Publications

Tuberculosis has been reported previously in patients with acquired immunodeficiency syndrome who are at increased risk of prior infection with Mycobacterium tuberculosis. We performed a population-based study of AIDS and tuberculosis in San Francisco using the Tuberculosis and AIDS Registries of the San Francisco Department of Public Health. Of 287 cases of tuberculosis in non-Asian-born males 15 to 60 yr of age reported from 1981 through 1985, 35 (12%) also had AIDS, including 23 American-born whites. Patients with tuberculosis and AIDS were more likely to be nonwhite and heterosexual intravenous drug users than were AIDS patients without tuberculosis. Fifty-one percent had tuberculosis diagnosed before AIDS, and 37 percent had AIDS diagnosed at least 1 month prior to the diagnosis of tuberculosis. Although the lungs were the most frequent site of tuberculosis in both AIDS and non-AIDS patients, 60% of the AIDS group had at least 1 extrapulmonary site of disease compared to 28% of the non-AIDS group (p less than 0.001). Nonsignificant tuberculin skin tests were more common in AIDS patients (14 of 23 patients tested) than in non-AIDS patients (12 of 129 patients tested; p less than 0.0001). Chest radiographs in AIDS patients showed predominantly diffuse or miliary infiltrates (60%), whereas non-AIDS patients had predominantly focal infiltrates and/or cavitation (68%). Response to antituberculosis therapy was favorable in AIDS patients, although adverse drug reactions occurred more frequently than in non-AIDS patients (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

The adult T cell leukemia (ATL) is a T cell neoplasm etiologically associated with human T lymphotropic virus type I (HTLV-I) infection. ATL cells often abnormally express interleukin 2 (IL-2) receptors, and ATL patients may show clinical evidence of hypercalcemia, osteolytic bone lesions, or increased bone turnover. Whereas interleukin 1 (IL-1) is not generally recognized as a product of T cells, this cytokine is capable of both altering IL-2 receptor expression and activating osteoclasts. Thus, we investigated the possibility that primary ATL leukemic T cells and HTLV-I-infected long-term ATL cell lines produce IL-1. S1 nuclease protection assays demonstrated that primary leukemic ATL cells from five out of six patients, as well as one patient with T4+ chronic lymphocytic leukemia, contained considerable quantities of IL-1 beta messenger RNA (mRNA) and small amounts of IL-1 alpha mRNA. These primary leukemic T cells also released biologically active IL-1 protein as evaluated in the murine thymocyte comitogenesis bioassay. In contrast to primary tumor cells, four out of six long-term ATL cell lines produced variable amounts of IL-1 alpha mRNA in the absence of detectable IL-1 beta mRNA as measured by S1 nuclease protection. These data demonstrate that IL-1 gene (especially IL-1 beta) expression occurs in many primary HTLV-I-infected leukemic T cells raising the possibility that this mediator may play a role in the pathological changes associated with this leukemia. Also, these studies show that the pattern of IL-1 alpha and IL-1 beta gene expression differs between primary ATL tumor cells and long-term cultured ATL cell lines, indicating an interesting biological difference in these two HTLV-I-infected cell populations.

High concentrations of interleukin 2 (IL 2) were shown to produce a delayed but pronounced proliferation of purified resting T cells in the apparent absence of other activation signals. Because these stimulatory effects of IL 2 occurred in the absence of detectable Tac+ cells, the possibility that IL 2 might be initially interacting with an IL 2 binding protein distinct from the Tac protein was studied. Chemical cross-linking studies with 125I-IL 2 revealed the presence of an IL 2 binding protein distinct from the Tac protein on the surface of these unstimulated T cells. This second IL 2 receptor has an estimated molecular size of 70,000 daltons, lacks reactivity with the anti-Tac antibody, and appears to be identical to the p70 protein recently proposed as a component of the high affinity IL 2 receptor. Scatchard analysis of IL 2 binding assays performed with the unactivated T cells revealed approximately 600 to 700 p70 sites per cell and an apparent Kd of 340 pM. These data indicate that the p70 protein present on resting T cells binds IL 2 with an intermediate affinity compared with the previously recognized high and low affinity forms of the receptor and may account for the high concentration of IL 2 needed to induce resting T cell proliferation. To investigate the early biologic consequences of IL 2 binding to the p70 protein, potential changes in the expression of genes involved in T cell activation were examined. Northern blotting revealed the rapid induction of c-myc, c-myb, and Tac mRNA after stimulation of resting T cells with a high concentration of IL 2. The anti-Tac antibody did not inhibit IL 2 induced expression of these genes, suggesting that the p70 protein rather than the Tac antigen or the high affinity IL 2 receptor complex mediated this signal. However, in contrast to these early activation events, the anti-Tac antibody significantly inhibited IL 2 induced T cell proliferation. This finding implicates the high affinity form of the IL 2 receptor in the proliferative response of the IL 2 activated T cells. Thus these data support a two step model for the induction of resting T cell proliferation by high doses of IL 2 involving the initial generation of an activation or "competence" signal through the p70 protein and a subsequent proliferation or "progression" signal through the high affinity form of the receptor.

