We have recently shown that mouse platelets adhere to and lyse sheep erythrocytes that have reacted with anti-SRBC serum and early acting components of complement. The phenomenon is conveniently studied with platelets and sera obtained from C5 deficient mice because of the absence of confounding effects of lytic complement. Through the use of such an experimental system we have shown that lysis occurs even when the ratio of platelets to target cells is less than one, and that lysis is limited to those cells that have been sensitized with antibody and have adherent platelets. The reaction is, in other words, highly efficient and without bystander effects. In the course of these studies we found that platelets secrete a low molecular weight, heat stable, lysin into the fluid portion of blood during the clotting process. Thus, lytic activity for unsensitized cells is found in serum derived from platelet rich plasma but not in serum obtained from platelet free plasma. Unclotted plasma and whole blood are also free of lytic activity. Release of platelet derived cytotoxic factor (PDCF) is also induced by antigen-antibody complexes as well as by a variety of well known stimulators of platelet secretion e.g. thrombin and the ionophor A21387. On the basis of these observations, we have set forth the hypothesis that platelets adhere to erythrocytes that have reacted with antibody and C, and are induced thereby to undergo a release reaction in which PDCF is secreted into the immediate environment of target cells leading to a highly localized lytic reaction. We suggested in our initial publication of these data that the lytic phenomenon probably functioned as an anti-microbial or anti-parasitic mechanism, and that sequestration of the effector substance in platelets facilitated its focussed delivery to targets. Subsequently, other laboratories have reported that platelet rich plasma, but not platelet free plasma, causes lysis of antibody coated schistosomula or trypanosomes. In the proposed study we plan to purify and characterize PDCF and to carry out a detailed analysis of its biological properties. Specifically we propose: (1) To isolate and initiate the physical and chemical characterization of a newly discovered platelet derived cytolytic factor (PDCF). (2) To determine the mechanism of action of PDCF. (3) To define the role of PDCF and other platelet derived substances in: (a) Immune destruction of normal and neoplastic tissues in vivo. (b) Anti-microbial and anti-parasitic defenses.
| Winn, H J (1989) Laws of transplantation. Immunol Ser 43:53-68 |
| Mayer, T G; Bhan, A K; Winn, H J (1988) Immunohistochemical analyses of skin graft rejection in mice. Kinetics of lymphocyte infiltration in grafts of limited immunogenetic disparity. Transplantation 46:890-9 |
