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.
