Project 4. Role of Functionally Distinct Dendritic Cell Subsets in Tolerance and Graft-Versus-Host Disease We recently discovered that effector T cell subsets, including THI, TH2 and Treg cells, can induce monocytes to differentiate into dendritic cells (DCs) that, in turn, selectively induce the formation of THI, TH2 and Treg cells from naive T cells, respectively. We hypothesize that this heretofore unknown immunoregulatory mechanism may play an important role in the control of protective immunity, including proinflammatory responses and tolerance induction, as well as pathologic immunity such as that seen in graft versus host disease (GVHD). We further believe that it may be possible to target and /or manipulate these novel DC subsets to treat or prevent such disorders. The overall goals of this project are to assess the possible role of immunoregulatory DCs (DCrreg) in immune tolerance and GVHD in recipients of hematopoetic stem cell transplants with or without organ transplants, and identify molecules that induce the formation and mediate the functions of these DCs. These goals will be pursued by 1) assessing and comparing the phenotypic, functional and gene expression profiles of T cells and non-T antigen presenting cells in the blood and kidneys of transplant recipients who are immunologically tolerant of their grafts versus those who are not, 2) using neutralizing antibodies and gene expression profiling to identify key factors expressed by Treg cells that are responsible for inducing monocytes to differentiate into DCxreg, as well as the key factors expressed by DCrreg that are responsible for inducing the formation of Treg cells from naive T cells, and 3) evaluating the effects of DCrreg, as well as Treg cells induced by DCrreg, in a murine model of acute GVHD and organ transplant tolerance. This Project is highly dependent on interactions with Projects 1 and 3 as well as Cores B and C, which are the sources of clinical materials, mouse models and immune and gene profiling assays, respectively. Success in this project should ultimately lead to safer and more effective ways to achieve immune tolerance in the setting of allogeneic transplantation.

Public Health Relevance

Some patients tolerate transplanted organs without the need for dangerous immunosuppressive drugs. The goal of this project is to identify the cells and substances responsible for this tolerant state. If we are successful, future organ transplant recipients may no longer need to be treated with such toxic drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL075462-08
Application #
8375902
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$279,872
Indirect Cost
$104,952
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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