The pathogenesis of experimental scrapie in inbred mice

Abstract

An outline is given of the present state of knowledge regarding the pathogenesis of scrapie agents in mice. Emphasis is laid on the unconventional nature of the disease and its causal agent. A methods section describes the relevant aspects of the special methodology which has been developed in the research institutes where this thesis was written. An investigation of the incubation periods of three different strains of scrapie agent injected at a range of ages from birth to weaning in three strains of inbred mice shows that the undeveloped state of these hosts at birth causes a considerable modification of pathogenesis: in particular, many newborn mice do not develop scrapie after a dose which would always kill weanlings. Reasons are given for suspecting that the relevant undeveloped organ system is the lymphoretioular system, and that some form of scrapie 'inactivation' must also be involved. Attempts to throw light on agent pathogenesis by looking for pharmacological treatments which will change inoubation periods, produced numerous negative results (outlined) and some positive ones (described in full). Using the i.p. route of agent injection and drug treatment in the weeks immediately before and after infection, signifioantly changed inoubation periods were obtained with prednisone acetate, arachis oil, prednisone acetate + cyclophosphamide, and prednisone acetate + peritoneal-oell provocation with thioglyoollate medium. Preliminary positive results using neonatal treatment with 6-hydroxydopamine and adult treatment with phytohaemagglutinin are also desoribed. Evidence is reported for a prolonging of inoubation period of i.o. injected agent by subsequent actinongrcin D injections. Experiments are desoribed in which the peripheral pathogenesis of ME7 sorapie appears to be greatly modified both in terms of incubation period and pattern of lesion distribution in the brain by donor-tissue components. Observations on the histological differences are reported and a number of experiments described which suggest that agent pathogenesis may require specific reactions of an immunological type on the part of the host to donor-specified antigens in the inoculum. It is shown in a large range of agent/host strain combinations that there are early changes in drinking (and in some cases feeding) habits of mice infected with scrapie. Reasons are given for believing that these are due to an upset of normal brain function by the agent the physiological basis of which is close to the primary lesion due to scrapie, i.e. some derangement of the function of the sinc gene or its immediate product (SECTION 2). The possibility that this is an upset in catecholamine function is discussed. A number of experiments and observations ancillary to the main seotions are collected in five appendices. Full discussions are given at the end of each SECTION, while in the Final Discussion an attempt is made to bring all the above observations together and to point the way to further research. Several alternative models of scrapie pathogenesis in peripheral organs are briefly reviewed.