It is the goal of this proposal to use the mouse as an experimental system to improve allogeneic bone marrow transplantation (BMT). Ultimately, we seek to develop long term chimerism in transplant recipients without graft-versus-host disease (GVHD), the most common clinical complication of transplant recipients. We will accomplish our goal by simultaneously investigating two very important aspects of BMT. 1) Conditioning of the recipient by various radiological regimens which will permit engraftment with minimal morbidity. We will evaluate various irradiation conditioning regimens including total lymphoid irradiation (single dose and fractionated) and total body irradiation (Fractionated, hyperfractionated and split-dose) with and without chemical conditioning. 2) Utilizing our new approach of depletion of GVHD-causing T cells from the donor graft. Our new approach involves the use of antibody linked to potent toxin, termed immunotoxin (IT). Our experimental and clinical data suggest that the use of IT to deplete marrow T cells will have a major impact on allogeneic BMT. Importantly, data from our laboratory as well as from other clinical centers indicate that in certain instances, transplants involving T cell depleted bone marrow sometimes result in engraftment failures. Because the use of T cell depletion in allogeneic BMT is gaining more momentum, it is urgent that the relationship between T cell depletion and recipient conditioning be determined. Therefore, we will investigate various conditioning regimens in animals that receive matched or mismatched bone marrow combined with T cell depletion using IT. The major challenge in the next grant period is to develop improved radiation conditioning regimens in animals that receive T-depleted bone marrow. If transplanted mice are to survive, it is important that their immune responses be intact. Therefore, in conditioning regimens which result in successful marrow engraftment, mice will be studied for immunocompetence employing in vivo and in vitro assays to measure immunological responses. Many responses will be measured, but we will concentrate on determining T cell function since T cells have been shown to contribute both to the development of GVHD and engraftment. We will also investigate the therapeutic use of thymic hormones or T cell growth factors that may accelerate engraftment and shorten the period of post transplant immunodeficiency. These studies will provide information which will be of great clinical value leading to the development of new protocols for the University of Minnesota BMT Program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031618-07
Application #
3169714
Study Section
Radiation Study Section (RAD)
Project Start
1982-02-01
Project End
1990-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Blazar, B R; Taylor, P A; Vallera, D A (1997) CD4+ and CD8+ T cells each can utilize a perforin-dependent pathway to mediate lethal graft-versus-host disease in major histocompatibility complex-disparate recipients. Transplantation 64:571-6
Blazar, B R; Taylor, P A; Bluestone, J A et al. (1996) Murine gamma/delta-expressing T cells affect alloengraftment via the recognition of nonclassical major histocompatibility complex class Ib antigens. Blood 87:4463-72
Blazar, B R; Taylor, P A; Panoskaltsis-Mortari, A et al. (1996) Lethal murine graft-versus-host disease induced by donor gamma/delta expressing T cells with specificity for host nonclassical major histocompatibility complex class Ib antigens. Blood 87:827-37
Chan, C H; Blazar, B R; Greenfield, L et al. (1996) Reactivity of murine cytokine fusion toxin, diphtheria toxin390-murine interleukin-3 (DT390-mIL-3), with bone marrow progenitor cells. Blood 88:1445-56
Chan, C H; Blazar, B R; Eide, C R et al. (1995) A murine cytokine fusion toxin specifically targeting the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor on normal committed bone marrow progenitor cells and GM-CSF-dependent tumor cells. Blood 86:2732-40
Blazar, B R; Taylor, P A; Smith, S et al. (1995) Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts. Blood 85:842-51
Blazar, B R; Taylor, P A; Panoskaltsis-Mortari, A et al. (1995) Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts. Blood 85:2607-18
Bergese, S; Pelletier, R; Vallera, D et al. (1995) Regulation of endothelial VCAM-1 expression in murine cardiac grafts. Roles for TNF and IL4. Am J Pathol 146:989-98
Vallera, D A; Taylor, P A; Panoskaltsis-Mortari, A et al. (1995) Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab')2-ricin toxin A chain immunotoxin. Blood 86:4367-75
Vallera, D A; Taylor, P A; Vannice, J L et al. (1995) Interleukin-1 or tumor necrosis factor-alpha antagonists do not inhibit graft-versus-host disease induced across the major histocompatibility barrier in mice. Transplantation 60:1371-4

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