Lack of correlation between promiscuity and seropositivity to HTLV-III from a low-incidence area for AIDS.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
J J Ellner
Publications and source records attributed to J J Ellner.
Increased blastogenic responses to worm antigen and loss of adherent suppressor cell activity after treatment for human infection with Schistosoma mansoni.
Fifteen Egyptian subjects infected with Schistosoma mansoni were evaluated parasitologically, clinically, and immunologically; treated with praziquantel; and reevaluated nine months later. Fecal egg counts were 97% lower after therapy; seven subjects no longer excreted eggs, as determined by Kato thick smears. Optimal [3H]thymidine incorporation induced by soluble adult worm antigenic preparation (SWAP) in peripheral blood mononuclear cells (PBMCs) increased significantly, from 4,041 +/- 434 (mean change in cpm +/- SE) before treatment to 11,232 +/- 3,414 after treatment (P less than .0005). The relation between dose of antigen and response also shifted; the SWAP concentration producing optimal responses was 30.0 micrograms/ml before and 1.0 microgram/ml after therapy. Before treatment, depletion of adherent cells from PBMCs in six subjects resulted in enhancement of responses to SWAP from 5,575 +/- 1,210 to 14,719 +/- 8,190 (P less than .025). However, in these same individuals after treatment, PBMC and nonadherent lymphocyte responses were similar (22,917 +/- 6,505 and 21,239 +/- 6,122). These studies indicate loss of activity of adherent suppressor cells after treatment of chronic infection with S. mansoni. Waning of cellular regulatory mechanisms as the parasite load decreases may contribute to restoration of blastogenic responses.
Adolescent↗
Immunoregulatory adherent cells in human tuberculosis: radiation-sensitive antigen-specific suppression by monocytes.
In human tuberculosis, adherent mononuclear cells (AMC) selectively depress in vitro responses to the mycobacterial antigen tuberculin purified protein derivative (PPD). The phenotype of this antigen-specific adherent suppressor cell was characterized by examining the functional activity of adherent cells after selective depletion of sheep erythrocyte-rosetting T cells or OKM1-reactive monocytes. Adherent cell suppression was studied in the [3H]thymidine-incorporation microculture assay by using T cells rigorously depleted of T cells with surface receptors for the Fc portion of IgG (T gamma cells) as antigen-responsive cells. PPD-induced [3H]thymidine incorporation by these non gamma T cells was uniformly reduced (mean, 42% +/- 10% [SD]) when autologous AMC were added to non gamma T cells at a ratio of 1:2. Antigen-specific suppression by AMC was not altered by depletion of sheep erythrocyte-rosetting T cells or treatment with indomethacin. However, AMC treated with OKM1 and complement or gamma irradiation (1,500 rads) no longer suppressed tuberculin responses in vitro. These studies identify the antigen-specific adherent suppressor cell in tuberculosis as an OKM1-reactive, non-erythrocyte-rosetting monocyte. The radiosensitivity of this monocyte immunoregulatory function may facilitate its further definition.
Adult↗
Pharmacokinetics of tobramycin and gentamicin in abusers of intravenous drugs.
The kinetics of aminoglycoside elimination were determined in 18 hospitalized narcotics abusers receiving gentamicin or tobramycin for treatment of severe infection. Rapid aminoglycoside elimination (requiring doses of greater than 5 mg/kg per day to maintain adequate drug levels) was noted in 12 of the 18 patients (18 of 27 clearance studies). Patients found to have rapid elimination were younger (P less than 0.01) and had larger drug distribution volumes (P less than 0.005), greater measured creatinine clearances (P less than 0.05), and lower creatinine levels in serum (P less than 0.001) than those with normal elimination. Nevertheless, by regression analysis, age, creatinine levels in serum, creatinine clearances, and drug distribution volumes proved to be unreliable predictors of individual aminoglycoside clearance. Measured drug half-life in serum appeared to be the only reliable predictor of drug clearance (r = 0.93). Patients with rapid drug elimination had aminoglycoside clearances 16 to 43% greater than measured creatinine clearances, suggesting an extraglomerular route of drug elimination. We conclude that in drug abuse patients a significant and clinically unpredictable interpatient variation occurs in aminoglycoside elimination and that accurate serum kinetics are needed to determine therapeutic dosing. In addicts younger than 35 years, with a creatinine level of less than 1.0 mg/100 ml in serum, the risk of inadequate therapy is high if standard dosing guidelines are followed. For this group, initial dosing of 8 mg/kg per day, with a drug half-life determination on the first dose, is recommended. Pharmacokinetic analysis is critical for all drug abusers treated with aminoglycosides for serious infection.
