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 Patients that achieve stable chimerism without GVHD or evidence of rejection will be withdrawn from immunosuppressive drugs at 6 months posttransplant.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 #
5P01HL075462-09
Application #
8470682
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
$337,036
Indirect Cost
$112,072
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Pierini, Antonio; Strober, William; Moffett, Caitlin et al. (2016) TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128:866-71
Strober, Samuel (2016) Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants. Blood 127:1539-43
Pierini, Antonio; Alvarez, Maite; Negrin, Robert S (2016) NK Cell and CD4+FoxP3+ Regulatory T Cell Based Therapies for Hematopoietic Stem Cell Engraftment. Stem Cells Int 2016:9025835
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
Spitzer, Matthew H; Gherardini, Pier Federico; Fragiadakis, Gabriela K et al. (2015) IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science 349:1259425
Pierini, Antonio; Colonna, Lucrezia; Alvarez, Maite et al. (2015) Donor Requirements for Regulatory T Cell Suppression of Murine Graft-versus-Host Disease. J Immunol 195:347-55
Pan, Yuqiong; Leveson-Gower, Dennis B; de Almeida, Patricia E et al. (2015) Engraftment of embryonic stem cells and differentiated progeny by host conditioning with total lymphoid irradiation and regulatory T cells. Cell Rep 10:1793-802
Kim, Byung-Su; Nishikii, Hidekazu; Baker, Jeanette et al. (2015) Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease. Blood 126:546-57
Pierini, Antonio; Schneidawind, Dominik; Nishikii, Hidekazu et al. (2015) Regulatory T Cell Immunotherapy in Immune-Mediated Diseases. Curr Stem Cell Rep 1:177-186
Schneidawind, Dominik; Baker, Jeanette; Pierini, Antonio et al. (2015) Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality. Blood 125:3491-500

Showing the most recent 10 out of 55 publications