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 #
5P01CA035048-03
Application #
3093607
Study Section
Clinical Cancer Program Project Review Committee (CCP)
Project Start
1984-08-01
Project End
1987-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
3
Fiscal Year
1986
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
Nemerow, G R; Cooper, N R (1987) Virus receptors on lymphoid cells. Methods Enzymol 150:548-58
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
Cooper, N R (1986) Assays for complement activation. Clin Lab Med 6:139-55
Schrier, R D; Rice, G P; Oldstone, M B (1986) Suppression of natural killer cell activity and T cell proliferation by fresh isolates of human cytomegalovirus. J Infect Dis 153:1084-91
Carrera, C J; Willis, E H; Chilcote, R R et al. (1986) 5'-deoxy-5'-methylthioadenosine phosphorylase deficiency in leukemia: genetics and biochemical aspects. Adv Exp Med Biol 195 Pt B:643-50
Kajander, E O; Kubota, M; Carrera, C J et al. (1986) Resistance to multiple adenine nucleoside and methionine analogues in mutant murine lymphoma cells with enlarged S-adenosylmethionine pools. Cancer Res 46:2866-70
Lo, D; Sprent, J (1986) Identity of cells that imprint H-2-restricted T-cell specificity in the thymus. Nature 319:672-5

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