Adult↗
Association of altered dynamics of monocyte surface expression of human leukocyte antigen DR with immunosuppression in tuberculosis.
Monocyte (MN) surface human leukocyte antigen DR was examined in 10 patients with pulmonary tuberculosis (TB) and 12 healthy individuals using OK11, a mouse monoclonal antibody to human DR, in a 51Cr-release cytotoxicity assay. Of freshly isolated MNs from TB patients, 39.1% +/- 4.4% (mean +/- SEM) were DR+, compared with 57.2% +/- 5.7% in healthy subjects (P less than 0.02). After 24 hr in culture, a sharp rise was observed in the TB group, to 78.1% +/- 11.6% (P less than 0.005), compared with 64.9% +/- 5.1% in the control group. The TB patient group could be subdivided on the basis of tuberculin purified protein derivative-induced [3H]thymidine incorporation in peripheral blood mononuclear cells (PBMCs). A significantly smaller fraction of MNs from tuberculin nonresponder TB patients was DR+ (34.6% +/- 6.0%) compared with healthy controls (59.4% +/- 8.6%; P less than 0.05). In the nonresponder group, a greater fraction of PBMCs was identifiable as MNs by cytochemical techniques (51.2% +/- 3.6% vs 38.0% +/- 5.0% in the responder group; P less than 0.02). Cell mixing experiments demonstrated increased suppressor activity of DR- MNs.
Adult↗
Modulation of macrophage activation and resistance by suppressor T lymphocytes in chronic murine Schistosoma mansoni infection.
Activated macrophages (M phi) appear responsible for at least part of the concomitant resistance in mice infected with Schistosoma mansoni. We found that as murine S. mansoni progressed from acute (8 to 12 wk of infection) to chronic (16 to 24 wk) stages, acquired resistance decreased (57% resistance to challenge with cercariae at 8 wk vs 28% by 24 wk, p less than 0.05), as did macrophage activation (21% +/- 2 killing of schistosomula by 8 wk M phi vs 8% +/- 2 for 24 wk M phi, p less than 0.01). T cells from the spleens of 8 wk-infected mice were capable of activating M phi from naive animals when stimulated with worm antigens (24% +/- 2 killing vs 8% +/- 2 induced by normal T cells, p less than 0.01); T cells obtained from 24 wk-infected mice did not activate M phi (13% +/- 2 killing). Furthermore, T cells from 24 wk-infected animals suppressed activation of M phi by 8 wk T cells. The addition of 10(5) 24 wk T cells to 3 X 10(5) antigen-stimulated 8 wk T cells reduced subsequent M phi killing from 27% +/- 4 to 13% +/- 2 (p less than 0.05). Week 24 T cells (3 X 10(5] reduced this additionally to 9% +/- 1 (p less than 0.01), a value no greater than that of unstimulated M phi. The subpopulation of T cells responsible for suppression of M phi activation was Lyt-2+1- nonadherent T cells. Cyclophosphamide treatment of chronically infected mice resulted in enhanced resistance (41%), M phi activation (18% +/- 1 killing), and T cell activation of naive M phi (10% +/- 1 killing). Thus, during chronic S. mansoni infection, resistance to reinfection wanes in parallel to and perhaps because of development of suppressor T cells that interfere with T-dependent M phi activation.
