MIC genes in non-human primates.

MIC molecules belong to the immunoglobulin superfamily, are encoded within the MHC region and are recognized by gamma/delta T-cell receptors. In humans, at least two functional genes (MIC-A* and MIC-B*) and two pseudogenes (MIC-C* and MIC-D*) exist. Functional MIC gene copies are characterized by a high degree of polymorphism, while pseudogenes bear several debilitating mutations either in the putative extracellular region or in the transmembrane region of the molecule. In this study we sequenced these segments of MIC genes in seven non-human primates in order to determine whether debilitating mutations were present. All the MIC primate genes studied were highly homologous to their human counterparts, and cystein residues involved in the maintenance of the immunoglobulin-like structure were highly conserved. Furthermore, none of the MIC genes studied contained stop codons in the extracellular or transmembrane segments of the molecule, which suggests that at least one functional gene copy exists in non-human primates. A distinct family of MHC immunoglobulin-like genes was recently identified within the MHC class I region in humans (Bahram et al., 1994; Leelayuwat et al., 1994). Members of this MIC (MHC class I chain related) gene family belong to the immunoglobulin superfamily. Similar to classical class I MHC genes, they are characterized by three distinct extracellular domains (alpha 1-3), a transmembrane (TM) segment and a cytoplasmic segment, each encoded by a separate exon (Bahram et al., 1994; Bahram et al., 1996). Other similarities between MIC genes and classical MHC genes include a high degree of polymorphism (Fodil et al., 1996; Pellet et al., 1997) and recognition by T-cell receptors (Groh et al., 1998). These findings suggest that the putative MIC-A* chain has evolved for a function that is related to, but quite distinct from, that of typical MHC class I chains.

Effect of immunosuppressive drug regimens on acute and chronic murine toxoplasmosis.

To evaluate the potential risk of dissemination or reactivation of toxoplasmosis following the administration of immunosuppressive therapy we examined the effect of corticoids, azathioprine, and cyclosporine given alone or in combination on the course of murine acute and chronic toxoplasmic infection. Swiss Webster mice were infected perorally with a high-level inoculum of cysts of the C strain of Toxoplasma gondii. The evolution of the kinetics of parasite loads in the blood, brain, and lungs of infected and immunosuppressed mice was then sequentially followed. In mice with orally acquired infections initiated 2 days after the beginning of drug treatment, immunosuppression led to the persistence of parasites, especially in the lungs, which was most marked in mice treated with azathioprine and/or cortisol acetate. Administration of immunosuppressive therapy in mice previously infected with T. gondii resulted in a brief resurgence of parasite loads when treatment was started early after infection. Finally, under our experimental conditions we found that the immunosuppressive drugs that were given altered the natural course of infection with a prolonged persistence of parasites in the lungs but did not significantly affect parasite loads in the brain or lead to disseminated infection with detectable parasitemia.

[Experimental models of toxoplasmosis. Pharmacological applications]. / Modèles expérimentaux de toxoplasmose. Applications pharmacologiques.

Toxoplasma gondii is an ubiquitous protozoan parasite causing severe or life-threatening infections in immunocompromised patients and in congenitally infected infants. Animal models have been extensively used to describe the pathology of infection and to identify new effective drugs for the treatment of congenital infections, chrorioretinitis and toxoplasmic encephalitis. Although inherent differences between man and animal can reduce the relevance of data obtained experimentally, animal models have greatly improved our knowledge on the various aspects of toxoplasmosis. Toxoplasma infection can be easily obtained in most laboratory animals, with exception of rats which are partially resistant. According to the strain used, the resulting infection may be acute, subacute or chronic, and can be monitored either by the survival of animals, the histopathological examination of lesions or, preferably, by titration of parasites in infected tissues using subinoculation to mice or tissue culture. This latter method has proved particularly useful to describe the kinetics of infection in host tissues and to assess the efficacy of drugs, according to their pharmacokinetics and tissue distribution. The relevance of results obtained in animal models of congenital toxoplasmosis and of chrorioretinitis is more questionable, due to the marked differences between the mode of infection in humans and in animals. Experiments performed in primates provided valuable informations for the management of therapy of congenital toxoplasmosis but were of limited interest for ocular toxoplasmosis. The pathogeny of toxoplasmic encephalitis is still poorly understood, and no experimental model is fully satisfactory to produce focal encephalitic lesions as observed in immunocompromised humans. Acute infections with highly virulent strains induce disseminated infection with major pulmonary and brain involvement, and thus can be used to assess the efficacity of drugs in these tissues. Direct inoculation of tachyzoites into brain tissue can induce focal encephalitis but this model is of difficult use for large scale studies. Although cellular immunity is mainly responsible for the control of toxoplasmosis at the chronic stage, administration of immunosuppressive drugs does not usually result in focal brain reactivation; such reactivation can only be obtained using antibodies against CD8 and CD4 T lymphocytes or interferon gamma. Another experimental approach is the use of genetically immunodeficient animals: these models are of limited interest for pharmacological research since infection of nude or T depleted mice usually results in a dissemination of infection; however, using these models it could be clearly demonstrated that immunity plays a major adjunctive role in the control of acute infection. Concurrent infections between viruses and parasites is a common feature in immunocompromised patients and especially during AIDS.(ABSTRACT TRUNCATED AT 400 WORDS)

Early kinetics of Toxoplasma gondii infection in mice infected orally with cysts of an avirulent strain.

We determined the early kinetics of Toxoplasma gondii infection in Swiss Webster mice inoculated with the avirulent C strain by counting parasites in the blood, spleen, Peyer's patches, liver, lungs, and brain. Animals were orally inoculated with cysts on day zero (D0), and parasites were counted using a tissue culture method at 12, 24, and 36 hr and 2, 3, 7, 10, 14, 21, 30, 50, and 72 days postinfection. The spleen and Peyer's patches were the first organs found parasitized, on D2 and D3, respectively, followed by the lungs and liver on D7 and the brain on D10. No parasitemia was detected. This suggests that early dissemination of this avirulent strain from the intestine into the general circulation occurs essentially via the lymphatic system. Parasites persisted at a high level in the brain during the chronic phase. In the lungs, parasites were no longer detected by D72, while parasite numbers initially declined in the spleen and Peyer's patches but then showed a second peak, possibly due to recirculation of T. gondii. These results suggest that lymphoid organs play a key role in T. gondii dissemination during the acute phase and may also constitute a persistent source of parasite resurgence.