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 #
5P01HL075462-09
Application #
8470685
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$266,438
Indirect Cost
$99,914
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Kawai, Tatsuo; Leventhal, Joseph; Wood, Kathryn et al. (2018) Summary of the Third International Workshop on Clinical Tolerance. Am J Transplant :
Scandling, John D; Busque, Stephan; Lowsky, Robert et al. (2018) Macrochimerism and clinical transplant tolerance. Hum Immunol 79:266-271
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
Simonetta, Federico; Alvarez, Maite; Negrin, Robert S (2017) Natural Killer Cells in Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation. Front Immunol 8:465
Zhang, Hong; Gregorio, Josh D; Iwahori, Toru et al. (2017) A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes. Proc Natl Acad Sci U S A 114:1988-1993
Chen, Yi-Bin; Efebera, Yvonne A; Johnston, Laura et al. (2017) Increased Foxp3+Helios+Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells. Biol Blood Marrow Transplant 23:625-634
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
Mavers, Melissa; Maas-Bauer, Kristina; Negrin, Robert S (2017) Invariant Natural Killer T Cells As Suppressors of Graft-versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 8:900
Revelo, Xavier S; Ghazarian, Magar; Chng, Melissa Hui Yen et al. (2016) Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance. Cell Rep 16:717-30

Showing the most recent 10 out of 70 publications