Successful allogeneic bone marrow transplantation (BMT) is contingent upon the establishment of durable donor engraftment, the retention of the graft-versus-leukemia effect and the amelioration of toxicity from graft-versus-host disease (GVHD). Donor T cells play a pivotal role in facilitating allo engraftment and mediating the GVL effect but also initiate GVHD, which is the major complication of allogeneic BMT. Current GVHD prevention strategies such as ex vivo T cell depletion of the donor marrow graft have been effective at preventing GVHD but have had the unintended effects of increasing graft rejection and disease relapse as well as impairing immune reconstitution. As an alternative strategy, the applicant has examined an approach that allows for the selective in vivo manipulation of donor T cells at defined time points in the host. He has developed a murine model using donor transgenic mice whose T cells have been engineered to express the thymidine kinase (TK) gene. Use of these mice as donors in allogeneic marrow transplant experiments permits the selective elimination of T cells at defined intervals by administration of the antiviral agent ganciclovir. Consequently, the role of donor T cells in preventing relapse, facilitating engraftment, and causing GVHD can be assessed in a dynamic fashion. He hypothesizes that GVHD can be successfully modulated using gene modified donor T cells such that the beneficial GVL and graft promoting effects associated with or independent of GVHD are retained while collateral GVH-related host tissue damage is mitigated.
The specific aims of this application are: 1) to determine whether the selective elimination of mature donor TK+ T cells post-transplant is able to mitigate GVHD without compromising GVL reactivity, 2) to define how the activation status of the donor T cell prior to transplantation affects GVL reactivity, 3) to determine how the elimination of host-reactive donor T cells affects the residual immune response to third party and viral infection, and 4) to determine how the elimination of TK+ transgenic donor T cells post-transplant affects GVH/GVL reactivity in suboptimally conditionally recipients. The overall goal of this project is to selectively modulate T-cell function and survival in vivo in order to augment the therapeutic index of allogeneic BMT.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064603-03
Application #
6537762
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Jensen, Lee Ann
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
3
Fiscal Year
2002
Total Cost
$312,615
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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Belle, Ludovic; Zhou, Vivian; Stuhr, Kara L et al. (2017) Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD. JCI Insight 2:
Zhou, Vivian; Agle, Kimberle; Chen, Xiao et al. (2016) A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease. J Clin Invest 126:3541-55
Belle, Ludovic; Agle, Kimberle; Zhou, Vivian et al. (2016) Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression. Blood 128:2068-2082
Chen, Xiao; Dodge, Joseph; Komorowski, Richard et al. (2013) A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease. Blood 121:3970-80
Beres, Amy J; Drobyski, William R (2013) The role of regulatory T cells in the biology of graft versus host disease. Front Immunol 4:163
Rangarajan, Hemalatha; Yassai, Maryam; Subramanian, Hariharan et al. (2012) Emergence of T cells that recognize nonpolymorphic antigens during graft-versus- host disease. Blood 119:6354-64
Beres, Amy J; Haribhai, Dipica; Chadwick, Alexandra C et al. (2012) CD8+ Foxp3+ regulatory T cells are induced during graft-versus-host disease and mitigate disease severity. J Immunol 189:464-74
Drobyski, William R; Pasquini, Marcelo; Kovatovic, Kathy et al. (2011) Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant 17:1862-8
Beres, Amy; Komorowski, Richard; Mihara, Masahiko et al. (2011) Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease. Clin Cancer Res 17:3969-83

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