Search PubMed⌕ Search

Biomedical subjects

J L Ho

Publications and source records attributed to J L Ho.

At least 37 records · Page 2Linked to original sources
PubMed1994

Cytokines in the treatment of leishmaniasis: from studies of immunopathology to patient therapy.

The genus Leishmania, an obligate intramacrophage parasite, causes a wide spectrum of clinical diseases. It is worldwide in distribution and causes 20 million new cases annually with an at risk population of approximately 1.5 billion persons. The most severe forms are associated with high morbidity, mortality and relapses with conventional therapy. The therapeutic issues and responses to standard and alternative therapies are reviewed. Recent developments in molecular biology and immunology methods employed in the study of leishmaniasis have defined an intricate interaction of the parasite with host immune system. Perturbation of the host immune responses may be part of the survival mechanisms of Leishmania. In murine model, the finding of T helper cells that differ by their panel of cytokines has allowed a more precise definition of immunopathogenesis of leishmaniasis. Preliminary data from leishmaniasis patients lend support to this concept of altered immunomodulation. Furthermore, the data from leishmaniasis patients lend support to this concept of altered enhancement of therapeutic response by interferon-gamma has provided a new approach for treatment of patients using recombinant cytokines and for the study of the disease. Current research for early diagnosis, alternative therapies and need for vaccines are reviewed in the context of the immunopathology of leishmaniasis.

Animals↗
PubMed1994

Granulocyte-macrophage colony-stimulating factor in combination with pentavalent antimony for the treatment of visceral Leishmaniasis.

The efficacy of GM-CSF was investigated in 20 neutropenic patients (< 1500 neutrophils/microliters) with acute visceral leishmaniasis due to Leishmania chagasi. Patients were randomized to receive either GM-CSF, 5 micrograms/kg daily (intravenously or subcutaneously), or placebo for ten days, in combination with pentavalent antimony, 10-20 mg/kg daily for 20 days. Neutrophil counts were significantly greater on days 5 and 10 of treatment in the GM-CSF group compared with the placebo group (p < 0.02). Eosinophil and monocyte counts were also significantly increased in the GM-CSF group at day 10 (p < or = 0.03). Interestingly, at day 30, platelet counts were significantly increased in the GM-CSF group on days 5 and 10 (p = 0.04 and 0.02, respectively). Patients in the GM-CSF group experienced fewer secondary bacterial or viral infections than placebo patients. Infections occurred in only three patients given GM-CSF compared with eight patients given placebo (p < 0.04). All patients had complete resolution of disease symptoms at three months. Few adverse events were recorded. GM-CSF given subcutaneously at a dose of 5 micrograms/kg daily for ten days was well tolerated, reversed neutropenia rapidly and reduced the number of secondary infections in patients with leishmaniasis.

Adolescent↗
PubMed1994

Recombinant human granulocyte-macrophage colony-stimulating factor reverses neutropenia and reduces secondary infections in visceral leishmaniasis.

Twenty-four patients with acute visceral leishmaniasis and leukopenia (< 1500 neutrophils/mm3) due to Leishmania chagasi were studied, 4 in an open-label pilot study and 20 in a double-blind, placebo-controlled trial. Patients received granulocyte-macrophage colony-stimulating factor (GM-CSF), 5 micrograms/kg daily, or placebo for 10 days, plus 10-20 mg/kg pentavalent antimony daily for 20 days. In GM-CSF recipients, neutrophil counts increased threefold and fourfold over baseline at 5 and 10 days, respectively, and were significantly higher than those in placebo recipients (P < .02). Eosinophil and monocyte counts were significantly increase in GM-CSF recipients at 10 days (P < or = .03). Secondary infections occurred in 3 GM-CSF and in 8 placebo recipients (P = .04). All patients had complete resolution of their leishmaniasis at 3 months. Few adverse events were recorded. GM-CSF, 5 micrograms/kg daily for 10 days, was safe, rapidly reversed neutropenia, and reduced the number of secondary infections in patients with leishmaniasis.

Adolescent↗
PubMed1993

IL-6 down-modulates the cytokine-enhanced antileishmanial activity in human macrophages.