Animals↗
Enhancement of monocyte immunoregulatory properties and effector functions by recombinant interferon-gamma.
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Antibody-Dependent Cell Cytotoxicity↗
Augmentation of natural killer cell activity by lipopolysaccharide through separable effects on the binding of nonadherent lymphocytes to tumor targets and tumor killing.
A single-cell assay was utilized to study the augmentation by Escherichia coli lipopolysaccharide (LPS) of the cytotoxicity of human lymphocytes for the human myeloid tumor K562. Preincubation with LPS at 20 micrograms/ml for 30 min at 37 degrees increased the binding of all nonadherent (NA) lymphocyte populations to K562 tumors [unseparated NA lymphocytes from 13.1 to 25.1%, immunoglobulin G Fc receptor-enriched lymphocytes from 27.6 to 42.9%, and immunoglobulin G Fc receptor-depleted lymphocytes from 14.0 to 23.7%, at p less than 0.001]. In contrast, interferon (IFN) at 10 units/ml had no effect on the overall binding of lymphocytes to K562 tumors. When lymphocyte-tumor conjugates were dispersed in agarose, cytotoxic activity of unseparated NA lymphocytes at 1 to 3 hr was markedly increased by preincubation with LPS (p less than 0.001). However, LPS did not enhance cytotoxicity if conjugates were formed in its absence. IFN, likewise, increased cytotoxic activity in unseparated NA lymphocytes at 1 to 3 hr (p less than 0.001). No synergistic cytotoxicity was seen with concurrent exposure to LPS and IFN. LPS increased cytotoxicity in the Fc receptor-enriched:tumor conjugates at 1 to 3 hr (p less than 0.001) and appeared to promote more efficient killing in individual conjugates over time. Cytotoxicity in the Fc receptor-depleted:tumor conjugates was not enhanced by LPS. Thus, LPS may enhance natural killer cell-like activity by increasing the binding of human lymphocytes to K562 tumors and by rearranging the population of binding cells to include more efficient killer cells. While the effects of LPS on binding appear independent of IFN, selective recruitment of more efficient killer cells could be through an IFN mechanism.
Cell Adhesion↗
Radioresistance of culture-induced augmented natural killer-like activity.
Human NK activity is radiosensitive under the control of X-linked genes. We have evaluated the expression of these genes in other forms of cellular cytotoxicity. The NK radioresistant and radiosensitive phenotype is expressed in ADCC. Specific cellular cytotoxicity, generated in a MLC with a radiosensitive donor as responder, was radioresistant. NK-like activity recruited from nonadherent cells of radiosensitive subjects stimulated with allogenic cells, mitogens (PHA, Con A or PWM), or recall antigens (TT or PPD) was radioresistant. The acquisition of radioresistance was relatively rapid, beginning within 24 hr after exposure to PHA, prior to detectable proliferation. Radioresistance of MLR augmented NK-like activity was maximal 3 days after initiation of the culture. MLR augmented NK-like activity was spared by the immunosuppressive polypeptide antibiotic CsA at doses up to 1 micrometer/ml. CsA did, however, reduce acquisition of radioresistance by the NK-like activity at doses above 0.01 mu gm/ml, a concentration which does not inhibit uptake of 3H-thymidine but does reduce the level of specific CML. These data suggest that mitogens and antigens, including allogeneic cells, are recruiting radioresistant NK-like activity which can be distinguished from the radiosensitive spontaneous NK activity of the cell donor. Further, in the MLR, both radiosensitive and radioresistant NK-like activity may be recruited.
Adult↗
Presence of antibodies to Mycoplasma pneumoniae in patients with bacterial meningitis.
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Adult↗
Recruitment of OKM1 staining lymphocytes with selective binding to K-562 tumour targets by interferon.
