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J J Ellner

Publications and source records attributed to J J Ellner.

At least 19 recordsLinked to original sources
PubMed1992

Macrophages, mycobacteria and HIV: the role of cytokines in determining mycobacterial virulence and regulating viral replication.

The marriage of two scourges, one old (mycobacterial disease) and one new (HIV), has presented an enormous challenge to the medical and public health communities, and has stirred renewed interest in mechanisms for immune control of mycobacterial infection. Virulence of both M. avium and M. tuberculosis appears to be inversely related to the capacity of the microorganisms to induce production of protective cytokines in infected hosts. TNF alpha and IFN gamma are central to this process, and mycobacterial polysaccharides may be their main determinant. Despite these similarities, M. tuberculosis and M. avium cause illnesses at the polar extremes of HIV disease. Tuberculosis, occurring early in the course of HIV disease, may promote HIV replication in otherwise latently infected cells via induction of cytokines. As such, the potential exists for accelerated progression to AIDS due to the mutual synergy of these pathogens.

AIDS-Related Opportunistic Infections↗
PubMed1992

Duration of fever during treatment of infective endocarditis.

We reviewed the duration of fever among 123 patients treated for infective endocarditis at University Hospitals of Cleveland between 1972 and 1984. One half of these patients became afebrile within 3 days after initiation of antibiotic therapy and nearly three quarters were afebrile after 1 week of therapy. After 2 weeks of therapy, nearly 90% had defervesced. Endocarditis due to Staphylococcus aureus or gram-negative bacilli, and culture-negative endocarditis, were associated with prolonged fever. Microvascular phenomena, major vessel embolization, or vegetations seen on 2-D echocardiogram also were associated with prolonged fever. Multivariate analysis revealed that only microvascular phenomena or major vessel embolization were independently associated with longer duration of fever. Endocarditis-associated mortality among patients who remained febrile after 1 week of therapy was 18%, and this was greater than the 2% mortality among patients who defervesced (p less than 0.002). These data suggest that prolonged fever during treatment of infective endocarditis is often due to tissue infarction or vascular injury. Prolonged fever also identifies patients at higher risk of a fatal outcome.

Age Factors↗
PubMed1992

Role of the mononuclear phagocyte as an antigen-presenting cell for human gamma delta T cells activated by live Mycobacterium tuberculosis.

gamma delta T cells, both human and murine, have been found to be highly responsive to mycobacterial antigens. However, the role and function of gamma delta T cells in the immune response to Mycobacterium tuberculosis remain largely unknown. In earlier studies, we demonstrated that monocytes infected with live M. tuberculosis were particularly effective inducers of human peripheral blood gamma delta T cells. The present studies were performed to further characterize the interaction between human mononuclear phagocytes, gamma delta T cells, and live M. tuberculosis, in comparison with CD4+ T cells. First, we found that resting gamma delta T cells expanded in vitro by live M. tuberculosis were specific for M. tuberculosis, and that heat killing and washing the mycobacteria removed the antigen(s) for gamma delta T cells. In contrast, the heat-killed mycobacteria retained significant antigenicity for CD4+ T cells. Second, live M. tuberculosis-expanded gamma delta T cells from healthy tuberculin-positive donors did not respond significantly to the antigens in M. tuberculosis culture filtrate, including the 65- and 71-kDa mycobacterial heat shock proteins. Third, the activation of gamma delta T cells by live mycobacteria was dependent on antigen-presenting cells, and mononuclear phagocytes were found to be very efficient antigen-presenting cells both for resting peripheral blood gamma delta T cells and for activated expanded gamma delta T cells. The mononuclear phagocyte carried the necessary costimulatory factors necessary for gamma delta T-cell proliferation. Fourth, the antigen repertoire and HLA requirements for CD4+ memory T cells and those for gamma delta T cells appear to be quite distinct from each other. CD4+ T cells recognized both soluble protein antigens and whole organisms in a class II major histocompatibility complex-restricted manner, whereas gamma delta T cells appeared to recognize only constituents associated with the whole organism and were not restricted by class I or class II major histocompatibility complex molecules. Finally, the assay system described to expand and purify responding CD4+ and gamma delta T cells after stimulation with live M. tuberculosis represented a simple approach to the direct comparison of these two T-cell populations in the interaction with mononuclear phagocytes infected with M. tuberculosis. Such studies provide insight not only into the relative roles of human CD4+ and gamma delta T cells in the human immune response to intracellular bacterial pathogens such as M. tuberculosis but also into the basic biologic role of human gamma delta T cells in antimicrobial immunity.