IL-6 is a cytokine synthesized by T cells and macrophages (M phi). It has pleiotropic effects on diverse cell types and is recognized for its "pro-inflammatory" properties. In mice, IL-4, IL-5, IL-6, and IL-10 are produced by Th-2 cells. Because IL-10 suppresses Th-1 clones, and IL-4 broadly deactivates M phi, experiments were carried out to investigate the in vitro effects of recombinant human IL-6 on cytokine activation of human M phi. Pretreatment with IL-6 induced a dose- and time-dependent suppression of IFN-gamma (1000 U/mL) and TNF-alpha (25 ng/mL) activation of M phi for the killing of L. amazonensis. At doses greater than 0.1 to 100 ng/mL, IL-6 inhibited IFN-gamma and TNF-alpha activation by 21 to 93% and 36 to 82%, respectively. IL-6 alone had no effect on M phi viability and intracellular L. amazonensis growth. Blockade of M phi activation was greatest when IL-6 was added 24 or 48 h before infection and treatment with IFN-gamma or TNF-alpha. Furthermore, mAb against IL-6 abrogated the inhibitory activity of IL-6. Similarly IL-6 pretreatment suppressed M phi activation for antileishmanial capacity by IL-3, granulocyte-monocyte-CSF (GM-CSF) and IL-1 beta. Because cytokine induction of antileishmanial activity is associated with enhancement of oxidative capacity, the effect of IL-6 on this mechanism was evaluated. Pretreatment with IL-6 down-modulated TNF-alpha (25 ng/mL) enhancement of M phi oxidative capacity in a dose- and time-dependent manner. A similar depression of oxidative capacity was observed for GM-CSF and IL-3 but not for IFN-gamma. Furthermore, NG-monomethyl-L-arginine (a nitric oxide synthase inhibitor) had no effect on IFN-gamma and TNF-alpha activation of antileishmanial activity and nitrites/nitrates were not reliably assayed from M phi culture supernatants. These findings suggest that IL-6 down-modulates cytokine activation of M phi antileishmanial capacity by inhibiting oxygen-dependent and undefined oxygen-independent mechanisms.

Animals↗
PubMed1993

Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection.

Tuberculosis occurring with human immunodeficiency virus (HIV) infection is a serious and growing public health problem. We have carried out a randomised clinical trial of a 12-month course of isoniazid plus vitamin B6 versus vitamin B6 alone in Port-au-Prince, Haiti, to assess the efficacy of isoniazid in preventing active tuberculosis in symptom-free HIV-infected individuals. The effect of prophylaxis on the development of HIV disease, AIDS, and death was also investigated. 118 subjects were assigned treatment with isoniazid plus B6 (n = 58) or B6 alone (n = 60) between 1986 and 1989. The treatment groups were similar at study entry in demographic, clinical, and immunological characteristics. Interim analysis in 1990 revealed no significant difference in tuberculosis outcome measures. Follow-up was continued until 1992, at which time significant protection by isoniazid against the development of tuberculosis was apparent, both for the whole study population and for subjects positive for purified protein derivative of tuberculin (PPD). The incidence of tuberculosis was lower in isoniazid recipients than in patients who received B6 alone (2.2 vs 7.5 per 100 person-years). The relative risk of tuberculosis was 3.4 (95% CI 1.1-10.6) for B6 alone versus isoniazid plus B6 (p < 0.05). Isoniazid also delayed progression to HIV disease and AIDS and death. Thus isoniazid effectively decreases the incidence of tuberculosis and delays the onset of HIV-related disease in symptom-free HIV-seropositive individuals. Isoniazid prophylaxis should be considered for HIV-seropositive, PPD-positive subjects, and may also be appropriate for PPD-negative patients in areas where tuberculosis is highly endemic.

AIDS-Related Opportunistic Infections↗
PubMed1993

A rapid manual method for CD4+ T-cell quantitation for use in developing countries.

