The goal of the research program is to develop immune tolerance to combined HLA haplotype matched living related kidney and hematopoietic cell transplants in order to remove the requirement for the lifelong use of maintenance immunosuppressive drugs and to improve long term graft survival. The program builds on the success of inducing tolerance in patients with combined HLA matched living related kidney and hematopoietic cell transplants during the previous grant period using a posttransplant conditioning regimen of total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (ATG). The regimen was shown to be safe and effective in achieving persistent mixed chimerism without graft versus host disease (GVHD). This allowed for immunosuppressive drug withdrawal without kidney allograft rejection episodes in chimeric patients. In addition, patients given HLA haplotype matched hematopoietic cell transplants for the treatment of leukemia and lymphoma using the TLI/ATG conditioning regimen developed persistent engraftment without acute GVHD. The results of these clinical studies performed during the previous grant period provide the basis for the proposed new trial for 25 HLA haplotype matched patients. Patients that achieve stable chimerism without GVHD or evidence of rejection will be withdrawn from immunosuppressive drugs at 6 months posttransplant. Patients will be monitored for evidence of the establishment of immune tolerance by testing specific immune unresponsiveness to donor alloantigens in vitro and by performing serial gene microarray testing of peripheral blood mononuclear cells to look for the posttransplant acquisition of a previously described "tolerant" gene expression pattern. Patients will also be monitored for immune reconstitution by studying the recovery of T cell subsets;T cell excision circles (TRECs), in vitro immune responses to new and recall microbial antigens, incidence of infections, and responses to vaccination. Outcome parameters will be compared at that of an equal number of HLA haplotype matched transplant patients given conventional therapy. The research project will interact with all other Projects and with Cores.

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 and long term graft loss.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL075462-10
Application #
8676858
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
$346,949
Indirect Cost
$115,369
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Müller, Antonia M S; Poyser, Jessica; Küpper, Natascha J et al. (2014) Donor hematopoiesis in mice following total lymphoid irradiation requires host T-regulatory cells for durable engraftment. Blood 123:2882-92
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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