Antigen-Presenting Cells↗
PubMed1992

Ultraviolet-irradiated monocytes efficiently inhibit the intracellular replication of Mycobacterium avium intracellulare.

The purpose of this study was to evaluate the effect of ultraviolet (UV) radiation on the antimicrobial activities of monocytes for the intracellular pathogen Mycobacterium avium intracellulare (MAI). UV radiation augmented monocyte antimicrobial activity for MAI in a dose-dependent fashion. UVB doses of greater than or equal to 25 J/m2 resulted in a 50-100-fold reduction in MAI growth 7 d after initiation of culture. The increased monocyte antibacterial effect could be blocked by a plate glass filter, indicating that wavelengths within the UVB were responsible for the effect. UV radiation did not stimulate monocyte phagocytosis, and enhanced inhibition of MAI growth was observed in populations of adherent mononuclear cells that were devoid of T cells. This suggested that UV radiation acted directly to augment intrinsic monocyte antimicrobial activities. The administration of 8-methoxypsoralen plus UVA radiation to monocytes also augmented their antimicrobial activities against MAI. UV radiation thus may serve as a unique agent by which to evaluate the mechanisms by which mononuclear phagocytes control the growth of MAI.

Blood Bactericidal Activity↗
PubMed1992

Absence of Mycobacterium avium complex disease in patients with AIDS in Uganda.

The absence of disease due to Mycobacterium avium in Ugandan patients with AIDS, which we previously observed in a blood culture study, has been confirmed and our observations have been extended to 165 additional clinical isolates. Fourteen soil and water samples from the Ugandan environment have been cultured and revealed a high frequency of isolation of M. avium. The absence of M. avium complex disease in Uganda remains unexplained.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Bidirectional effects of cytokines on the growth of Mycobacterium avium within human monocytes.

Certain cytokines including IFN-gamma possess macrophage-activating factor activity that enhances the ability of these effector cells to destroy intracellular pathogens. A panel of recombinant and highly purified human cytokines was screened to detect this effect on the activation of human monocytes to kill Mycobacterium avium in an in vitro model. Peripheral blood monocytes obtained from 15 healthy donors were precultured for 2 days before infection. Monocytes were infected with two strains of M. avium, one AIDS-associated and relatively avirulent strain (86m2096), and the other a non-AIDS-associated isolate that demonstrated consistent and rapid growth in cultured human monocytes (LR114F). The effects of recombinant and purified human cytokines on M. avium infection were assayed by determining CFU of M. avium in lysates of infected monocytes after 0, 4, and 7 days of culture. After infection, monocytes were cultured in medium alone or continuously in the presence of the following cytokines: IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-6, IFN-gamma, granulocyte-macrophage-CSF, or macrophage-CSF. In some experiments, cultures were performed in the presence of indomethacin (IM) in addition to cytokines. Culture in the presence of rIFN-gamma was associated with a decrease in mycobacterial growth within human monocytes. The combination of 300 U/ml of IFN-gamma plus 1 micrograms/ml of IM was associated with a 10-fold decrease (p less than 0.01) in intracellular growth of the virulent strain (LR114F) compared with unstimulated cultures. No other cytokine or combination of a cytokine with IM inhibited the intracellular growth of either strain of M. avium in human monocytes. Rather, several cytokines enhanced the intracellular growth of M. avium. IL-3, IL-6, and macrophage-CSF increased the growth of one, and IL-1 alpha of both strains of M. avium tested. IL-1 alpha and IL-6 also induced M. avium growth in tissue culture medium without monocytes. These studies indicate bidirectional effects of cytokines on intracellular parasitism that may influence the outcome of M. avium infection.

Acquired Immunodeficiency Syndrome↗
PubMed1991

The accessory function of B lymphocytes is resistant to the adverse effects of UV radiation.

The effect of UV radiation on the accessory activities of B lymphoblastoid cell lines (B-LCL) was investigated in three types of in vitro T lymphocyte proliferation assay, each of which differed in its accessory requirements. In contrast to monocytes whose accessory function was universally sensitive to UV radiation, B-LCL were resistant to UV in oxidative mitogenesis and staphylococcal enterotoxin B assays, in which stimulus processing was not a requirement. Expression of membrane interleukin (IL) 1 and HLA-DR antigens by B-LCL and monocytes was not affected by UV, nor was surface membrane expression of intercellular adhesion molecule-1 (ICAM-1) on B-LCL. These results were in marked contrast to monocytes in which there was a greater than 65% reduction in ICAM-1 expression. When UV-irradiated B-LCL were employed as antigen-presenting cells for tetanus toxoid-dependent T cell stimulation, a reduction in antigen-presenting function was observed. However, pulsing of B-LCL with tetanus toxoid prior to UV irradiation preserved their antigen-presenting capacity in this system also. These findings indicate that there is differential UV sensitivity among accessory cells which may be explained by different effects of UV radiation on antigen processing and adhesion molecule expression.

