This program project grant (PPG) application is an integrative endeavor by the Emory Center for Transfusion and Cellular Therapies to institute a major, interdisciplinary, and synergistic research effort to improve the safety and effectiveness of blood dell transfusions, particularly in immuno-compromised transfusion recipients. The central theme is to address mechanisms of, and mitigate the effects of, several of the most serious causes of morbidity and mortality in transfusion medicine, including GVHD following cellular therapies, opportunistic and transfusion-transmitted infections including CMV, and immunization to RBC antigens in recipients of multiple transfusions. Each project uses innovative and novel approaches, strategies and/or technologies to address the central theme including vaccine enhanced- (Project 1) and pharmacologically modified- (Project 3) donor lymphocyte infusions, nucleic acid testing and automated capillary cytometric leukocyte counting (Project 2), and a genetically engineered murine model allowing a step-by-step analysis of the cellular and molecular pathways to RBG immunization (Project 4). In brief, Project 1 extends our previous studies with a mouse BMT model by developing a novel method of combining donor lymphocyte infusion (DLI) with an effective listeria-based vaccination strategy. Project 2 is a multihospital trial, proposed in conjunction with more basic laboratory studies, designed to validate optimized methods to prevent transfusion-transmitted GMV infections. Project 3 extends our previous studies with a mouse BMT model and employs in humans a novel strategy to adoptively transfer antigen-specific donor T-cells without inducing lethal GVHD. Project 4 utilizes a novel murine model of RBC immunization developed in our laboratories to identify the cellular and molecular events that regulate immune responses to transfused RBC. The team of investigators in the PPG spans Public Health, Oncology, Hematology, Pediatrics, and Blood Banking disciplines and has worked together to create a series of synergistic proposals. As each of these 4 projects addresses important cellular and immunologic events in Transfusion Medicine, project completion should lead to novel, improved transfusion and transplantation therapeutic components and/or strategies to protect high-risk transfusion recipients. The successful execution of the Projects will be facilitated by three Cores including an Administrative Core (Core A), an Immunologic and Virologic Monitoring Laboratory Core (Core B), and a Biostatistics and Data Management Gore (Core G).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL086773-05
Application #
8316323
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Mondoro, Traci
Project Start
2008-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$1,820,356
Indirect Cost
$608,326
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Josephson, Cassandra D; Caliendo, Angela M; Easley, Kirk A et al. (2014) Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study. JAMA Pediatr 168:1054-62
Marin, Terri; Josephson, Cassandra D; Kosmetatos, Niki et al. (2014) Feeding preterm infants during red blood cell transfusion is associated with a decline in postprandial mesenteric oxygenation. J Pediatr 165:464-71.e1
Stowell, Sean R; Girard-Pierce, Kathryn R; Smith, Nicole H et al. (2014) Transfusion of murine red blood cells expressing the human KEL glycoprotein induces clinically significant alloantibodies. Transfusion 54:179-89
Girard-Pierce, Kathryn R; Stowell, Sean R; Smith, Nicole H et al. (2013) A novel role for C3 in antibody-induced red blood cell clearance and antigen modulation. Blood 122:1793-801
Lu, Ying; Giver, Cynthia R; Sharma, Akshay et al. (2012) IFN-ýý and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity. Blood 119:1075-85
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
Patel, Seema R; Hendrickson, Jeanne E; Smith, Nicole H et al. (2011) Alloimmunization against RBC or PLT antigens is independent of TRIM21 expression in a murine model. Mol Immunol 48:909-13
Hendrickson, Jeanne E; Hod, Eldad A; Cadwell, Chantel M et al. (2011) Rapid clearance of transfused murine red blood cells is associated with recipient cytokine storm and enhanced alloimmunogenicity. Transfusion 51:2445-54
Josephson, Cassandra D; Castillejo, Marta-Inés; Caliendo, Angela M et al. (2011) Prevention of transfusion-transmitted cytomegalovirus in low-birth weight infants (?1500 g) using cytomegalovirus-seronegative and leukoreduced transfusions. Transfus Med Rev 25:125-32
Josephson, Cassandra D; Glynn, Simone A; Kleinman, Steve H et al. (2011) A multidisciplinary "think tank": the top 10 clinical trial opportunities in transfusion medicine from the National Heart, Lung, and Blood Institute-sponsored 2009 state-of-the-science symposium. Transfusion 51:828-41

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