The clinical forms of leprosy constitute a spectrum that correlates closely with the degree of cellmediated immunity. Patients with tuberculoid leprosy develop strong cell-mediated responses and have only a few, localized lesions, whereas patients with multibacillary lepromatous leprosy are specifically unresponsive to antigens of Myobacterium leprae. T cells of the CD4+ subset predominate in tuberculoid lesions, whereas CD8+ cells predominate in lepromatous lesions. Monoclonal antibodies that distinguish subpopulations of CD4+ and CD8+ cells were used to analyze the distribution of T cells infiltrating lesions across the disease spectrum. In lepromatous lesions, T cells of T-suppressor phenotype (9.3-) were the predominant CD8+ cells and suppressor/inducer cells (2H4+, Leu-8+) represented half of the CD4+ subset. In tuberculoid lesions, helper T cells (CD4+4B4+) outnumbered suppressor/inducer T cells by 14:1, compared with a ratio of 1.2:1 in peripheral blood. Analysis of the precursor frequency of antigen-reactive T cells permitted us to estimate that there was a 100-fold enrichment of T cells able to proliferate in response to M. leprae antigens in tuberculoid lesions (2/100), when compared with blood from the same patients. The methods used here to characterize the T-lymphocyte subsets and frequency of antigen-reactive T cells in leprosy may be useful in analyzing imunological reactions occurring in lesions of other inflammatory and autoimmune diseases.There are at least two compelling reasons to study leprosy. The disease itself, affecting 10-15 million people worldwide, poses a significant health and economic burden on thirdworld countries. Second, because leprosy is a spectral disease in which pathology and immunology are inextricably related, it provides a unique critical model for investigating immunoregulatory mechanisms in humans.Leprosy is not a single critical entity but rather comprises a spectrum of clinical manifestations that correlate remarkably well with immunological responses to the organism (1). Patients with tuberculoid leprosy have a few localized lesions with rare organisms and a strong cell-mediated immune response directed against Myobacterium leprae antigens that ultimately kills and clears the bacilli, although often with concomitant injury to nerves. In contrast, lepromatous leprosy patients have numerous skin lesions containing extraordinarily high numbers of acid-fast bacilli and show specific immunological unresponsiveness to antigens of M. leprae in vivo and in vitro.The selective mechanisms of accumulation of lymphocytes, their antigen specificity, and immunological functions in inflammatory lesions of human infectious or autoimmune diseases remain largely unknown. Since the focal point of the immune response to M. leprae is the tissue granuloma, consisting of a collection of lymphocytes and macrophages, some of these questions can be approached directly through the study of cells infiltrating the lesions across the spectrum of leprosy.Immunohistological studies using m...

Cell walls of Mycobacterium leprae, prepared by differential solvent extraction, were shown to contain arabinogalactan, mycolates, and peptidoglycan. In addition, amino acid analysis revealed the unexpected presence of large amounts of protein that retained potent immunological reactivity. Purified cell walls stimulated proliferation of T cells from tuberculoid, but not from lepromatous leprosy, patients and elicited delayed-type hypersensitivity skin reactions in guinea pigs and patients sensitized to M. leprae. Analysis of the precursor frequency of antigen-reactive human peripheral T cells revealed that as many cells (41/6000) proliferate to antigen contained in cell walls as to intact M. keprae. Sequential removal of mycolates and arabinogalactan resulted in a large peptidoglycan-protein complex that retained all the immunological activity. This immunological reactivity and the inherent protein were destroyed by proteolysis. Thus, cell wall protein is a major contributor to cell-mediated immune reactivity to this pathogenic mycobacterium.Leprosy is a chronic infectious disease that afflicts 10-13 million people, primarily living in developing countries (1). Although the incidence of leprosy is declining in many parts of the world, largely due to greater control efforts, the cost of multidrug therapy to combat emergent drug resistance of Mycobacterium leprae is high, and the development of an effective vaccine is widely agreed to offer the best hope for disease eradication (2, 3). Because M. leprae is one of few major pathogens of man that has not been successfully cultivated in vitro, the principal available source of antigens for study and vaccines remains infected tissues of the nine-banded armadillo Dasypus novemcinctus, which is inevitably limited and costly. Consequently, immunological and molecular biological approaches that permit identification and production of protective antigens are needed. Thus far, using murine monoclonal antibodies, genes for six major antigens of M. leprae have been isolated from Agtll libraries (4).From a variety of studies, cell-mediated immunity, which is regulated by specifically sensitized T lymphocytes, is clearly required for protection and resistance to leprosy (1).The disease encompasses an immunological spectrum. At one pole, lepromatous leprosy, patients selectively lack cell-mediated immunity to antigens of M. leprae and fail to restrict the growth of the pathogen; at the tuberculoid end of the spectrum, the patients exhibit cell-mediated immunity to antigens of M. leprae and develop one or a few sharply defined local lesions that contain only few acid-fast bacilli. However, when we and other workers derived M. lepraespecific CD4 + (helper T cell) clones from strongly leprominpositive healthy contacts of lepromatous patients or from blood or lesions of patients with tuberculoid leprosy, only a small proportion of clones tested are responsive to the known serologically defined recombinant antigens (ref. 5; J.M.-K., R.L.M., and B.R.B., unpublished data).For m...

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The role of splenic leukocyte oxidative activity and macrophage activation in the development of protective immunity was examined during acute Plasmodium chabaudi adami malaria. Splenic leukocyte oxidative activity was compared in infected BALB/c and P/J mice; the latter are known to suffer from defects in macrophage function. Phorbol myristate acetate-stimulated chemiluminescence and superoxide anion production by splenic leukocytes from infected BALB/c mice were found to be increased dramatically, while the response of splenic leukocytes from infected P/J mice was elevated only minimally. Hydrogen peroxide release was slightly increased in splenic leukocytes from infected BALB/c mice but remained essentially unchanged in those from infected P/J mice. Macrophage function was assessed on the basis of measurements of tumoricidal activity. Splenic macrophages from uninfected BALB/c mice displayed significant tumoricidal activity against L929 target cells. As a result of splenomegaly during infection, tumoricidal activity, when calculated on a per-spleen basis, was increased further in infected BALB/c mice. In contrast, the tumoricidal activity of splenic macrophages from P/J mice was minimal, regardless of infection. Despite these differences, both strains of mice developed malarial infections that resolved within 16 days. Thus, while the production of reactive oxygen radicals by splenic leukocytes and the phenomenon of macrophage activation have traditionally been associated with the resolution of malarial infection, this study failed to establish a correlation between these parameters and the development of protective immunity to blood-stage infection with P. chabaudi adami.