B-Lymphocytes↗
PubMed1991

Mycobacterium avium infection and AIDS: a therapeutic dilemma in rapid evolution.

Note from Dr. Merle A. Sande--The role of Mycobacterium avium as a pathogen in the human immunodeficiency virus-infected population has been confusing and controversial to clinicians who care for AIDS patients. The organism is commonly isolated from respiratory secretions of patients with other infections and often seems part of the resident flora; even when isolated from the bone marrow or bloodstream, its impact on the course of AIDS and contribution to systemic diseases are unknown. However, an increasing subset of patients without other documented opportunistic infections or malignancies has symptoms that respond to therapy directed against M. avium. Studies are in progress to evaluate chemotherapeutic agents. Accordingly, the subject is here reviewed and guidelines offered to infectious disease clinicians by one with a long-standing interest in mycobacterial disease who has made numerous contributions to the field.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Preservation of monocyte effector functions against Mycobacterium avium-M. intracellulare in patients with AIDS.

Mycobacterium avium-M. intracellulare is a frequent cause of late disseminated infection in patients with AIDS. The ability of human peripheral blood monocytes to phagocytose and kill M. avium was examined in an in vitro model. Monocytes were obtained from 13 healthy volunteers and 11 patients with AIDS, three of whom had documented disseminated M. avium infection. Monocytes were precultured for 2 days before infection with two AIDS-associated and two non-AIDS-associated strains of M. avium. Uptake of M. avium as measured by counting intracellular acid-fast bacilli did not differ among healthy subjects, patients with AIDS, or patients with AIDS and previously documented disseminated M. avium infection. Intracellular growth of M. avium was examined by a CFU assay of cell lysates from M. avium-infected monocytes after 0, 4, and 7 days of culture. Intracellular growth inhibition of M. avium at 7 days after infection was comparable between patients with AIDS and healthy donors for all M. avium strains tested. The effects of the addition of recombinant gamma interferon on M. avium uptake and intracellular growth in monocytes also were studied. Pretreatment of monocytes with gamma interferon prior to infection suppressed monocyte phagocytosis of M. avium. Continuously coculturing of monocytes with gamma interferon after infection augmented killing of M. avium among both patients with AIDS and healthy controls for three of the four strains of M. avium tested. The magnitude of this effect, however, was variable from donor to donor and strain to strain. No significant differences were noted between the growth-inhibiting abilities of gamma-interferon-treated monocytes obtained from healthy volunteers and those obtained from patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Human immune response to Mycobacterium tuberculosis antigens.

Little is known about the immunodominant or protective antigens of Mycobacterium tuberculosis in humans. Cell-mediated immunity is necessary for protection, and healthy tuberculin-positive individuals are relatively resistant to exogenous reinfection. We compared the targets of the cell-mediated immune response in healthy tuberculin-positive individuals to those of tuberculosis patients and tuberculin-negative persons. By using T-cell Western blotting (immunoblotting) of nitrocellulose-bound M. tuberculosis culture filtrate, peaks of T-cell blastogenic activity were identified in the healthy tuberculin reactors at 30, 37, 44, 57, 64, 71 and 88 kDa. Three of these fractions (30, 64, and 71 kDa) coincided with previously characterized proteins: antigen 6/alpha antigen, HSP60, and HSP70, respectively. The blastogenic responses to purified M. tuberculosis antigen 6/alpha antigen and BCG HSP60 were assessed. When cultured with purified antigen 6/alpha antigen, lymphocytes of healthy tuberculin reactors demonstrated greater [3H]thymidine incorporation than either healthy tuberculin-negative controls or tuberculous patients (8,113 +/- 1,939 delta cpm versus 645 +/- 425 delta cpm and 1,019 +/- 710 delta cpm, respectively; P less than 0.01). Healthy reactors also responded to HSP60, although to a lesser degree than antigen 6/alpha antigen (4,276 +/- 1,095 delta cpm; P less than 0.05). Partially purified HSP70 bound to nitrocellulose paper elicited a significant lymphocyte blastogenic response in two of six of the tuberculous patients but in none of the eight healthy tuberculin reactors. Lymphocytes of none of five tuberculin-negative controls responded to recombinant antigens at 14 or 19 kDa or to HSP70. Antibody reactivity generally was inversely correlated with blastogenic response: tuberculous sera had high titer antibody to M. tuberculosis culture filtrate in a range from 35 to 180 kDa. This is the first systematic evaluation of the human response to a panel of native and recombinant antigens in healthy tuberculin reactors and tuberculous patients. Antigens which stimulated prominent lymphocyte blastogenic responses were identified in seven fractions on T-cell Western blot analysis. Two of these may represent previously characterized proteins; the others may contain immunodominant proteins that will require further characterization.

