Abstract

Acute graft versus host disease (GVHD) is a leading cause of death following allogeneic bone marrow transplantation. Current modalities for the prevention and treatment of GVHD are not entirely effective, and lack specificity for the T lymphocytes that cause the disease. Recent results from this and other laboratories have suggested that analogs of deoxyadenosine and deoxyguanosine resistant to cellular catabolism can inhibit selectively the proliferation and/or survival of mature T lymphocytes, without severely harming other cell types. The proposed experiments will use novel enzymatic and cell culture systems for the synthesis and identification of T cell specific anti-metabolites. The ability of the individual nucleosides to alter the generation of allospecific cytotoxic T cells will be tested. The most promising new compounds will be applied for the prevention and treatment of acute GVHD in experimental animals, and eventually in patients with leukemia who receive allogeneic bone marrow transplants.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA035048-02
Application #
3093606
Study Section
Clinical Cancer Program Project Review Committee (CCP)
Project Start
1984-08-01
Project End
1987-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037

  Publications

Willis, E H; Carson, D A; Shultz, L D (1989) Adenosine deaminase activity in recipients of bone marrow from immunodeficient mice homozygous for the wasted mutation. Adv Exp Med Biol 253B:209-12
Fujinami, R S; Nelson, J A; Walker, L et al. (1988) Sequence homology and immunologic cross-reactivity of human cytomegalovirus with HLA-DR beta chain: a means for graft rejection and immunosuppression. J Virol 62:100-5
Cooper, N R (1988) Complement and infectious agents. Rev Infect Dis 10 Suppl 2:S447-9
Willis, E H; Carson, D A; Shultz, L D (1987) Adenosine deaminase activity in recipients of bone marrow from immunodeficient mice homozygous for the wasted mutation. Biochem Biophys Res Commun 145:581-5
Nemerow, G R; Cooper, N R (1987) Virus receptors on lymphoid cells. Methods Enzymol 150:548-58
Sprent, J; Schaefer, M; Lo, D et al. (1986) Properties of purified T cell subsets. II. In vivo responses to class I vs. class II H-2 differences. J Exp Med 163:998-1011
Schrier, R D; Oldstone, M B (1986) Recent clinical isolates of cytomegalovirus suppress human cytomegalovirus-specific human leukocyte antigen-restricted cytotoxic T-lymphocyte activity. J Virol 59:127-31
Carson, D A; Carrera, C J; Kubota, M et al. (1986) Genetic analysis of deoxyadenosine toxicity in dividing human lymphoblasts. Adv Exp Med Biol 195 Pt B:207-11
Seto, S; Carrera, C J; Wasson, D B et al. (1986) Inhibition of DNA repair by deoxyadenosine in resting human lymphocytes. J Immunol 136:2839-43
Cooper, N R (1986) Assays for complement activation. Clin Lab Med 6:139-55

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