Spontaneous cytotoxicity of human lymphocytes for tumours is increased by interferon (IFN) without change in the overall fraction of cells binding to targets. We developed an indirect immunofluorescent technique to stain lymphocytes conjugated to K-562 tumour cells in agarose with monoclonal antibodies. This allowed assessment of lymphocyte subpopulations binding to tumour cells without disruption of conjugates. Overall binding of non-adherent (NA) lymphocytes to tumour targets following incubation at 37 degrees C for 6 h was 13.3 +/- 0.3% compared to 12.5 +/- 0.7% with inclusion of IFN at 100 u/ml. When NA lymphocytes were incubated with K-562 tumour cells without IFN, OKM1 and OKT3 staining lymphocytes comprised 16.8 +/- 3.5% and 83.0 +/- 1.3% of the total lymphocyte population and 32.5 +/- 1.3% and 70.2 +/- 2.6% of lymphocytes conjugated to tumours. Incubation with IFN significantly increased OKM1 staining cells in the total NA population to 57.2 +/- 5.6% (P less than 0.01) and within tumour conjugates to 59.2 +/- 2.7% (P less than 0.01) while OKT3 staining cells decreased to 58.3 +/- 5.2% (P less than 0.02) and 45.3 +/- 1.2% (P less than 0.01), respectively. IFN increased cytotoxicity of NA cells for 51Cr-labelled K-562 by 66% at an effector to target ratio of 30:1 (P less than 0.001). These results demonstrate that OKM1 staining cells bind more avidly to tumour targets in the absence of IFN. IFN selectively increases the proportion of OKM1 staining lymphocytes with a concomitant increase in their binding to tumour cells. Therefore, enhancement of cytotoxicity by IFN in the NK system may result, in part, from conversion of OKT3 to OKM1 staining cells which are more efficient killers.
Adult↗
Divergent T gamma cell functions in antigen-induced blastogenesis: facilitory interactions with Tnon gamma cells and participation in monocyte- and prostaglandin-mediated suppression.
The contribution of T gamma cells, i.e., T cells bearing surface receptors for the Fc portion of IgG, to the immunologic response to antigen has not been assessed in health or disease. We examined the role of T gamma cells in antigen-induced blastogenesis of T cells from healthy subjects and characterized their participation in monocyte- and prostaglandin-mediated suppression. Cell fractions enriched in the depleted of T gamma cells were prepared from nonadherent T cells by preparative rosetting with IgG-sensitized ox erythrocytes; antigen-induced blastogenesis was assayed as 3H-thymidine incorporation (3H-TdR), by microculture techniques. Removal of T gamma cells resulted in a Tnon gamma cell fraction whose in vitro response to soluble antigen was a mean 40% +/- 8 less than the response of the unseparated T cells from the same donors. Antigen did not induce 3H-TdR in cultures of T gamma cells; however, in cell-mixing experiments, addition of autologous T gamma cells reconstituted the antigen responsiveness of the Tnon gamma cell fraction. Monocytes (MN) added to cell cultures at a ratio known to be suppressive in vitro (MN to T = 1:4) significantly decreased antigen-induced 3H-TdR of unseparated T cells but did not alter the antigen responses of Tnon gamma cells. MN-dependent suppression was abrogated by co-culture with indomethacin. Exogenous prostaglandin E2, an immunosuppressive cyclooxygenase product of MN, selectively decreased antigen-induced 3H-TdR of cell cultures containing T gamma cells but did not affect antigen responses of Tnon gamma cell fraction. Thus these studies show that MN and their cyclooxygenase products modulate T gamma cells to function in a suppressive mode. This demonstration of divergent T gamma cell functions indicates that the contribution of an expanded T gamma cell population to altered antigen reactivity in disease can be determined only by careful functional studies.
Adult↗
Abnormalities of immunosuppression in patients with hepatosplenic schistosomiasis mansoni.