OBJECTIVE: To evaluate a manual method (Cytosphere) for quantifying CD4+ T-cell numbers. DESIGN: Cross-sectional study of HIV-1-seronegative and HIV-1-seropositive individuals evaluated for absolute CD4 counts by both standardized flow cytometric measurements and manual Cytosphere technology using a hemacytometer. SETTING: University research hospitals in both the United States and Africa. PATIENTS, PARTICIPANTS: Blood specimens from 382 patients were evaluated. These were broken down into 294 samples obtained from HIV-1-seropositive patients and 88 samples obtained from HIV-1-seronegative patients. INTERVENTIONS: None. OUTCOME MEASURED: Absolute CD4 cell number. RESULTS: Evaluation of samples obtained from HIV-1 patients in both the United States and Africa demonstrated an overall correlation of the Cytosphere assay with flow cytometry of 0.912 (95% confidence interval, 0.895-0.928; P < 0.001). When samples were stratified based on CD4+ T-cell counts determined by flow cytometry, the Cytosphere assay had a 96% predictive value for correctly identifying individuals with CD4 T-cell counts > 200 x 10(6)/l and a 92% predictive value for correctly identifying individuals with CD4 T-cell counts < 200 x 10(6)/l. CONCLUSIONS: This assay appears to have the potential for the quantitation of CD4 cells in the limited laboratory facilities in developing countries and to have a strong correlation with standard flow cytometric technology.

Adult↗
PubMed1993

A prospective study of HIV-seropositive asymptomatic women of childbearing age in a developing country.

An observational study of 140 HIV-seropositive asymptomatic women of childbearing age was conducted in Haiti from 1984 to 1992 as part of a larger natural history study. Forty-four women were pregnant or became pregnant during the study period. The progression to HIV-related disease, AIDS, and mortality from AIDS was compared in the pregnant and nonpregnant cohorts. The mean follow-up time was 44 months. Overall, 32 of the 140 women (38%) developed AIDS, and 26 (19%) died from AIDS during the study period, with a cumulative AIDS incidence rate of 16% at 3 years after study entry. There was a trend toward earlier manifestation of HIV-related symptoms among the pregnant cohort, but no significant difference was observed in the rate of progression to AIDS or death between the pregnant and nonpregnant women.

Acquired Immunodeficiency Syndrome↗
PubMed1992

IL-4 receptor signal transduction in human monocytes is associated with protein kinase C translocation.

IL-4 regulates B cell differentiation and monocyte functions. Protein kinases, such as kinase C (PKC), transduce receptor signals. The involvement of PKC in IL-4R signaling was investigated in human monocytes. Treatment with IL-4 (10 ng/ml) for 10 min resulted in a significant redistribution of the PKC activity from cytosol to nuclear fraction. Total PKC activity localized in the nuclear fraction of IL-4-treated and control monocytes was, respectively, 68 and 19%. In contrast, similar PKC activity was found in membrane fraction of IL-4-treated and control cells. The kinetics of IL-4-mediated redistribution of PKC activity to the nuclear fraction were rapid. Within 30 s of IL-4 exposure, 29% of the total PKC activity localized in the nuclear fraction as compared to 15% in control monocytes and increased to 69% at 10 min. The PKC activity in the nuclear fraction appears to be a sequestered form. Extraction with Triton X-100 and additional sonication were required for functional assay of PKC activity. Additional support for PKC involvement in IL-4R signaling is provided by the dose-dependent effect of IL-4 on PKC activity and the abrogation of this effect after heat denature and immunoabsorption of IL-4. Furthermore, electron microscope examination and subcellular marker enzyme assays excluded significant contamination of the nuclear fraction by plasma membranes or subcellular organelles and IL-4 altering membrane disruption. The data presented indicate that IL-4R signaling in human monocytes involves PKC translocation to a nuclear fraction.

Cell Compartmentation↗
PubMed1992

Interleukin-4 inhibits human macrophage activation by tumor necrosis factor, granulocyte-monocyte colony-stimulating factor, and interleukin-3 for antileishmanial activity and oxidative burst capacity.

