The main goal of the Program Grant is to obtain a deeper understanding of the immunobiology of nonmyeloablative allogeneic hematopoietic cell transplantation with or without concomitant organ transplantation such that a state of immune tolerance can be achieved. The Program Project has one clinical project (Project 1) (S. Strober, Leader) that will attempt to induce immune tolerance to HLA haplotype matched combined kidney and hematopoietic cell transplants by altering the balance of residual host T cells with the non-myeloablative conditioning regimen of total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (ATG). Project 2, (J. Shizuru, Leader), will perform new preclinical studies of TLI and ATG to investigate the cellular basis by which this conditioning regimen promotes the engraftment of hematopoietic stem cells. Project 3 (R. S. Negrin, Leader) will perform additional preclinical studies that elucidate the function of donor CD4+CD25+ Treg cells and show how they can be used more effectively to prevent GVHD while maintaining graft anti-tumor (GVT) activity. The interactions between donor T cells and subsets of host antigen presenting cells defined in Projects 1 and 4 will be determined also. Project 4 (E. Engleman, Leader) studies the mechanisms by which different subsets of host antigen presenting cells including dendritic cells activate and interact with different subsets of donor T cells including CD4+CD25+ regulatory T cells and Thi and Th2 conventional T cells. Core A (S. Strober, Leader) will provide statistical and administrative assistance to all Projects. Core B (R. Lowsky, Leader) will perform all human donor cell collections and cell purifications for purposes of transplantation into patients in Project 1, and will provide whole or purified subsets of peripheral blood mononuclear cells (PBMCs) from recipients, donors and controls to Projects 1, 2, and 4 and to Core C. Core C (E. Engleman, Leader) will provide immune monitoring assays of lymphocyte function as well as gene microarray assays to Projects 1, 2, and 4.

Public Health Relevance

The results of the proposed studies are expected to allow for the discontinuation of immunosuppressive drugs in kidney transplant patients, and avoid cumulative drug side effects. The results are also expected to reduce the risk of graft versus host disease in patients given hematopoietic cell transplants to treat leukemia and lymphoma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL075462-07
Application #
8092655
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Welniak, Lisbeth A
Project Start
2003-12-01
Project End
2015-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
7
Fiscal Year
2011
Total Cost
$1,882,757
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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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
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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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