PrOJeCt 3 Regulation of immune responses is critical in health and disease. Nowhere is this clearer than following allogeneic hematopoietic cell transplantation (HCT) where induction of effective immune responses eliminates residual disease in the graft vs tumor (GVT) effect, whereas an aberrant immune reaction towards the host can result in life threatening graft vs host disease (GVHD). We and others have found that CD4+CD25+FoxP3+ regulatory T cells (Treg) are capable of controlling GVHD yet allow for GVT effects and promote more effective immune reconstitution. In this proposal we will build upon extensive progress in the initial funding period to study critical biological characteristics of the mechanisms by which Treg control GVHD reactions. We have developed novel imaging technology utilizing bioluminescence (BLl) that allows us to serially and non-invasively study the trafficking and survival of distinct cell populations including Treg. Our hypothesis is that Treg traffic to critical nodal sites where they interact with antigen presenting cells (APCs) and through this interaction down modulate the proliferation of effector CD4+ and CD8+ alloreactive T cells. In this proposal we will study the role of the interaction between Treg and CD11C+ APCs by selectively depleting this latter population from recipient animals. We will evaluate the role of critical molecules expressed by Treg in this process and explore the importance of interaction with APCs and expression of cell surface receptors and enzymes in immune regulation mediated by Treg. Using BLl and novel transgenic mouse lines developed in our laboratories we will explore mechanisms utilized by Treg including trafficking to critical sites, proliferation and control of alloreactive T cell expansion. We will also utilize data generated in the initial term of this grant to explore novel approaches to expanding Treg both in vitro and in vivo. In particular we have demonstrated the Treg utilize different signaling pathways upon activation than conventional CD4+ T cells and we will explore approaches to the expansion of Treg both in living animals and in cultures. We expect that these studies will significantly increase our basic understanding of the biology and mechanisms of Treg in the settings of HCT and organ transplantation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Stanford University
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Müller, Antonia M S; Poyser, Jessica; Küpper, Natascha J et al. (2014) Donor hematopoiesis in mice following total lymphoid irradiation requires host T-regulatory cells for durable engraftment. Blood 123:2882-92
Alonso, Michael N; Gregorio, Josh G; Davidson, Matthew G et al. (2014) Depletion of inflammatory dendritic cells with anti-CD209 conjugated to saporin toxin. Immunol Res 58:374-7
Strober, Samuel (2014) Path to clinical transplantation tolerance and prevention of graft-versus-host disease. Immunol Res 58:240-8
Medeiros, B C; Tian, L; Robenson, S et al. (2014) European LeukemiaNet classification intermediate risk-1 cohort is associated with poor outcomes in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Blood Cancer J 4:e216
Sega, Emanuela I; Leveson-Gower, Dennis B; Florek, Mareike et al. (2014) Role of lymphocyte activation gene-3 (Lag-3) in conventional and regulatory T cell function in allogeneic transplantation. PLoS One 9:e86551
Hongo, D; Tang, X; Baker, J et al. (2014) Requirement for interactions of natural killer T cells and myeloid-derived suppressor cells for transplantation tolerance. Am J Transplant 14:2467-77
Schneidawind, Dominik; Pierini, Antonio; Negrin, Robert S (2013) Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. Blood 122:3116-21
Colonna, Lucrezia; Florek, Mareike; Leveson-Gower, Dennis B et al. (2013) IL-17 gene ablation does not impact Treg-mediated suppression of graft-versus-host disease after bone marrow transplantation. Biol Blood Marrow Transplant 19:1557-65
Davidson, Matthew G; Alonso, Michael N; Kenkel, Justin A et al. (2013) In vivo T cell activation induces the formation of CD209(+) PDL-2(+) dendritic cells. PLoS One 8:e76258
Kohrt, Holbrook E; Tian, Lu; Li, Li et al. (2013) Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation. Clin Immunol 148:124-35

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