The basis for development of hepatosplenic disease and attendant morbidity in only a minority of S. mansoni-infected individuals is uncertain but may relate to defective modulation of immunopathology. We explored the possibility that schistosomiasis mansoni with hepatosplenomegaly is characterized by failure of immunosuppressive mechanisms. Individuals (14-30 years of age) from an agricultural village in the Nile Delta were selected for study: 12 were uninfected, 9 had S. mansoni infection and hepatosplenomegaly (mean fecal egg excretion 1267 +/- 197 eggs/g), 32 were infected but lacked hepatosplenomegaly (1142 +/- 79 eggs/g). The ratio of OKT4 helper/OKT8 suppressor cells in PBMC was increased in the group with hepatosplenomegaly to 2.7 +/- 0.3 compared to a ratio of 1.7 +/- 0.1 (p less than 0.01) in uninfected subjects; in contrast, this ratio was reduced in infected subjects without hepatosplenomegaly to 1.4 +/- 0.1 (p less than 0.05). Schistosome antigen-induced [3H]thymidine incorporation in PBMC was similar in infected subjects, with hepatosplenomegaly (3329 +/- 738 cpm) and without (5837 +/- 1009 cpm, p greater than 0.01). However, depletion of suppressor adherent cells significantly increased the responses only in the group lacking organomegaly (14,028 +/- 1,683 cpm, p less than 0.001). Thus, among subjects with S. mansoni infection, those with hepatosplenomegaly are distinctive in their failure to develop an immunosuppressive balance of T lymphocyte subpopulations and in the absence of functional adherent suppressor cells.
Adolescent↗
Ultraviolet radiation inhibits human natural killer activity and lymphocyte proliferation.
Exposure to ultraviolet radiation (UVR) has been implicated in the predisposition to certain neoplasms and leads to viral reactivation. Natural killer (NK) activity may play a role in immunosurveillance and response to certain viral infections. We have evaluated the sensitivity to UVR of human NK activity, a nonproliferative function, and the proliferative response to the mitogen phytohemagglutinin (PHA). In vitro exposure to UVR resulted in a dose-dependent inhibition of NK activity and response to PHA. The wavelength dependence for UVR inhibition of NK activity and of the PHA response of lymphocytes were virtually superimposable at wavelengths at or above 300 nm, but NK activity was less sensitive to UVR at 260 and 280 nm. Maximal sensitivity for both functions was found at 260 nm, consistent with a nucleic acid chromophore mediating UVR inhibition of both activities. The DNA-directed drugs mitomycin C, acridine orange, and adriamycin at concentrations that inhibit proliferation are poor inhibitors of NK activity. These results suggest that UVR inhibition of NK activity as well as proliferation may be mediated by a nucleic acid chromophore. NK activity, however, is less sensitive to direct damage of DNA by alkylation, distortion, or oxidation. At 300 nm, the amount of radiation required to inhibit NK activity and proliferation is within the range penetrating to the dermis and capillaries during environmental exposure to sunlight.
Adult↗
Non-specific suppression of antigen-induced lymphocyte blastogenesis in Onchocerca volvulus infection in man.
Lymphocyte blastogenic responses to O. volvulus antigen (Oncho Ag), SKSD, and the mitogen PHA were tested in three groups of persons: light to moderately infected persons (INF); previously exposed but uninfected persons (EXP) and normal controls (NC). The exposed group showed significant responsiveness to Oncho Ag (delta ct/min = 6,002 +/- 1,375), while the infected (delta ct/min = 943 +/- 418) and normal control (delta ct/min = 428 +/- 418) groups did not. The mean blastogenic response to SKSD were EXP, 8,644 +/- 5,249; NC 6,039 +/- 2,880; INF, 2,619 +/- 1,012. The reduced reactivity in the INF group to Oncho Ag showed a significant correlation with reactivity to SKSD (P less than 0.05). To elucidate the mechanism of hyporesponsiveness in the infected group rigorous adherent cell depletion, by adherence to plastic followed by a nylon wool column, was utilized. When 20% plastic adherent cells were added back to the T cells prepared in this fashion, the mean blastogenic response to SKSD was significantly augmented (P less than 0.01). In contrast, the responsiveness to Oncho Ag was not significantly altered. The addition of indomethacin (1 microgram/ml) or autologous plasma had no significant effect on reactivity to either SKSD or Oncho Ag. There were no significant differences in the mean reactivity of the three groups to PHA-M (delta ct/min EXP 78,514 +/- 12,564; INF 62,393 +/- 14,447; NC 61,423 +/- 4,465). These results suggest that O. volvulus infection is associated with decreased lymphocyte reactivity to both parasite related and unrelated antigens, and imply that the mechanism for the two types of hyporesponsiveness may be distinct. While a weakly adherent suppressor cell may account for non-specific hyporesponsiveness, the mechanism of parasite specific decreased reactivity remains unknown.
