The applicant's broad objective is to decrease the infectious morbidity and mortality of long-term marrow transplant survivors and, at the same time, to provide insight into the physiology of immune memory. The part of the application leading to clinical outcome: Patients undergoing bone marrow transplantation are immunodeficient for at least one year after grafting due in part to the lack of B cells. The applicant desires to attempt to improve these patients' humoral immunity by providing them with B cells from their marrow donors at one to two months after grafting. The work is divided into 4 steps: (1) Work out the large scale separation of B cells from donor blood. (2) Establish the safety of transfusions of the enriched B cells. (3) Perform a pilot prospective randomized trial comparing the responsiveness to vaccines in B cell-transfused vs. control patients. (4) If the pilot results are encouraging, perform a definitive large prospective randomized trial comparing the number and severity of infections in B cell-transfused vs. control patients. In this application, support is requested only for steps (1)-(3). The part of the application leading to immunologic information: This application also seeks to determine (A) the approximate life span of naive and memory B cell clones following infusion into human beings, and (B) whether long-term antibody production is due to periodic differentiation of B cells into plasma cells or due to long-lived plasma cells. (A) To define the approximate life span of naive and memory B cell clones, serial measurements of the mounts of naive and memory B cells will be performed in both the B cell-transfused and control patients. The longer the life span of a particular B cell subpopulation, the longer after the transfusions should the B cell transfused patients have higher blood counts of this subpopulation compared to the controls. Therefore, the time period from transfusing B cells to the last time point at which significantly higher naive or memory B cell counts are detected in the B cell-transfused vs. the control patients will be called the approximate life span of the naive or memory B cell clones. (B) At the same time, the patients will be used to find out whether the long-term production of antibodies to recall antigens like smallpox virus is mediated through smallpox-specific B cells some of which periodically differentiate into plasma cells or by long smallpox-specific plasma cells. Compared to the controls, the B cell transfused patients will have received substantially more B cells but the same amount of plasma cells. Therefore, if several months after the B cell transfusion the B cell transfused patients have higher serum levels of smallpox IgG, it will be assumed that B cells rather than long lived plasma cells are responsible for the long term IgG production, and vice versa.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA068496-03
Application #
2443195
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1995-07-10
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Storek, Jan (2008) Immunological reconstitution after hematopoietic cell transplantation - its relation to the contents of the graft. Expert Opin Biol Ther 8:583-97
Storek, J; Dawson, M A; Lim, L C-L et al. (2004) Efficacy of donor vaccination before hematopoietic cell transplantation and recipient vaccination both before and early after transplantation. Bone Marrow Transplant 33:337-46
Storek, Jan; Viganego, Federico; Dawson, Monja A et al. (2003) Factors affecting antibody levels after allogeneic hematopoietic cell transplantation. Blood 101:3319-24
Storek, Jan; Dawson, Monja A; Maloney, David G (2003) Correlation between the numbers of naive T cells infused with blood stem cell allografts and the counts of naive T cells after transplantation. Biol Blood Marrow Transplant 9:781-4
Storek, Jan; Joseph, Ansamma; Dawson, Monja A et al. (2002) Factors influencing T-lymphopoiesis after allogeneic hematopoietic cell transplantation. Transplantation 73:1154-8
Storek, J (2002) B-cell immunity after allogeneic hematopoietic cell transplantation. Cytotherapy 4:423-4
Storek, Jan; Lalovic, Bojan B; Rupert, Kate et al. (2002) Kinetics of B, CD4 T, and CD8 T cells infused into humans: estimates of intravascular:extravascular ratios and total body counts. Clin Immunol 102:249-57
Storek, J; Joseph, A; Espino, G et al. (2001) Immunity of patients surviving 20 to 30 years after allogeneic or syngeneic bone marrow transplantation. Blood 98:3505-12
Storek, J; Dawson, M A; Storer, B et al. (2001) Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 97:3380-9
Storek, J; Wells, D; Dawson, M A et al. (2001) Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation. Blood 98:489-91

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