Studies from our laboratories have demonstrated a requirement for a source of preformed purine and/or pyrimidine bases for maintenance of cellular immunity. A nucleotide-free diet (NFD) delays rejection of H2-incompatible murine cardiac allografts, and suppresses lymphocyte proliferation to alloantigens. NFD acts synergistically with cyclosporine in suppression of allograft rejection. It slows development of graft versus host disease, decreases interleukin-2 production, suppresses induction of phenotypic T-helper cell populations, and increases suppressor cell activity. Mice maintained on NFD are more susceptible to S. aureus and C. albicans infections. Our results indicate that the T-helper cell population is the most affected. T-cell tumors also show this dependence upon exogenous purine and/or pyrimidines. Enzyme and function studies in NFD fed hosts suggest delay in lymphocyte maturation in the G1 phase of the cell cycle. This maturation arrest is similar to that observed with various immunosuppressive agents, including cyclosporine. To dissect the mechanism by which these substrates exert this influence, we propose the following experiments: 1) To determine the effect of dietary nucleotides on lymphokine (IL-3, Gamma-IFN) and monokine (IL-1) production and upon IL-2 responsiveness; 2) to determine in vitro the specific purine or pyrimidine requirements of T-helper and T-cytotoxic cell clones; 3) to determine the synergism of cyclosporine with specific purines or pyrimidines upon helper or cytotoxic clone function; 4) to determine the influence of dietary nucleotides on phagocytic cell function (O-2 generation, lysosomal enzyme activity, macrophage mobility); 5) to determine dose response curves of specific purines or pyrimidines to immune responses measured in vivo (PLN,DCH, allograft rejection) or in vitro (MLC, lectin); the minimum period of acclimatization to NFD to exert an immunosuppressive response will also be examined; 6) to determine the influence of NFD in combination with blood transfusion and cyclosporine in a vascularized heterotopic heart transplant model; and 7) to examine the possible synergism of NFD with chemotherapeutic anti-metabolites in the treatment of T-cell lymphomas. By clarifying both the mechanism by which NFD suppresses cellular immunity and host defenses and by defining the specific dose of pyrimidines or purines which will maintain immunity, these studies should define dietary regimens which will better support the host defenses of critically ill patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035492-06
Application #
3173066
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1987-03-20
Project End
1990-11-30
Budget Start
1989-03-01
Budget End
1990-11-30
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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Kulkarni, A D; Fanslow, W C; Rudolph, F B et al. (1992) Immunohemopoietic effects of dietary nucleotide restriction in mice. Transplantation 53:467-72
Rudolph, F B; Kulkarni, A D; Fanslow, W C et al. (1990) Role of RNA as a dietary source of pyrimidines and purines in immune function. Nutrition 6:45-52;discussion 59-62
McVaugh, W; Lawrence, B; Kulkarni, A et al. (1989) Suppression of opiate withdrawal by cyclosporin A and dietary modification. Life Sci 44:977-83
Kulkarni, A; Fanslow, W; Higley, H et al. (1989) Expression of immune cell surface markers in vivo and immune competence in mice by dietary nucleotides. Transplant Proc 21:121-4
Fanslow, W C; Kulkarni, A D; Van Buren, C T et al. (1988) Effect of nucleotide restriction and supplementation on resistance to experimental murine candidiasis. JPEN J Parenter Enteral Nutr 12:49-52
Kulkarni, A D; Fanslow, W C; Rudolph, F B et al. (1987) Modulation of delayed hypersensitivity in mice by dietary nucleotide restriction. Transplantation 44:847-9
Kulkarni, A D; Fanslow, W C; Drath, D B et al. (1986) Influence of dietary nucleotide restriction on bacterial sepsis and phagocytic cell function in mice. Arch Surg 121:169-72
Van Buren, C T; Kulkarni, A D; Fanslow, W C et al. (1985) Dietary nucleotides, a requirement for helper/inducer T lymphocytes. Transplantation 40:694-7