Antibodies, Bacterial↗
PubMed1991

The influence of human immunodeficiency virus infection on tuberculosis in Kampala, Uganda.

The clinical, radiographic, and microbiologic features of 59 patients with pulmonary tuberculosis in Kampala, Uganda were studied and correlated with the serologic reactivity to the human immunodeficiency virus (HIV) of these patients. Two-thirds of the patients with tuberculosis were HIV-seropositive. Histories of fever and weight loss were more prominent in HIV-seropositive patients, and perihilar and basilar infiltrative diseases were more frequently seen in HIV-seropositive patients. Although all patients responded similarly to drug therapy, cutaneous drug reactions were seen in nearly one-third of HIV-seropositive patients receiving thiacetazone.

Adolescent↗
PubMed1991

Requirement for cell-to-cell contact for the immunosuppressive activity of human alveolar macrophages.

The ability of alveolar macrophages (AM) obtained by bronchoalveolar lavage of healthy volunteers to suppress T lymphocyte responses to the mitogen phytohemagglutinin (PHA) in vitro was investigated. AM but not monocytes (MN) inhibited responses of peripheral blood mononuclear cells (PBMC) to PHA as measured by incorporation of [3H]thymidine [( 3H]TdR) and interleukin-2 (IL-2) expression. Supernatants of AM generated for various periods and with various concentrations of cells did not, however, inhibit PBMC responses to PHA. To examine the role of cell contact in the inhibitory activity of AM, AM or MN were added to PBMC in 6-well plates either directly (in co-culture) or separated by a 0.45-micron filter. MN did not inhibit PBMC blastogenic responses under either condition. AM at a 1:2 ratio with PBMC inhibited blastogenesis by 75 +/- 11% (mean +/- SD, n = 3, P less than 0.01) when cultured directly with PBMC but had no inhibitory effect on blastogenesis when physically separated from target PBMC. AM in co-culture with PBMC also inhibited PHA-stimulated IL-2 production by 70% but did not inhibit IL-2 production when AM were separated from PBMC in dual chambers. To assess the role of the cell surface in the inhibitory activity of AM, AM and MN were fixed with 2% paraformaldehyde. Neither fixed nor unfixed MN inhibited PBMC blastogenic responses, but both fixed and unfixed AM inhibited responses similarly (77 to 95%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Selective expansion of human gamma delta T cells by monocytes infected with live Mycobacterium tuberculosis.

Gamma delta (gamma delta) T cell receptor (TCR) expressing T cells comprise 3% of human peripheral blood lymphocytes, yet their role in the immune response remains largely unknown. There is evidence both in humans and in animal models that these cells participate in the immune response to mycobacterial antigens. In mice, exposure to mycobacterial antigens leads to the expansion of gamma delta T cells in draining lymph nodes and lungs. In humans, gamma delta T cell lines with reactivity to mycobacterial antigens have been derived from synovial fluid of a rheumatoid arthritis patient, skin lesions of leprosy patients, and peripheral blood of a healthy tuberculin reactor. Very little is known, however, about the factors which induce human gamma delta T cells to expand. In studies comparing the human T cell response to live and heat-killed Mycobacterium tuberculosis (MT), we have found that monocytes infected with live MT are very effective inducers of human gamma delta T cell expansion. After 7 d of exposure to live MT, gamma delta T cells were greatly increased in all healthy tuberculin reactors (PPD+) tested and frequently were the predominant T cell population. In contrast, heat-killed MT or purified protein products of MT induced a CD4+, alpha beta TCR+ T cell response with very little increase in gamma delta T cells. Furthermore, a similar selective induction of gamma delta T cells was observed when monocytes infected with live Salmonella were used to stimulate T cells. Heat-killed Salmonella, like heat-killed MT, induced a predominantly CD4+ alpha beta TCR+ T cell response. These findings suggest that human gamma delta T cells are a major reactive T cell population during the early stages of infection with living intracellular bacteria and are therefore likely to exert an important role in the initial interaction between host and parasite.

