We propose to study the mechanism of release of cell membrane components, in particular the role of the cytoskeleton, the nature, composition and characteristics of released vesicles, and their interaction with cells, particularly of the immune system. We have found that vesicles from cancer cells inhibit the induction of macrophage Ia antigen by gamma interferon. Ia antigen expression by the macrophage is essential for antigen presentation to T helper cells and, since it is not constitutive, is subject to regulation. Therefore, the abrogation of Ia induction by vesicles shed from cancer cells may compromise the crucial role of the macrophage in immune regulation. We plan to investigate the nature of the suppressive molecule and the mechanism of such inhibition by vesicles. Vesicles also inhibit other effector mechanisms of the immune system and we will determine by in vitro experiments whether these effects are secondary to macrophage dysfunction. The effect of in vivo administration of vesicles, particularly on macrophage Ia expression and function, host cytotoxic T cells, and suppressor cell induction, will be examined, as well as their effect(s) on tumor formation and progression. Our long term objectives are to determine the precise mechanism(s) of release, the inhibitory molecule(s) on the shed vesicles, and its immune target(s). By determining the nature of these shed vesicles, their release, and the way in which they suppress the immune system, it may be possible to prevent this immunosuppression. This might be done by blocking shedding or by clearing shed material by, for example, plamapheresis. (IS)