Studies on the molecular mechanisms of lymphocyte extravasation.

The cells of the mammalian immune system exhibit special migratory properties within their in vivo environment, a characteristic that is thought to be important in the protection of the organism by a process known as immunological surveillance. The present study utilized a radiotracer technique to establish that ultraviolet radiation (UVR), an environmental carcinogen, can induce alterations in the physiology of the immune apparatus, as reflected by the migration of lymphoid cells within mice exposed to UVR. The impact of the recirculation of lymphocytes on adoptive immunity was addressed by characterizing and utilizing inhibitors of in vivo cellular migration. Pertussis toxin, a protein secreted by the bacterium Bordetella pertussis, was shown to induce a selective and long-lasting inhibitition of the emigration of lymphocytes from the bloodstream into solid tissue. This blockade was associated with an inhibition of certain cell-mediated immune responses in vivo. The inhibitory effect was established to be a direct result of the toxin-mediated defect in cellular migration. The molecular mechanism of the inhibition was investigated in vitro, using as a model the well-defined system of chemotaxis of polymorphonuclear neutrophils. The characteristics of inhibition which were observed in this in vitro assay system were quite similar to those observed in vivo. Further, the mechanism of inhibition was demonstrated to be associated with a defect in the regulation of the intracellular channeling of free calcium, a postulated second messenger in the biochemical process of cellular stimulus-response coupling. The results of the present studies support the conclusion that the recirculation of lymphocytes plays a major role in the in vivo function of the immune system, and thus homeostasis of the host organism. Further, these studies provide a basis for further experimentation to define the molecular processes which control cellular migration in vivo.