A study of the immunological effects of cimetidine in patients with lepromatous leprosy.

To test the capacity of cimetidine to enhance cellular immunity in patients with lepromatous leprosy (LL), cimetidine was given for one month to 29 inactive LL patients and 3 active LL patients. Immune function was monitored with skin tests (lepromin, PPD, candida, and trichopytin), lymphocyte transformation tests (phytohemagglutinin, BCG, and Dharmendra lepromin), and quantitation of peripheral blood lymphocyte subpopulations. A small but significant "booster" response to PPD was the only change observed in the study of patients with inactive disease, and leprosy-related reactions did not occur. In the few active LL patients studied, neither immune enhancement nor leprosy-related reactions were observed. The results of this investigation suggest that cimetidine can be used safely in patients with inactive lepromatous leprosy.

Rifampin in the treatment of leprosy.

The minimal inhibitory concentration of rifampin for Mycobacterium leprae is less than 1 microgram/ml. Therapy with rifampin has proved efficacious both in mice experimentally infected with M. leprae and in humans with leprosy. Rifampin kills M. leprae more rapidly than do other antileprosy drugs currently available. Consequently, M. leprae bacilli from patients with lepromatous disease are rendered noninfectious within three weeks after the institution of rifampin therapy, as determined in the mouse footpad test system. Administration of this antibiotic substantially reduces the quantities of M. leprae discharged in the nasal secretions of lepromatous patients within three weeks, thus rapidly decreasing the potential infectivity of these individuals. Intermittent rifampin therapy for leprosy has been successful, with a low incidence of adverse reactions to the drug. Worldwide, the prevalence of primary and secondary resistance of M. leprae to dapsone has increased markedly. Therefore, the World Health Organization recommends a multidrug regimen that includes intermittent administration of rifampin for the treatment of leprosy.

Aberrant immunoregulatory control of B lymphocyte function in lepromatous leprosy.

The capacity of peripheral blood mononuclear (PBM) cells from patients with leprosy to generate immunoglobulin-secreting cells in response to pokeweed mitogen (PWM) was evaluated by a reverse haemolytic plaque forming cell (PFC) assay. The PFC responses of PBM cells from patients with lepromatous (Lpr) leprosy were significantly higher (P less than 0.01) than those of PBM cells from normal controls and patients with tuberculoid leprosy. Co-culture of T lymphocytes from normal donors with PBM cells from Lpr patients reduced the PFC response of these cells to the normal range. T4+-helper lymphocytes from Lpr donors did not induce supranormal responses to PWM by normal PBM cells enriched for B lymphocytes. T8+-suppressor lymphocytes from normal donors greatly reduced the response of cultures containing normal allogeneic B cells plus T4+ cells. Conversely, when T8+ cells from Lpr donors were cocultured with normal B cells plus T4+ cells, they failed to suppress the response to PWM. In summary, these studies have demonstrated abnormally high PWM-stimulated PFC responses by B lymphocytes from patients with Lpr leprosy. This aberration, in turn, is associated with a loss of regulatory function by T8+-suppressor cells in Lpr patients.

Comparison of 22 species of Mycobacteria by immunodiffusion against an absorbed reference leprosy serum.

Lithium acetate antigenic extracts of 22 species of acetone-treated mycobacteria were tested by immunodiffusion precipitation for reactivity with a pool of sera from treated lepromatous leprosy patients (ARLS). This ARLS had been adsorbed with M. bovis (BCG, M. vaccae, cardiolipin, and lecithin to make it specific for M. leprae when used in an indirect immunofluorescence test. The ARLS produced two precipitin lines with M. leprae extract, one of which formed a line of identity with extracts of M. lepraemurium and M. bovis (BCG). Aso, recognition without reactions of identity was produced between ARLS and M. flavecens, M. gastri, M. gordonae, and M. nonchromogenicum. The ARLS did not recognize the 15 other species including the human pathogens, M. tuberculosis, M. intracellulare, M. kansasii, M. scrofulaceum, and M. marinum. These data suggest that serologic tests for M. leprae infection might be affected by antibodies to antigens shared by M. leprae and other mycobacteria. The significance of these shared antigens will depend upon the prevalence of human immune responses to mycobacteria containing the shared antigens in any given community.

Fatal reaction to dapsone during treatment of leprosy.

A Burmese boy being treated with dapsone (diaminodiphenylsulfone [DDS]), 100 mg daily, for lepromatous leprosy had a fatal reaction to the drug 3 weeks after therapy was started. The clinical symptoms and progression of illness conform well to a "DDS syndrome" first described in the early 1950s. Although the syndrome clinically resembles infectious mononucleosis, neither Epstein-Barr virus nor cytomegalovirus was implicated as an etiologic agent in this case. The syndrome has been recognized during initiation of dapsone therapy for lepromatous leprosy and has led to the use of a prolonged induction period with initial dosages as low as 25 mg/week. However, because dapsone resistance has been recognized in some strains of Mycobacterium leprae, slow induction of therapy has been replaced with the schedule used for this patient. This report of a fatal reaction to dapsone emphasizes the need for caution when initiating therapy with the drug at full dosage.

Decreased suppressor cell activity in disseminated granulomatous infections.

