The risk of GVHD may be less when cord blood (containing naive T cells) rather than adult BM (containing memory T cells) is infused. Male recipients of donor BM from multiparous females and recipients exposed to herpes virus pre-BMT have a higher incidence of GVHD despite post-BMT immunosuppression. These data suggest that memory T cells differ from naive T cells in their capacity or requirements for mediating GVHD. This project is directed toward investigating the potential biological differences between naive and memory T cells in responses relevant to BMT using new models of adoptive T cell transfer to analyze alloresponses and peptide-specific responses. For characterizing the requirements for alloresponses, GVHD studies will be performed in primary BMT recipients of allogeneic lymph node-T cells and secondary recipients of allosensitized memory T cells which have been generated by parking of GVHD effector cells prior to isolation and infusion into secondary BMT recipients. Primary or secondary recipients will be treated with monoclonal antibodies (mAbs) blocking one or more costimulatory/adhesogenic (B7-CD28; LFA-1:ICAM; CD2:CD48;OX40:OX40L) pathways, and alloreactive donor T cells, isolated by thoracic duct cannulation, will be analyzed to quantify the degree of expansion, activation/memory cell conversion, and function. We will use the D0.11 adoptive transfer model to follow responses of naive or memory D0.11 T cells to Oval peptide in the presence of mAbs known to inhibit GVHD responses, and analyze D0.11 T cell responses by quantifying D0.11 T cell expansion, activation and function. To determine whether costimulatory blockade has selectively influenced T cell responses to Ova and not altered T cell function to other antigens, we will perform studies in which adoptive transfer recipients will be immunized with a viral peptide antigen prior to adoptive transfer, the follow both viral and Ova peptide responses after immunizing these mice with Ova in the presence of costimulatory blockade. Pathways deemed critical for conversion of naive to memory T cell responses and prevention of GVHD lethality and peptide responsiveness will be further studied using D0.11 mice lacking these constimulatory ligands/receptors. These studies will establish the hierarchy of requirements for the pathways examined and will enable the design of GVHD preventive approaches that take into account the hierarchial pathways important for alloresponses.

Project Start
2001-08-01
Project End
2003-07-31
Budget Start
Budget End
Support Year
5
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Tapper, Elliot B; Finkelstein, Daniel; Mittleman, Murray A et al. (2016) A Quality Improvement Initiative Reduces 30-Day Rate of Readmission for Patients With Cirrhosis. Clin Gastroenterol Hepatol 14:753-9
Davies, Jeff K; Gribben, John G; Brennan, Lisa L et al. (2008) Outcome of alloanergized haploidentical bone marrow transplantation after ex vivo costimulatory blockade: results of 2 phase 1 studies. Blood 112:2232-41
Lafuente, Esther M; van Puijenbroek, Andre A F L; Krause, Matthias et al. (2004) RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev Cell 7:585-95
Rodig, Nancy; Ryan, Timothy; Allen, Jessica A et al. (2003) Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur J Immunol 33:3117-26
Hirano, Naoto; Butler, Marcus O; Von Bergwelt-Baildon, Michael S et al. (2003) Autoantibodies frequently detected in patients with aplastic anemia. Blood 102:4567-75
Tzachanis, Dimitrios; Appleman, Leonard J; Van Puijenbroek, Andre A F L et al. (2003) Differential localization and function of ADP-ribosylation factor-6 in anergic human T cells: a potential marker for their identification. J Immunol 171:1691-6
Baecher-Allan, Clare; Brown, Julia A; Freeman, Gordon J et al. (2003) CD4+CD25+ regulatory cells from human peripheral blood express very high levels of CD25 ex vivo. Novartis Found Symp 252:67-88; discussion 88-91, 106-14
Brown, Julia A; Dorfman, David M; Ma, Feng-Rong et al. (2003) Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 170:1257-66
Molrine, Deborah C; Antin, Joseph H; Guinan, Eva C et al. (2003) Donor immunization with pneumococcal conjugate vaccine and early protective antibody responses following allogeneic hematopoietic cell transplantation. Blood 101:831-6
Appleman, Leonard J; Tzachanis, Dimitrios; Grader-Beck, Thomas et al. (2002) Induction of immunologic tolerance for allogeneic hematopoietic cell transplantation. Leuk Lymphoma 43:1159-67

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