Adolescent↗
Two distinctive patterns of monocyte immunoregulatory and effector functions in heavy human infections with Schistosoma mansoni.
We evaluated the relationship between immunoregulatory and effector functions of monocytes in subjects with heavy S. mansoni infection (greater than 400 eggs/g of stool). Two main patterns were found. In seven individuals (mean 601 eggs/g), the depletion of adherent cells from peripheral blood mononuclear cells (PBMC) increased blastogenic responses to soluble worm antigenic preparation (SWAP) from a stimulation index (SI) of 3.2 +/- 1.0 to 11.0 +/- 3.0 (p less than 0.01). The presence of indomethacin (1.0 micrograms/ml) in cultures of PBMC from these subjects increased the SWAP response to 7.1 +/- 2.0 (p less than 0.05). In contrast, neither adherent cell depletion nor indomethacin affected blastogenesis induced by nonschistosome antigens or nonspecific mitogens. In this group of infected individuals, monocyte killing of schistosomula and adherence to plastic were increased 122% (p less than 0.01) and 50% (p less than 0.01) over the respective values obtained in uninfected, age-matched controls. A second pattern was found in 10 individuals with a significantly higher intensity of infection (1339 eggs/g of stool (p less than 0.02)). PBMC from these subjects failed to respond significantly to SWAP (SI = 2.0 +/- 0.5), whereas the levels of responses to other antigens and mitogens were maintained at rates comparable to controls. Adherent cell depletion did not significantly affect the blastogenic response (1.8 +/- 0.2), nor did the presence of indomethacin in cultures (2.0 +/- 0.5). Moreover, monocyte-mediated schistosomula killing was depressed in these individuals (50% of controls, p less than 0.05) as was adherence to plastic (77% of controls, p less than 0.05).
Adolescent↗
Destruction of the multicellular parasite Schistosoma mansoni by T lymphocytes.
The role of cytotoxic T lymphocytes in host defenses against infectious agents is unknown as these cells have not previously been demonstrated to kill microorganisms directly. We studied the cytotoxicity of T lymphocytes purified from peripheral blood mononuclear cells of healthy subjects for the multicellular schistosomula of Schistosoma mansoni. Unstimulated and phytohemagglutinin (PHA)-stimulated T cells were cultured with schistosomula at a 5,000:1 effector/target (E:T) ratio for 18 h at 37 degrees C. Unstimulated T cells killed 2.1 +/- 0.6% of schistosomula as judged by dye uptake and did not change their infectivity for mice. In contrast, PHA-stimulated T cells killed 41.3 +/- 3.1% of schistosomula by dye uptake and 56.7 +/- 7.7% of these organisms could not mature to adult worms in vivo. Killing was associated with and dependent on increased binding of PHA-stimulated T lymphocytes to schistosomula. Significant schistosomula killing first was noted after 2 h of exposure to T cells to PHA and peaked at 24; enhanced killing by PHA-stimulated cells was observed at an E:T ratio of 500:1 and was maximal at 5,000:1. Exposure of T lymphocytes to oxidative mitogens, soluble antigens, and alloantigens also resulted in enhanced killing of schistomula. These studies show that T lymphocytes activated by a variety of stimuli develop the capacity to kill schistosomula of Schistoma mansoni. Direct killing of infectious agents by cytotoxic T cells may contribute to host resistance to infections.
Animals↗