The overall objective of this proposal is to bring together a group of investigators with complementary expertise, whose research will address defined and related areas in the multi-disciplinary field of Transfusion Medicine. The general theme of this SCORE Program Project is t he study of cellular and humoral aspects on immunonomodulation in Transfusion medicine. Immunomodulation may occur as a result of allogeneic blood transfusion. The characterization of such altered and """"""""unwanted"""""""", immunity is essential to developing approaches of specific therapeutic intervention. Alternatively, immunomodulation may e intentional as in the treatment of center. The later pertains to the transfusion therapy of allogeneic, immunocompetent cells to induce graft versus leukemia. Collectively, the proposed studies involve unique approaches to characterize allo-and auto-immune responses and further define cell biological features of blood group antigenic targets. In addition, athe SCOR Program will develop novel cellular therapies and examine the mechanisms of their induced immunomodulatory effects. The Program comprises 5 major research projects. Project 1 will access the molecular basis of naturally occurring and pathogenic RBC autoantibodies with respect to their B-cell origin, the role of selection by antigen as opposed to polyclonal activation, and the characterization the odontogenic structures, which remain ill-defined; Project 2 will investigate the anti- Rb alloimmune response at the genetic and serologic level and design inhibitors of anti-Rb antibody - Rh antigen binding; Project 3 pertains to the biology of blood group antigen glycophorus utilizing Chinese hamster ovary cells transfected with glycophorin genes as a model to study both biochemical and immunological aspects of this complex membrane antigen; Project 4 will develop a human umbilical and blood collection, banking and expansion program, which is tailored to the correction of homozygous Sickle Cell Anemia by human umbilical cord cell transplantation; Project 5 will develop in vitro and in vivo animal models relevant to the transfusion of allogeneic human T cells as a novel form of immunomodulatory intervention in cancer therapy. These 5 projects will use complementary approaches and different methodologies to address pathologically related questions, which will accelerate progress through interactions and communication. Together they will bridge disciplines of genetics and biochemistry with a basis in pathophysiology. The information and reagents derived from these studies should be useful in devising immunomodulators in transfusion therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL054516-03
Application #
2638052
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S1))
Project Start
1996-02-01
Project End
2000-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Siegel, Don L (2008) Translational applications of antibody phage display. Immunol Res 42:118-31
Siegel, Don L (2007) Phage display-based molecular methods in immunohematology. Transfusion 47:89S-94S
Xie, Kefang; Song, Shuh Chyung; Spitalnik, Steven L et al. (2005) Crystallographic analysis of the NNA7 Fab and proposal for the mode of human blood-group recognition. Acta Crystallogr D Biol Crystallogr 61:1386-94
Siegel, Don L (2005) Developing phage display tools for use in transfusion medicine. Transfusion 45:100S-108S
Song, Shuh Chyung; Xie, Kefang; Czerwinski, Marcin et al. (2004) Purification, crystallization and X-ray diffraction analysis of a recombinant Fab that recognizes a human blood-group antigen. Acta Crystallogr D Biol Crystallogr 60:788-91
Czerwinski, Marcin; Krop-Watorek, Anna; Lisowska, Elwira et al. (2002) Construction of dimeric F(ab) useful in blood group serology. Transfusion 42:257-64
Young, Donald S; Sachais, Bruce S; Jefferies, Leigh C (2002) Effect of disease complications on hospital costs. Clin Chem 48:140-9
Honczarenko, Marek; Le, Yi; Glodek, Aleksandra M et al. (2002) CCR5-binding chemokines modulate CXCL12 (SDF-1)-induced responses of progenitor B cells in human bone marrow through heterologous desensitization of the CXCR4 chemokine receptor. Blood 100:2321-9
Siegel, D L (2002) Recombinant monoclonal antibody technology. Transfus Clin Biol 9:15-22
Jefferies, L C; Sachais, B S; Young, D S (2001) Blood transfusion costs by diagnosis-related groups in 60 university hospitals in 1995. Transfusion 41:522-9

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