• Determining control parameters for dendritic cell-cytotoxic T lymphocyte interaction

      Ludewig, Burkhard; Krebs, Philippe; Junt, Tobias; Metters, Helen; Ford, Neville J.; Anderson, Roy M.; Bocharov, Gennady; University of Zürich ; University of Zürich ; University of Zürich ; University of Zürich ; University College Chester ; Imperial College, University of London ; Institute of Numerical Mathematics, Russian Academy of Sciences (WILEY-VCH Verlag GmbH & Co. KGaA, 2004-08-05)
      Dendritic cells (DC) are potent immunostimulatory cells facilitating antigen transport to lymphoid tissues and providing efficient stimulation of T cells. A series of experimental studies in mice demonstrated that cytotoxic T lymphocytes (CTL) can be efficiently induced by adoptive transfer of antigen-presenting DC. However, the success of DC-based immunotherapeutic treatment of human cancer, for example, is still limited because the details of the regulation and kinetics of the DC-CTL interaction are not yet completely understood. Using a combination of experimental mouse studies, mathematical modeling, and nonlinear parameter estimation, we analyzed the population dynamics of DC-induced CTL responses. The model integrates a predator-prey-type interaction of DC and CTL with the non-linear compartmental dynamics of T cells. We found that T cell receptor avidity, the half-life of DC, and the rate of CTL-mediated DC-elimination are the major control parameters for optimal DC-induced CTL responses. For induction of high avidity CTL, the number of adoptively transferred DC was of minor importance once a minimal threshold of approximately 200 cells per spleen had been reached. Taken together, our study indicates that the availability of high avidity T cells in the recipient in combination with the optimal application regimen is of prime importance for successful DC-based immunotherapy.