A central theme of the program project is the use of allogeneic blood progenitor cell transplantation to induce host versus donor and donor versus host immune tolerance in patients and laboratory animals after the development of chimerism without the development of graft versus host disease (GVHD). The role of regulatory T cells in the protection against GVHD will be studied as well as the immune competence of the protected hosts. We will test the hypothesis that sustained chimerism achieved with a novel conditioning regimen will induce immune tolerance in patients given kidney transplants such that all immune suppressive drugs can be withdrawn. We will also test the hypothesis that regulatory natural killer T cells in the blood of these patients will suppress immune responses to donor and host alloantigens. We will use a conditioning regimen to induce full chimerism in patients with life threatening systemic lupus erythematosus who will be protected against GVHD by regulatory T cells. We will test the hypothesis that sustained chimerism will induce a complete remission in the autoimmune disease allowing for immunosuppressive drug withdrawal. We will test the hypothesis that regulatory T cells (CD4+CD25+or NK1.1+ T cells) can separate GVHD from graft versus tumor/lymphoma (GVL) activity in mice by blocking different immune effector pathways such that potent GVL activity occurs in the absence of GVHD. We will test the hypothesis that donor Langerhans cell replacement of host Langerhans cells in the skin after allogeneic bone marrow transplantation is dependent on the function of donor T cells that facilitate replacement even in the absence of clinical or microscopic GVHD. We will also study Langerhans cell replacement in chimeric kidney transplant and autoimmune disease patients, and Langerhans cell replacement in mice protected from GVHD with regulatory T cells. The administrative and biostatistical core will serve the needs of all projects, and the immune assay and flow cytometry core will service all projects as well.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL075462-03
Application #
7086194
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Di Fronzo, Nancy L
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$1,991,366
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Scandling, John D; Busque, Stephan; Lowsky, Robert et al. (2018) Macrochimerism and clinical transplant tolerance. Hum Immunol 79:266-271
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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
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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
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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
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

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