Interleukin (IL)-4 has been implicated in the pathogenesis of leishmaniasis in a murine model. Experiments were done to examine the effect of IL-4 on cytokine activation of macrophages. Interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF alpha), and IL-3 activate macrophages to inhibit replication of leishmaniae. IL-4 abrogated in a dose- and time-dependent manner the induction of antileishmanial activity by these cytokines. The depression of oxidative burst capacity is one mechanism by which IL-4 inhibits macrophage activation. IL-4 diminished in a dose- and time-dependent manner the TNF alpha enhancement of oxidative capacity. Pretreatment with IL-4 for 48, 24, or 0 h, respectively, inhibited the generation of superoxide induced by TNF alpha by 90%, 60%, and 40%. Furthermore, IL-4 abrogated the enhancement of oxidative capacity by IFN-gamma, GM-CSF, and IL-3. These data suggest that IL-4 is a potent deactivator of macrophage antimicrobial functions and may contribute to the pathogenesis of visceral leishmaniasis.

Animals↗
PubMed1992

Diminished in vitro production of interleukin-1 and tumor necrosis factor-alpha during acute visceral leishmaniasis and recovery after therapy.

Disturbance of T cell-mediated immunity has been reported in acute visceral leishmaniasis (AVL). In a study of 16 patients with AVL, defective production of interleukin-1 (IL-1) by peripheral blood mononuclear cells was demonstrated in response to leishmania antigens, heat-killed Listeria organisms, and lipopolysaccharide when compared to posttherapy values or controls. This global defect in IL-1 production was corrected after successful therapy. Twelve of 16 patients responded with a greater than or equal to 2.5-fold increase in IL-1 production that correlated with clinical cure, P less than .01. Depressed production of tumor necrosis factor (TNF) was leishmania antigen-specific and similarly recovered after therapy. In vitro TNF production during the follow-up period did not correlate with clinical status but high serum levels were associated with AVL. Since T cells are activated by processed antigens presented on class II major histocompatibility molecules and by newly synthesized IL-1, defective IL-1 production may contribute to the immunosuppression observed in AVL.

Acute Disease↗
PubMed1992

Interleukin-3 induces antimicrobial activity against Leishmania amazonensis and Trypanosoma cruzi and tumoricidal activity in human peripheral blood-derived macrophages.

The ability of interleukin-3 (IL-3) to induce antimicrobial and tumoricidal activity was evaluated. Macrophages infected with two intracellular protozoa, Leishmania amazonensis or Trypanosoma cruzi, were treated with cytokines. IL-3 induced a dose-dependent enhancement of microbistasis against leishmanias, and the activity of IL-3 (100 ng/ml) was comparable to that of gamma interferon (IFN-gamma) (1,000 U/ml). In addition, IL-3 in combination with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage CSF (M-CSF) or with IFN-gamma reduced infection and lowered the required dose. IL-3 similarly activated macrophages to inhibit intracellular replication of T. cruzi. Furthermore, IL-3 induced antibody-independent tumoricidal activity against melanoma cells that was dose dependent and comparable to that of lipopolysaccharide and GM-CSF. The mechanisms by which IL-3 induced antimicrobial activity may involve at least the augmentation of oxidative capacity. IL-3, at concentrations of 0.5 ng/ml or greater, led to a significantly increased oxidative burst which paralleled the inhibition of protozoan replication. The enhancement of oxidative capacity by IL-3 (5 ng/ml or higher) was comparable to that of IFN-gamma. The induction of tumoricidal activity was associated with the production of tumor necrosis factor alpha (TNF-alpha), which in this system may feed back to enhance the macrophage inhibition of leishmanias, as demonstrated by neutralization of IL-3 activation by anti-TNF-alpha antibody. Thus, peripheral blood macrophages remain responsive to IL-3, as demonstrated by enhanced antimicrobial and tumoricidal activity. IL-3 may have potential clinical applications because of these properties and its effect on myelopoiesis.

Animals↗
PubMed1992

Cytokine activation of human macrophages infected with HIV-1 to inhibit intracellular protozoa.

