The long-term goal for the proposed studies is to improve survival in patients who undergo allogeneic hematopoietic progenitor cell transplantation (HPCT). HPCT recipients will benefit from novel therapies that enhance graft versus tumor (GvT) effects while minimizing graft versus host disease (GvHD). Recent data indicate that """"""""memory"""""""" CD44(high) CD4+ donor T-cells have GvT activity without dose-limiting GvHD. The applicant has developed a novel method of selectively depleting CD44(Iow) and preserving CD44(high) CD4+ T-cells donor T-cells using ex vivo exposure to fludarabine that will be studied with three specific aims: #1: To characterize the GvHD and GvT activity of naive CD44(Iow) versus CD44(high) CD4+ T-cells. The hypothesis is that fludarabine selectively deletes CD44(Iow) naive T-cells via enhanced apoptosis reducing allo-reactive naive T-cells. GvHD and GvT activity of FACS sorted CD44(Iow) and CD44(high) CD4+ T-cell subsets will be compared in allogeneic BMTs. #2: To determine the mechanisms by which fludarabine-treatment leads to reduction in the allo-reactivity of donor T-cells. In vitro and in vivo model systems will test the following hypotheses: 1) reduced synthesis of the pro-inflammatory cytokines following deletion of the CD4(Iow) CD4+ T-cells; 2) reduced homing of allo-reactive T-cells to the gastro-intestinal epithelium; 3) enrichment of regulatory/suppressor T-cells. #3 To determine the ability of CD44(high) CD4+ T-cells to transfer antigen-specific cellular immunity without causing GvHD. The hypothesis is that antigen specific memory T-cells survive fludarabine exposure and proliferate in allogeneic BMT recipients without producing pro-inflammatory cytokines. An established mouse model of CMV infection after allogeneic BMT and CMV peptide-MHC tetramer reagents will be used to measure anti-mCMV donor T-cells. The overall objective of these studies is to develop a novel methods of allograft engineering to improve immune reconstitution and enhance GvT activity without increasing GvHD. Our studies will improve the understanding of the role of donor cells in inducing GvHD and GvT effects after allogeneic HPCT and facilitate development of novel approaches in immunotherapy cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA074364-04A2
Application #
6721020
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Welch, Anthony R
Project Start
1998-09-30
Project End
2008-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$283,671
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Sanyi, Allen; Jaye, David L; Rosand, Cecilia B et al. (2018) Diagnosis of GATA2 haplo-insufficiency in a young woman prompted by pancytopenia with deficiencies of B-cell and dendritic cell development. Biomark Res 6:13
Li, Jian-Ming; Petersen, Christopher T; Li, Jing-Xia et al. (2016) Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling. Cancer Res 76:6802-6815
Hossain, Mohammad S; Ramachandiran, Sampath; Gewirtz, Andrew T et al. (2014) Recombinant TLR5 agonist CBLB502 promotes NK cell-mediated anti-CMV immunity in mice. PLoS One 9:e96165
Darlak, Katarzyna A; Wang, Ying; Li, Jian-Ming et al. (2013) Enrichment of IL-12-producing plasmacytoid dendritic cells in donor bone marrow grafts enhances graft-versus-leukemia activity in allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 19:1331-9
Li, Jian-Ming; Hossain, Mohammad S; Southerland, Lauren et al. (2013) Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients. Blood 121:2347-51
Li, Jian-Ming; Darlak, Kasia A; Southerland, Lauren et al. (2013) VIPhyb, an antagonist of vasoactive intestinal peptide receptor, enhances cellular antiviral immunity in murine cytomegalovirus infected mice. PLoS One 8:e63381
Hossain, Mohammad S; Jaye, David L; Pollack, Brian P et al. (2011) Flagellin, a TLR5 agonist, reduces graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity. J Immunol 187:5130-40
Li, Jian-Ming; Southerland, Lauren; Hossain, Mohammad S et al. (2011) Absence of vasoactive intestinal peptide expression in hematopoietic cells enhances Th1 polarization and antiviral immunity in mice. J Immunol 187:1057-65
Li, Jian-Ming; Giver, Cynthia R; Lu, Ying et al. (2009) Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Immunotherapy 1:599-621
Li, Jian-Ming; Southerland, Lauren T; Lu, Ying et al. (2009) Activation, immune polarization, and graft-versus-leukemia activity of donor T cells are regulated by specific subsets of donor bone marrow antigen-presenting cells in allogeneic hemopoietic stem cell transplantation. J Immunol 183:7799-809

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