The effect of granulomatous infections upon the activity of a T lymphocyte subclass in human peripheral blood that can be induced by concanavalin A (Con A) to function in a suppressor mode was studied. Peripheral blood lymphocytes (PBL) from eleven patients with disseminated mycotic or mycobacterial infections or from controls were preincubated with and without Con A, washed and cultured with allogeneic PBL freshly drawn from healthy donors sensitive to histoplasmin. DNA synthesis was then measured in co-cultures stimulated by Con A, histoplasmin, or by the mixed lymphocyte culture (MLC) reaction alone. As compared with cells preincubated without Con A, the Con A-pretreated cells were significantly less effective in suppressing the responses of normal PBL to histoplasmin (P < 0.01), and in a one-way MLC reaction (P < 0.05). The Con A-induced suppressor activity of PBL from nine patients with localized granulomatous infections did not differ significantly from that exerted by PBL of normal controls in two of the three co-culture systems employed. These studies suggest that either dysfunction or a reduction of the Con A-inducible T-suppressor cell subpopulation in peripheral blood is frequent among patients was disseminated granulomatous infections.

Impairment of cell-mediated immune responses by infection with Mycobacterium lepraemurium.

The effect of chronic infection with Mycobacterium lepraemurium upon cell-mediated immune responses was studied in Lewis rats. Rats infected for 40 to 175 days were completely protected from attempted induction of experimental adjuvant disease, and the severity of experimental allergic encephalomyelitis in leprous rats was markedly attenuated. Full manifestations of each autoimmune disease were expressed in littermate control groups. Skin homograft rejection by infected rats was significantly impaired (P less than 0.001) as was the delayed-type hypersensitivity response to sheep erythrocytes (P less than 0.02). It is suggested that chronic infection with M. lepraemurium exerts a nonspecific inhibitory effect on cell-mediated immunity by perturbation of normal lymphocyte recirculation and by induction of immuno-suppressor cell activity.

Perturbation of lymphocyte circulation in experimental murine leprosy. I. Description of the defect.

Infection of Lewis rats with Mycobacterium lepraemurium is characterized by granulomatous pathology primarily involving the paracortical areas of lymph nodes and periarteriolar lymphocyte sheaths of the splenic white pulp. Intravenous infusion of radiolabeled thoracic duct lymphocytes (TDL)2 from normal syngeneic donors failed to produce a significant increase of cell output and radioactivity in the thoracic duct lymph of infected rats as compared with a marked increase in matched control recipients. Conversely, the migration of TDL from infected donor rats was normal in uninfected control rats that had been infused with serum from infected donors. The onset of the lymphocyte traffic disturbance takes place between 2 and 6 weeks after inoculation of viable M. lepraemurium. However, inoculation of heat-killed organisms produces little perturbation of lymphocyte circulation. Thus, the abnormal circulation of TDL in rats with active infection appears to be secondary to granulomatous pathology in lymphoid organs that disturbs cell traffic through these organs.

Perturbation of lymphocyte circulation in experimental murine leprosy. II. Nature of the defect.

Intravenous infusion of radiolabeled thoracic duct lymphocytes (TDL)2 from normal syngeneic donors to rats experimentally infected with Mycobacterium lepraemurium fails to produce a significant increase of cell output and radioactivity within the thoracic duct lymph. Conversely, ther is a marked increase in cell counts and radioactivity in the thoracic duct lymph of control recipients. Splenectomy of infected rats prior to the infusion significantly increased the ouptut of cells and radioactivity from the TD of these rats although it was not restored to normal. Serial quantitation of radioactivity in lymphoid organs of infected rats after infusion of 51Cr-labeled TDL revealed significantly increased uptake by the spleen as compared with the spleens of controls. Thus, the spleen of infected rats was a major trap for recirculating TDL. TDL were also trapped to a lesser extent by the lymph nodes and liver of infected rats. The circulation of TDL was not disturbed significantly in control rats with massive splenomegaly and red pulp hyperactivity induced by i.p. injection of methyl cellulose. Since murine leprosy preferentially involves the periarteriolar lymphocyte sheaths of the splenic white pulp and paracortical area of lymph nodes, it is suggested that the disturbance of lymphocyte circulation is secondary to pathology within these areas.

Defective leukotaxis in patients with lepromatous leprosy.

Serums from patients with lepromatous leprosy show a high incidence of a chemotactic inhibitor. This inhibitor acts directly on leukotactic factors (bacterial chemotactic factor, C3 fragment, and C5 fragment) to render the factors irreversibly inactive. Functionally, the inhibitor acts as a chemotactic factor inactivator. While normal serum shows no inhibitory activity under the conditions employed, inhibitory activity causing more than 30 per cent reduction of the bacterial chemotactic factor was found in the serums from 14 of 19 patients with lepromatous leprosy. Although exceptions were noted, a correlation was found between the presence of the inhibitor and depressed skin reactivity to a series of antigens (Lepromin, Trichophytin, Candida, PPD, and mumps antigen) used for elicitation of delayed-type hypersensitivity reactions. The presence in leprosy serums of this inhibitor may be responsible, at least in part, for some of the defects of cellular inflammatory responses in patients with lepromatous leprosy.

Defective leukotaxis in patients with lepromatous leprosy.

Sera from patients with lepromatous leprosy contain a leukotactic (chemotactic) inhibitor that irreversibly inhibits a variety of chemotactic factors. The presence of this inhibitor correlates with lack of skin reactivity to a variety of antigens. The inhibitor appears to be similar to a serum factor recently termed the chemotactic factor inactivator. The presence in leprosy sera of this inhibitor may be responsible for some of the defects of cellular inflammatory responses found in patients with lepromatous leprosy.