A major challenge in allogeneic hematopoietic cell transplantation is how to transfer the beneficial effects mediated by T cells without causing graft-versus-host disease (GVHD). Our long-term goal is to develop a clinically relevant strategy that allows transfer of allogeneic T-cell immunity against malignancies and infectious pathogens without causing GVHD. The objective of this application, which is the next step toward achieving this goal, is to further characterize and develop our central hypothesis that memory T cells do not cause severe GVHD. We also hypothesize that memory T cells have the potential to provide robust anti-infective and anti-malignancy activity. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1)To delineate the mechanism by which memory T cells have decreased ability to induce GVHD;2)To determine the anti-tumor potential of memory T cells;and 3)To conduct a Phase I clinical trial using memory T cells to promote immune recovery without GVHD induction. Under the first aim, the mechanism by which memory T cells have decreased ability to induce GVHD will be studied using both a classic and a novel GVHD model mediated by allospecific transgenic T cells. Under the second aim, we will analyze the anti-tumor activity of memory T cells and test whether the anti-tumor activity can be enhanced by vaccination of the donor. Under the last aim, we will determine the safety of a naive T-cell depleted donor lymphocyte infusion given to recipients of haploidentical allogeneic hematopoietic cell transplantation. The impact on post-transplant immune recovery will also be studied. The proposed research is an important step toward use of this innovative approach for prevention of GVHD in humans. The proposed research is significant, because this approach has great potential to improve the safety and to broaden the scope and effectiveness of allogeneic hematopoietic cell transplantation. It is also expected that the results will fundamentally advance the understanding of how memory T cells respond to alloantigens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA047741-19
Application #
8381927
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
19
Fiscal Year
2012
Total Cost
$174,756
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Rowland, Christopher R; Colucci, Lina A; Guilak, Farshid (2016) Fabrication of anatomically-shaped cartilage constructs using decellularized cartilage-derived matrix scaffolds. Biomaterials 91:57-72
Flynn, Ryan; Paz, Katelyn; Du, Jing et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 127:2144-54
Brennan, Todd V; Lin, Liwen; Brandstadter, Joshua D et al. (2016) Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation. J Clin Invest 126:207-19
Sung, Anthony D; Sung, Julia A M; Thomas, Samantha et al. (2016) Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial. Clin Infect Dis 63:999-1006
Brennan, Todd V; Rendell, Victoria R; Yang, Yiping (2015) Innate immune activation by tissue injury and cell death in the setting of hematopoietic stem cell transplantation. Front Immunol 6:101
Tuchman, Sascha A; Bacon, Wendi A; Huang, Li-Wen et al. (2015) Cyclophosphamide-based hematopoietic stem cell mobilization before autologous stem cell transplantation in newly diagnosed multiple myeloma. J Clin Apher 30:176-82
Brandstadter, Joshua D; Huang, Xiaopei; Yang, Yiping (2014) NK cell-extrinsic IL-18 signaling is required for efficient NK-cell activation by vaccinia virus. Eur J Immunol 44:2659-66
Horwitz, Mitchell E; Chao, Nelson J; Rizzieri, David A et al. (2014) Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest 124:3121-8
Brunger, Jonathan M; Huynh, Nguyen P T; Guenther, Caitlin M et al. (2014) Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Proc Natl Acad Sci U S A 111:E798-806
Macintyre, Andrew N; Gerriets, Valerie A; Nichols, Amanda G et al. (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20:61-72

Showing the most recent 10 out of 122 publications