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 #
5P01HL075462-10
Application #
8676857
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
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
$1,845,101
Indirect Cost
$677,175
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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Alonso, Michael N; Gregorio, Josh G; Davidson, Matthew G et al. (2014) Depletion of inflammatory dendritic cells with anti-CD209 conjugated to saporin toxin. Immunol Res 58:374-7
Strober, Samuel (2014) Path to clinical transplantation tolerance and prevention of graft-versus-host disease. Immunol Res 58:240-8
Medeiros, B C; Tian, L; Robenson, S et al. (2014) European LeukemiaNet classification intermediate risk-1 cohort is associated with poor outcomes in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Blood Cancer J 4:e216
Sega, Emanuela I; Leveson-Gower, Dennis B; Florek, Mareike et al. (2014) Role of lymphocyte activation gene-3 (Lag-3) in conventional and regulatory T cell function in allogeneic transplantation. PLoS One 9:e86551
Hongo, D; Tang, X; Baker, J et al. (2014) Requirement for interactions of natural killer T cells and myeloid-derived suppressor cells for transplantation tolerance. Am J Transplant 14:2467-77
Schneidawind, Dominik; Pierini, Antonio; Negrin, Robert S (2013) Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. Blood 122:3116-21
Colonna, Lucrezia; Florek, Mareike; Leveson-Gower, Dennis B et al. (2013) IL-17 gene ablation does not impact Treg-mediated suppression of graft-versus-host disease after bone marrow transplantation. Biol Blood Marrow Transplant 19:1557-65
Davidson, Matthew G; Alonso, Michael N; Kenkel, Justin A et al. (2013) In vivo T cell activation induces the formation of CD209(+) PDL-2(+) dendritic cells. PLoS One 8:e76258
Kohrt, Holbrook E; Tian, Lu; Li, Li et al. (2013) Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation. Clin Immunol 148:124-35

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