Collectively, these findings provide a foundation for understanding the immunological mechanisms that confer resistance or susceptibility to H. hepaticus-induced typhlitis.

The therapeutic efficacies of human recombinant alpha interferon (IFN-alpha), IFN-alpha plus zidovudine (AZT), and AZT alone were evaluated in presymptomatic cats with established feline leukemia virus (FeLV)-acquired immunodeficiency syndrome (FAIDS) infection and high levels of persistent antigenemia. Subcutaneous injection of 1.6 x 10(6) U of human recombinant IFN-alpha 2b per kg delivered peak concentrations in plasma of 3,600 U/ml at 2 h postadministration with a half-life of elimination of 2.9 h. This dosage of IFN-alpha could be delivered to cats for up to 12 weeks without significant clinical toxicity. Oral administration of AZT (20 mg/kg three times daily) resulted in peak concentrations in plasma of 3 micrograms/ml at 2 h with a half-life of elimination of approximately 1.60 h. Treatment of FeLV-FAIDS-infected cats with IFN-alpha, either alone or in combination with orally administered AZT, resulted in significant decreases in circulating p27 core antigen beginning 2 weeks after the initiation of therapy. AZT alone had no effect on circulating virus antigen. Depending upon whether high (1.6 x 10(6) U/kg)- or low (1.6 x 10(4) to 1.6 x 10(5) U/kg)-dosage IFN-alpha was used, cats became refractory to therapy 3 or 7 weeks after the beginning of treatment. At these times, IFN-alpha-treated animals developed antibodies to IFN-alpha that were neutralizing, specific for human recombinant IFN-alpha, and dose dependent in magnitude. The results of this study indicate that human recombinant IFN-alpha is effective in reducing circulating virus antigenic load in cats persistently infected with FeLV-FAIDS. However, the continued efficacy of IFN-alpha therapy appeared to be limited by the formation of cytokine-specific neutralizing antibodies.

The inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. The causes of these diseases remain unknown; however, prevailing theories suggest that chronic intestinal inflammation results from a dysregulated immune response to ubiquitous bacterial antigens. While a substantial body of data has been amassed describing the role of the adaptive immune system in perpetuating and sustaining inflammation, very little is known about the early signals, prior to the development of inflammation, that initiate and direct the abnormal immune response. To this end, we characterized the gene expression profile of A/JCr mice with Helicobacter hepaticus-induced typhlitis at month 1 of infection, prior to the onset of histologic disease, and month 3 of infection, after chronic inflammation is fully established. Analysis of the gene expression in ceca of H. hepaticus infected mice revealed 25 up-regulated and 3 down-regulated genes in the month-1 postinoculation group and 31 up-regulated and 2 down-regulated genes in the month-3 postinoculation group. Among these was a subset of immune-related genes, including interferon-inducible protein 10, monokine induced by gamma interferon, macrophage-induced protein 1 alpha, and serum amyloid A1. Semiquantitative real-time reverse transcriptase PCR confirmed the increased expression levels of these genes, as well as elevated expression of gamma interferon. To our knowledge, this is the first report profiling cecal gene expression in H. hepaticus-infected A/JCr mice. The findings of altered gene expression prior to the development of any features of pathology and the ensuing chronic disease course make this an attractive model for studying early host response to microbe-induced inflammatory bowel disease.

The FeLV-FAIDS strain of feline leukemia virus consistently induces fatal immunodeficiency. To investigate the immunopathogenesis and viral genetic determinants responsible for the induction of immunodeficiency disease in vivo, we have generated chimeras between the two major viral genomes in the original virus isolate, designated common form clone 61E and major variant clone 61C, which were molecularly cloned directly from DNA of the same animal and tissue. Each of three 61E/C chimeras, containing at minimum a 34-amino-acid segment (including a 6-amino-acid insertion and one amino acid substitution) near the C terminus of the 61C surface glycoprotein (gp7O), induced fatal immunodeficiency disease in all (12 of 12) infected animals over a course of 33 10 weeks. By contrast, animals infected with virus 6iE, although persistently antigenemic, remained asymptomatic throughout a 48-week observation period. Beginning 14 weeks after infection, a significant decrease (8 to 10%) in the percent of circulating CD4+ T lymphocytes developed in the 61E/C chimera-infected cats, compared with either 61E-infected or control animals. At this time, no significant changes were seen in CD8 cells, B cells, or mitogen-induced blastogenesis. Prior to this initial decline in CD4 cells, the ability of all antigenemic 61E/C-infected cats to generate a primary antibody response to the T-cell-dependent antigen keyhole limpet hemocyanin was markedly impaired, whereas all 61E-infected cats, one 61E/C-infected but nonviremic cat, and all uninfected control cats produced normal antibody responses. The results reported here demonstrate that a major determinant of in vivo immunodeficiency induction by FeLV-FAIDS is contained within a 34-amino-acid C-terminal segment of its surface glycoprotein and that this gp7O alteration determines the early and persistent deficits in CD4+ T lymphocytes and T-cell-dependent antibody responses. We hypothesize that these early immunologic alterations could result from early deletion of a CD4+ helper T-cell subset.

The pathogenesis of inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, is due in part to interactions between the immune system, genetics, the environment, and endogenous microbiota. Gonadal sex hormones (GSH), such as estrogen, are thought to be involved in the development of IBD as variations in disease severity occur during pregnancy, menopause, or oral contraceptives use. In certain strains of mice, infection with Helicobacter hepaticus triggers IBD-like mucosal inflammation that is more severe in female mice than in males, suggesting a role for GSH in this model. To determine the role of estrogen signaling in microbiota-induced intestinal inflammation, estrogen receptor (ER) α and β knock-out (KO) mice, ER agonists, and adoptive transfers were utilized. We demonstrate that, when signaling is limited to ERβ on a non-CD4+ cell subset, disease is less severe and this correlates with decreased expression of pro-inflammatory mediators.