No abstract

The nonobese diabetic (NOD) mouse is an animal model of type I diabetes and develops a characteristic autoimmune lesion in the islets of Langerhans with lymphocytic infiltration and destruction of pancreatic beta cells. The result is hypoinsulinemia, hyperglycemia, ketoacidosis, and death. Diabetes usually begins by the sixth month of age but can occur earlier when young NOD mice are infused with lymphocytes from older NOD donors. When newborn or adult NOD mice were infected with a lymphotropic virus they did not become diabetic. The interaction between viruses and lymphocytes is pivotal in aborting diabetes, as established by experiments in which lymphocytes from virus-infected donors failed to transfer diabetes. In contrast, lymphocytes from age- and sex-matched uninfected donors caused disease. Therefore, viruses and, presumably, their products can be developed to be beneficial and may have potential as a component for treatment of human diseases. Further, these results point to the utility of viruses as probes for dissecting the pathogenesis of a nonviral disease.

The Armstrong CA 1371 (ARM) and WE strains of lymphocytic choriomeningitis virus (LCMV) differ in the ability to produce disease in adult guinea pigs. Infection with the ARM strain is not lethal, even at high virus doses (>10,000 PFU), whereas the WE strain causes 100% mortality even at low doses (<10 PFU). To determine the genetic basis of this virulence, intertypic reassortants were made between the ARM and WE strains of LCMV. The two reassortants with the genotypes WE/ARM (L segment of WE and S segment of ARM) and ARM/WE (L segment of ARM and S segment of WE) were tested for their pathogenicity in guinea pigs. The ARM/WE reassortant was avirulent like the ARM/ARM parental strain. Minimal viral replication was observed in organs of guinea pigs inoculated with 102 or 105 PFU of ARM/ARM or ARM/WE, and all animals survived. In contrast, the WE/ARM reassortant was highly virulent like the WE/WE parental strain and killed all of the infected animals. High levels of viral replication were observed in guinea pigs infected with the latter two strains. In contrast to these in vivo observations, both the parental strains and the ARM/WE or WE/ARM reassortants had similar growth potential in cultured guinea pig fibroblasts. Thus, the L RNA segment of LCMV WE is important for viral replication in vivo and is associated with fatal acute disease after infection of adult guinea pigs.

A pore-forming protein (PFP;t also termed perforin or cytolysin) has previously been identified in the granules of CTL and NK cells (1-4). In the presence of calcium, isolated PFP/perforin lyses a variety of target cells nonspecifically. The pore formation model for cell killing, taking into account the lytic function of perforin, is attractive in that it provides a unifying concept that explains cytotoxicity mediated by both CTL and NK cells. Since all previous biochemical analyses of perforin have been conducted with CTL and NK cells propagated in long-term cultures in vitro, it is not clear whether perforin is expressed in vivo by lymphocytes actively engaged in cell-mediated killing. Moreover, the reported absence of measurable amounts of perforin in CTL primed in vivo (5-7) has led to the suggestion that expression of perforin is inextricably driven by IL-2 in vitro, raising the question as to whether this mechanism of lymphocyte-mediated killing occurs in vivo.To address this issue, we investigated the expression of perforin in animals undergoing acute viral infections . CTL and NK cells have long been associated with antiviral immunity (8-12), and in some instances have been implicated directly in the development of immunopathologic injury (11)(12)(13)(14). We chose to analyse the murine infection produced by lymphocytic choriomeningitis virus (LCMV), a member of the arenavirus family. During acute infection it produces intense but localized inflammatory changes, like leptomeningitis and choroiditis or hepatitis, with massive accumulation of CTL and NK cells in the diseased tissues (11)(12)(13)(14). Using two strains ofLCMV (one primarily causing leptomeningitis and the other primarily hepatitis) and by means of immunohistochemical analysis, we show here that perforin is found