A limited antigen-specific cellular response is sufficient for the early control of Mycobacterium tuberculosis in the lung but is insufficient for long-term survival.

Mice that were transgenic for a T-cell receptor (TCR) specific for ovalbumin peptide(323-339) (DO11.10) were able to survive an infection with Mycobacterium tuberculosis for approximately 80 days. This limited early control of infection was associated with gamma interferon production, inducible nitric oxide synthase expression within the lung, and an influx of clonotypic lymphocytes. The control of M. tuberculosis was lost in DO11.10 mice bred in a rag mutant background, demonstrating that the immune responsiveness was recombinase dependent and likely to be associated with the expression of an alternative alpha TCR by DO11.10 mice. A characterization of the antigen specificity in DO11.10 TCR transgenic mice demonstrated that the specificity was limited and dominated by the 26-kDa (Rv1411c) lipoprotein of M. tuberculosis. This study identifies this lipoprotein as an important and potent inducer of protective T cells within the lungs of mice infected with M. tuberculosis and therefore as a possible target for vaccination.

Survey of cattle in northeast Colorado for evidence of chronic wasting disease: geographical and high-risk targeted sample.

A geographically targeted survey of potentially high-risk, adult cattle in chronic wasting disease (CWD)-endemic areas in Colorado was initiated to assess the possibility of the spread of CWD from deer to cattle under natural conditions. Surveyed cattle were sympatric with free-roaming deer in geographically defined areas where CWD occurs and where CWD prevalence has been estimated. To qualify for inclusion in the survey, cattle had to be at least 4 years old and had to have spent a minimum of 4 years in surveyed areas. Brains from culled cattle were examined microscopically and immunohistochemically for tissue alterations indicative of a transmissible spongiform encephalopathy (TSE). Two hundred sixty-two brains were suitable for evaluation and were found to lack changes indicative of a TSE infection. Prion deposition was not demonstrable using a method involving formic acid and proteinase-K treatment before application of monoclonal antibody to bovine prion protein (F99/97.6.1). Some incidental neuropathologic changes unrelated to those of TSEs were detected. Findings from this study suggest that large-scale spread of CWD from deer to cattle under natural range conditions in CWD-endemic areas of northeast Colorado is unlikely.

CD4 is required for the development of a protective granulomatous response to pulmonary tuberculosis.

To confirm the primary role of CD4 T cells in pulmonary tuberculosis, mice with a disruption of their CD4 gene (CD4 KO) were exposed to an aerosol of Mycobacterium tuberculosis and survival, cellular responses in the lung and granuloma development followed. CD8 and NK cells from the lungs of infected CD4 KO mice expressed IFN-gamma and were recruited in numbers similar to those seen in the C57BL/6 mice; recruitment correlated with initial control of bacteria. The major defect in mice lacking CD4 was the significant reduction in total cellular recruitment into the lungs. CD4 KO mice did not generate the typical mononuclear granulomatous lesions, instead the cellular influx was macrophage in character and was localized as perivascular cuffing. Early control of M. tuberculosis growth is therefore independent of CD4+ cells but such cells are required to ensure recruitment of mononuclear cells to the lung and thus ensure long-term survival.

Old mice express a transient early resistance to pulmonary tuberculosis that is mediated by CD8 T cells.

During the natural aging process the immune system undergoes many alterations. In particular, both the CD4 and CD8 T-cell compartments become compromised, and these changes have serious implications for the capacity of the elderly to control infection. As a result, the elderly are more susceptible to many infectious diseases, including primary infection and reactivation of latent infections. In this study we addressed the capacity of old mice to control an infection with Mycobacterium tuberculosis and to characterize the mechanism by which old mice, paradoxically, can express a transient early resistance to infection. This resistance was shown to be associated with the presence of CD8 T cells within the lungs that were capable of secreting gamma interferon, as illustrated by the demonstration that early resistance was lost in aged CD8 gene-disrupted mice. These studies therefore show that, despite a documented decline in general CD8 T-cell responsiveness in the elderly, a subset of CD8 T cells is an important early mediator of protection in the lungs of old mice that have been infected with M. tuberculosis.

The study of Mycobacterium leprae infection in interferon-gamma gene--disrupted mice as a model to explore the immunopathologic spectrum of leprosy.

Mycobacterium leprae infection was evaluated in interferon-gamma knockout (GKO) mice. At 4 months, growth of the bacilli in the footpads of GKO mice plateaued a log(10) higher than that in control mice. Control mice exhibited mild lymphocytic and histiocytic infiltrates, whereas GKO mice developed large, unorganized infiltrates of epithelioid macrophages and scattered CD4 and CD8 T cells. Flow cytometric analysis of popliteal lymph node cells demonstrated similar profiles of T cells; however, GKO cells exhibited an elevated proliferative response to M. leprae antigen. Expression of inducible nitric oxide synthase mRNA was decreased in GKO mice, whereas macrophage inflammatory protein-1alpha and interleukin-4 and -10 mRNA expression were augmented. Control and GKO activated macrophages inhibited bacterial metabolism and produced nitrite. Thus, although deficient in an important Th1 cytokine, GKO mice possess compensatory mechanisms to control M. leprae growth and feature elements resembling mid-borderline leprosy in humans.