Antigens, Bacterial↗
PubMed1991

A 19-year follow-up of tuberculin reactors. Assessment of skin test reactivity and in vitro lymphocyte responses.

Tuberculin skin test reactivity decreases with time such that repeat PPD skin testing may result in reactions of less than 10 mm. This reactivity may be boosted in some individuals with a second tuberculin skin test. The immunologic basis of these observations remains unclear. We studied the relationship between skin-test reactivity and in vitro blastogenic response to PPD in a cohort of 22 individuals (aged 28 to 81 years) known to be tuberculin reactors (induration greater than or equal to 10 mm) in 1970. In 1989, 18 subjects remained reactive to PPD on the first skin test and responded to PPD in vitro (mean incorporation of 3H-thymidine by peripheral blood mononuclear cells, 22,650 cpm). Three subjects reverted (induration in response to PPD less than 10 mm) and lost in vitro reactivity to PPD (mean incorporation of 3H-thymidine, 2,205 cpm). One subject boosted (increase of induration of at least 6 mm to greater than or equal to 15 mm) on the second skin test and showed a concomitant in vitro boost in the blastogenic response to PPD (from 1,008 cpm to 47,837 cpm). In this cohort, interpretation of the two-step tuberculin skin test correlated closely with in vitro proliferative responses. Over a 19-year period, the majority of individuals maintained skin test reactivity and strong in vitro responses to PPD despite a lack of ongoing exogenous exposure to Mycobacterium tuberculosis. The immunologic basis for reversion appears to depend in part on a loss of lymphocyte blastogenic capacity. In the one individual who exhibited the booster phenomenon, repeat antigen stimulation resulted in a dramatic increase in the in vitro blastogenic responses.

Adult↗
PubMed1991

Release of a suppressor cell-inducing factor by monocytes from patients with pulmonary tuberculosis.

We observed that blood monocytes from tuberculous patients secreted a factor which induced suppressor cells. Monocyte-enriched adherent cells were prepared from peripheral blood mononuclear cells (PBMC) of 14 patients with active pulmonary tuberculosis or nine healthy tuberculin skin reactors and were cultured without any stimulus for 5 days. For induction of suppressor cells, PBMC from a healthy tuberculin reactor were cultured with the monocyte culture supernatants (MN SUP). After 2 days, those cells were washed and irradiated, then tested for their ability to suppress blastogenesis in autologous PBMC stimulated with purified protein derivative (PPD). Mean activity of suppressor cell induction in MN SUP of patients with pulmonary tuberculosis was significantly greater than that of healthy controls. In contrast, PPD-induced blastogenic responses in PBMC from tuberculous patients were lower than in controls. When we divided those tuberculous patients into high and low secretor groups on the basis of the magnitude of suppressor cell induction by MN SUP, PBMC from the high secretors had lower direct blastogenic responses to PPD than those of the low secretors. The blastogenic responses of PBMC from the high secretors, but not the low secretors, were significantly lower than those of healthy subjects. MN SUP which contained high suppressor cell-inducing activity had no effect on PPD-induced blastogenesis of PBMC from a healthy donor. These data suggest that monocytes from some tuberculous patients indirectly depress lymphocyte blastogenesis through a suppressor cell-inducing factor.

Adult↗
PubMed1991

Direct mitogenic properties of interleukin-1.

Optimal lymphocyte activation generally requires two concurrent signals, one involving the T cell receptor, and another supplied by an accessory cytokine such as interleukin-1. We investigated the conditions under which partial cellular activation occurs in the absence of signal to the T cell receptor. Both murine thymocytes and the T cell clone D10.G4.1 responded to recombinant interleukin-1 in the absence of a mitogenic signal, although the magnitude of these responses was smaller and required higher concentrations of interleukin-1 than if a comitogen had been present. Interleukin-1 and interleukin-6 in combination were synergistic and induced tritiated thymidine incorporation in D10.G4.1 cells equal to 15% of that obtained with optimal concentrations of concanavalin A. Such synergy suggests that a significant degree of nonspecific activation of lymphocytes may occur in the presence of combinations of monocyte-derived cytokines.

Animals↗