pathway (using blocking Abs) in promoting T17 responses. Together these studies should provide important new insights into mechanisms of, and strategies for, tolerance.

Public Health Relevance

Transplantation is often the treatment of choice for organ failure. A significant barrier to its use is the fact that patients need to take powerful drugs to suppress their immune systems in order to prevent rejection of the transplanted organ. These drugs in turn cause significant complications including infection, cancer and heart disease. Cells know as T lymphocytes are the critical component of the immune system responsible for transplant rejection. This proposal will focus on particular pathways used by T cells in the response to transplanted organs in efforts to develop new approaches to prevent rejection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI037691-19
Application #
8695640
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2013-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
19
Fiscal Year
2013
Total Cost
$396,267
Indirect Cost
$143,556
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Yeung, Melissa Y; McGrath, Martina M; Nakayama, Masafumi et al. (2013) Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival. J Immunol 191:4447-55
Zhang, Ruan; Huynh, Alexandria; Whitcher, Gregory et al. (2013) An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest 123:580-93
Zhao, X; Boenisch, O; Yeung, M et al. (2012) Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance. Am J Transplant 12:90-101
Shariff, Hina; Tanriver, Yakup; Brown, Kathryn L et al. (2010) Intermittent antibody-based combination therapy removes alloantibodies and achieves indefinite heart transplant survival in presensitized recipients. Transplantation 90:270-8
D'Addio, Francesca; Yuan, Xueli; Habicht, Antje et al. (2010) A novel clinically relevant approach to tip the balance toward regulation in stringent transplant model. Transplantation 90:260-9
Yuan, Xueli; Ansari, M Javeed; D'Addio, Francesca et al. (2009) Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells. Proc Natl Acad Sci U S A 106:10734-9
Yang, J; Riella, L V; Boenisch, O et al. (2009) Paradoxical functions of B7: CD28 costimulation in a MHC class II-mismatched cardiac transplant model. Am J Transplant 9:2837-44
Turka, Laurence A; Lechler, Robert I (2009) Towards the identification of biomarkers of transplantation tolerance. Nat Rev Immunol 9:521-6
Yuan, Xueli; Paez-Cortez, Jesus; Schmitt-Knosalla, Isabela et al. (2008) A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med 205:3133-44

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