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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL075462-10
Application #
8676860
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
$274,277
Indirect Cost
$102,854
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Pierini, Antonio; Nishikii, Hidekazu; Baker, Jeanette et al. (2017) Foxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis. Nat Commun 8:15068
Hongo, David; Tang, Xiaobin; Zhang, Xiangyue et al. (2017) Tolerogenic interactions between CD8+ dendritic cells and NKT cells prevent rejection of bone marrow and organ grafts. Blood 129:1718-1728
Du, Jing; Paz, Katelyn; Thangavelu, Govindarajan et al. (2017) Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells. Blood 129:3121-3125
Pierini, Antonio; Alvarez, Maite; Negrin, Robert S (2016) NK Cell and CD4+FoxP3+ Regulatory T Cell Based Therapies for Hematopoietic Stem Cell Engraftment. Stem Cells Int 2016:9025835
Nishikii, Hidekazu; Kim, Byung-Su; Yokoyama, Yasuhisa et al. (2016) DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease. Blood 128:2846-2858
Penny, Hweixian Leong; Prestwood, Tyler R; Bhattacharya, Nupur et al. (2016) Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice. Cancer Immunol Res 4:917-926
Strober, Samuel (2016) Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants. Blood 127:1539-43
Erickson, K F; Winkelmayer, W C; Busque, S et al. (2016) A Cost Analysis of Tolerance Induction for Two-Haplotype Match Kidney Transplant Recipients. Am J Transplant 16:371-3
Pierini, Antonio; Strober, William; Moffett, Caitlin et al. (2016) TNF-? priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128:866-71
Müller, Antonia M S; Florek, Mareike; Kohrt, Holbrook E K et al. (2016) Blood Stem Cell Activity Is Arrested by Th1-Mediated Injury Preventing Engraftment following Nonmyeloablative Conditioning. J Immunol 197:4151-4162

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