Peripheral blood mononuclear cells (PBMCs) from HIV-seronegative donors were infected in vitro with HIV-1. Infection was monitored by cytopathology, supernatant p24 antigen, and by immunocytochemical staining. After 14 days in culture, approximately 70-90% of the cells became infected with HIV, as indicated by cell fusion and immunostaining for virus. At this time, recombinant HuIFN-gamma was added to the cultures, followed by infection 24 h later with the intracellular protozoan parasites Toxoplasma gondii, Trypanosoma cruzi, or Leishmania chagasi. Percentages of intracellular parasites were determined at various points thereafter. Using a system capable of detecting both virus and parasite infection, we determined that (a) cells infected with HIV were capable of ingesting and/or being infected by each of these parasitic protozoa, (b) HIV-infected macrophages could be activated to inhibit the replication of all three parasites following treatment with IFN-gamma, and (c) cultures of HIV-infected macrophages could respond to IFN-gamma with increased oxidative burst activity. The degree of parasite infection or inhibition observed in infected cells was not significantly different from that observed in non-HIV-infected cells. From these observations, we concluded that HIV-1 infection does not render macrophages unresponsive to IFN-gamma activation for microbicidal activity.

Animals↗
PubMed1990

Granulocyte-macrophage and macrophage colony-stimulating factors activate intramacrophage killing of Leishmania mexicana amazonensis.

Leishmania organisms are important pathogens, causing diseases worldwide. Standard therapies are often toxic and are not always effective. The effect of recombinant human granulocyte-macrophage and macrophage colony-stimulating factors (GM-CSF and M-CSF) on intramacrophage survival of Leishmania mexicana amazonensis (Lma) were compared with those of interferon-gamma (IFN-gamma). Macrophages previously infected with Lma were treated with or without GM-CSF and M-CSF. Compared with no cytokine treatment, treatment with GM-CSF (0.1-100 ng/ml) or M-CSF (1:3.5 X 10(6) - 1:3.5 X 10(3) dilutions) caused a significant dose-dependent reduction in intracellular parasites, 427 +/- 20 (mean +/- SE) Lma/100 macrophages. GM-CSF or M-CSF in combination with IFN-gamma resulted in more effective inhibition of intracellular parasites. Thus, the cytostatic activity appears to require interaction between cytokines, macrophages, and amastigotes. These cytokines are potential therapeutic agents for visceral leishmaniasis.

Animals↗
PubMed1989

An evaluation of the effect of repeated doses of oral activated charcoal on salicylate elimination.

The authors investigated the effect of repeated doses of oral activated charcoal on salicylate elimination in six healthy volunteers. On two occasions (phase I and phase II; separated by one week) each subject received 1300 mg of aspirin as an aqueous solution. On the second occasion (phase II) each subject also received a total dose of 55 g of aqueous activated charcoal initiated 4 hours after salicylate administration (25 g initial dose, followed by three 10 g doses at two hour intervals). Serum salicylate levels were measured from one to twelve hours post aspirin ingestion. The pharmacokinetic analysis showed no significant change between phase I and phase II for either the salicylate elimination half-life or the area under the concentration versus time curve from 4-12 hours post aspirin ingestion. Reasons for the lack of effect of repeated doses of charcoal on salicylate elimination are discussed and, these results cannot necessarily be extrapolated to the overdose situation. Further investigation is warranted to assess the effect of repeated doses of activated charcoal in the salicylate-overdosed patient.

Administration, Oral↗
PubMed1988

Diminished activity of protein kinase C in tetanus toxin-treated macrophages and in the spinal cord of mice manifesting generalized tetanus intoxication.

In previous studies, we have demonstrated that tetanus toxin (TT) inhibits macrophage (MO) lysozyme secretion and that the inhibition of secretion was not directly linked to perturbation of cytosolic calcium homeostasis. Because MO secretion in response to phorbol myristate acetate, a stimulus that activates protein kinase C (PKC), was inhibited by TT, we examined whether TT might interfere with PKC activity. We report that MOs treated with TT have diminished PKC activity. Purified TT as well as commercial TT diminished PKC activity, whereas heated TT and supernatant from which TT had been removed had no effect on PKC activity. We further examined PKC activity in homogenates of brain and spinal cord from mice manifesting generalized tetanus. Spinal cord cytosolic PKC activity (pmol/mg of protein per min) was depressed in TT-intoxicated mice (87.3 +/- 25) compared with controls (182.6 +/- 47; P less than .02, n = 7). In contrast, cytosolic protein kinase A activity was similar in control- and TT-treated MOs and mice. These results provide the first evidence that PKC activity is diminished during TT intoxication.

Animals↗