We recently made the novel discovery that platelet derived growth factor (PDGF) is capable of profoundly altering the responsiveness of murine T cells, through its capacity to control the species and patterns of lymphokines produced following cellular activation. this finding takes on a significant degree of importance, when one considers that most experimentalists in immunology, who utilize in vitro procedures in their research, routinely employ some source of serum as a culture medium supplement. Serum, unlike plasma, is heavily contaminated by a number of biologically active growth factors (including PDGF) as a consequence of blood clotting and the resultant platelet activation. By considering the types of T cell responses controlled by PDGF, and the duration of this regulatory influence prior to growth factor desensitization, some of the reported """"""""differentiation"""""""" events that occur in vitro following cellular activation under serum containing conditions are easily explained. Maybe these model systems, some of which represent presently accepted paradigms, will have to now be restructured. We have chosen to look beyond the effects of PDGF, as a creator of biologic artifacts on T cell function in vitro. Our present studies investigate the in vivo role(s) played by this growth factor in orchestrating the potential of T cells to respond under special sets of circumstances. As will become apparent from the data presented, PDGF could be playing a central, although totally overlooked, role in controlling mammalian immune responses in vivo. This regulatory system is proving to be beautifully complex, and involves both active and antagonistic PDGF isoforms. Also important to the system is a requirement for cell surface expression of both alpha- and beta-type receptor subunits for T cell responsiveness. T cells isolated from gut mucosa draining lymphoid organs of normal murine donors were found to lack responsiveness to the effects of PDGF, and PDGF responsiveness is totally lost as a consequence of old age. Both of these phenomena appear to be directly linked to activities mediated by the cytokine IL-6. IL-6 may be produced locally in gut- mucosa draining lymphoid compartments. We have recently discovered that control over the production of IL-6 is dysregulated as a consequence of normal aging, a finding which possesses significant biologic and immunobiologic importance. The experimental plan presented herein is purposefully comprehensive, and includes an analysis of PDGF-influences on cytokine production by human T cells. We will investigate PDGF isoform dependence, receptor subunit requirements, the modulatory influence by IL-6, and the effect of donor age on growth factor responsiveness. Also included in this proposal, is a research plan to advance our understanding of the murine system. Studies to investigate T cell subset responsiveness, dependence on lymphoid organ source, the effects of T cell donor age and its relationship to dysregulated production of IL-6 are all planned for investigation. Also presented with this proposal are studies designed to further our understanding of the mechanisms which serve to restore normal IL-6 regulation in old animals supplemented with dehydroepiandrosterone (DHEAS).
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