Nonhuman primates with chronic systemic hypertension provide an ideal model for studying structural and functional alterations associated with compensatory cardiac hypertrophy. Since noninvasive techniques are useful for the longitudinal evaluation of these animals, we sought to critically asses the M-mode echocardiographic estimation of left ventricular mass in the baboon and to characterize estimates of left ventricular size and function in baboons with chronic renal hypertension. In 23 baboons (12 normotensive, 11 chronic hypertensive), M-mode echocardiography-determined left ventricular mass was 73 +/- 13 (SE) g as compared with the necropsy weight of 69 +/- 11 g (p = NS), and the correlation was excellent (r = 0.94). When 30 chronically hypertensive baboons being observed longitudinally were compared with 10 normotensive control animals studied under identical conditions, several differences were noted in measures derived from echocardiography and high fidelity pressure measurements. Left ventricular systolic pressure was considerably higher in the hypertensive baboons (113 +/- 23 vs 90 +/- 11 mm Hg; p less than 0.001), as was left ventricular mass (148 +/- 60 vs 103 +/- 38 g; p less than 0.03). However, since the ratio of posterior wall thickness to cavity dimension was larger in the hypertensive baboons (0.52 +/- 0.17 vs 0.43 +/- 0.07; p less than 0.05), this concentric hypertrophy maintained values for left ventricular meridional stress at the same level as in the control animals. Despite matched heart rate and left ventricular stress, the rates of change in left ventricular dimensions and wall thickness in systole and diastole were all approximately 25% less in the hypertrophied baboons.(ABSTRACT TRUNCATED AT 250 WORDS)

Depletion of critical T cell subsets in vivo by treatment with anti-L3T4 antibody (mAb GK1.5) enables BALB/c mice to heal subsequent Leishmania major infection. To investigate the mechanisms by which healing is established, anti-leishmania cellular and humoral responses in anti-L3T4-treated BALB/c mice were compared to those in control BALB/c and genetically resistant C57BL/6 mice. Lymph node and spleen cells were harvested from L. major-infected animals at 1, 2, 3, 4, and 8 wk post-infection and examined in vitro for concanavalin A- or L. major antigen (either promastigote or amastigote)-induced IFN-gamma production. Serum was harvested for Western blot analysis against L. major promastigote antigens. Lymph node cells from resistant C57BL/6 mice generated Leishmania antigen-induced IFN-gamma that was maximal by 3 wk; spleen cell IFN-gamma production peaked a week later. Lymph node and spleen cells from susceptible BALB/c mice generated minimal levels of IFN-gamma activity in response to Leishmania antigen stimulation throughout the experiment. Lymph node and spleen cells from BALB/c mice which had been pretreated with GK1.5 generated IFN-gamma in response to Leishmania antigens in vitro at levels that approached those generated by C57BL/6 mice. When splenic mRNA from infected animals was hybridized with a labeled murine IFN-gamma cDNA probe, there were corresponding differences in the amount of IFN-gamma message present, demonstrating that the differences observed in IFN-gamma production in vitro were also apparent in vivo, and were due to differences in transcription. In contrast to C57BL/6 mice which generated only a limited array of Leishmania-specific antibodies, BALB/c mice produced antibodies which reacted with a large number of Leishmania antigens. The GK1.5-treated BALB/c mice developed Leishmania-specific antibodies at a slower rate than did untreated BALB/c mice. However, by 8 wk after infection, the humoral responses of the anti-L3T4-treated BALB/c mice and the untreated BALB/c mice were comparable. These data document the kinetics of ascending immunity from the draining local lymph nodes to the spleen and confirm, both in vitro and in vivo, the correlation of IFN-gamma production with control of infection in leishmaniasis. Further, an L3T4+ T cell subpopulation may be incriminated in the failure of genetically susceptible BALB/c mice to activate curative cell-mediated immunity in response to Leishmania antigens.