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Biomedical subjects

H M Wolf

Publications and source records attributed to H M Wolf.

At least 37 records · Page 2Linked to original sources
PubMed1995

Immunization of chimpanzees with recombinant gp160, but not infection with human immunodeficiency virus type 1, induces envelope-specific Th1 memory cells.

The human immunodeficiency virus (HIV) type 1 envelope protein (recombinant [r] gp160)-induced T cell lymphokine release pattern of chimpanzees immunized with HIVIIIB rpg160 tested and compared with rpg160-induced lymphokine releases of T cells from unimmunized, HIV-1-infected chimpanzees. The results showed that infection of chimpanzees with HIV-1 did not induce rgp160-specific memory T cells (as evidenced by the lack of Th1 and 2 type lymphokine releases after rgp160 stimulation). In contrast, T cells of rgp160-immunized chimpanzees released Th1 type lymphokines upon stimulation with rgp160 of HIVIIIB, HIVMN, and HIVRF. release was comparable whether chimpanzees were immunized with rgp160 only or also challenged with HIV-1 and protected or not protected. Thus, rgp160 immunization leads to generation of Th1 type memory cells. Whether Th1 type responses contribute to protection against HIV-1 infection has yet to be clarified.

Animals↗
PubMed1995

Defective TCR surface expression associated with impaired TCR beta-chain assembly in a patient with cutaneous T-cell lymphoma.

We report on a patient with cutaneous T-cell lymphoma (CTCL) of long-standing duration. Phenotypic analysis of his peripheral blood mononuclear cells revealed an increased CD4+ T-helper subset and a decreased CD8+ cytotoxic T-cell population. Eighty-three to ninety-three percent of the patient's CD4+ T cells in the peripheral blood and 70% of the CD4+ T cells in the lesional skin lacked surface expression of the TCR/CD3 complex and showed a clonal rearrangement pattern of the TCR gamma-chain gene (V11-J1/J2). The lack in TCR surface expression correlated with defective assembly of the TCR beta-chain. Although mRNA for the TCR constant region beta 1 was found in the patient's purified CD4+ TCR-CD3- T cells, no intracytoplasmic TCR beta protein was detectable. In contrast, the patient's purified CD4+ TCR-CD3- T cells not only expressed mRNA specific for the TCR alpha-chain and for all CD3 chains, but intracytoplasmic TCR alpha and CD3 epsilon proteins could also be found. The lack of TCR beta protein clearly explains the defective surface expression of the TCR/CD3 complex in the patient's malignant T cells.

CD3 Complex↗
PubMed1994

A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by an impairment of specific antibody production and a decrease in all or selected Ig isotypes. Abnormalities at the level of the B cells, T cells, and antigen-presenting cells have been described. In the present study, we have focused our attention on T-cell activation in CVID. T cells from 15 of 24 patients failed to respond to recall antigens (eg, tetanus toxoid, Escherichia coli). Of these 15 patients, 11 were studied in detail and showed significantly decreased T-cell proliferative responses and/or decreased interleukin-2 and interferon-gamma production on T-cell receptor-mediated stimulation with recall antigens and superantigens (staphylococcal enterotoxins [SE]); however, T-cell response to mitogens (anti-CD3 monoclonal antibody, phytohemagglutinin) was normal. The defect in interleukin-2 and interferon-gamma release on tetanus toxoid stimulation could also be documented in purified CD4 T cells of the patients and was present in patients with high and normal CD8 counts alike. Furthermore, patients' T cells failed to mount a significant elevation in free intracellular calcium (Ca++ flux) in response to superantigen, whereas the response to phorbol myristate acetate and ionomycin, bypassing receptor-mediated signaling, was unimpaired. These results indicate a defect in the early phase of T-cell activation after triggering of the T-cell receptor in a significant subgroup of CVID patients.

Adolescent↗
PubMed1994

Human serum IgA downregulates the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6) in human monocytes.

While the protective effect of IgA antibodies against infection of the mucosal surfaces is well documented, the mechanisms involved are not entirely clear. The aim of the current study is to investigate the effect of human serum IgA on the release of inflammatory cytokines in human monocytes activated with a particulate stimulus, Haemophilus influenzae type b (Hib), or soluble lipopolysaccharide (LPS) purified from Escherichia coli. Our results show that IgA downregulates tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) production, whereas IgG examined in parallel had no effect. IgA had no inhibitory effect on Hib-induced granulocyte-macrophage colony-stimulating factor release. TNF-alpha and IL-6 release were downmodulated if IgA was present during cytokine induction, and IgA was also inhibitory if added to Hib-pretreated monocytes during the phase of cytokine release. These findings indicate that there are at least two mechanisms whereby IgA antibodies can downregulate TNF-alpha and IL-6 release in human monocytes: by a mechanism acting during the time of monocyte activation, and a mechanism that downregulates the production and/or the release of these cytokines in activated monocytes. Regulation of TNF-alpha and IL-6 release by IgA may be among the antiinflammatory mechanisms preventing an uncontrolled release of potentially noxious levels of inflammatory cytokines during acute and/or chronic inflammation.

Antigen-Presenting Cells↗
PubMed1994

Impaired TCR signal transduction, but normal antigen presentation, in a patient with common variable immunodeficiency.

We describe a 27-year-old white man with common variable immunodeficiency (CVID) who has two healthy histoidentical brothers and one IgA-deficient sister who shares one HLA haplotype with the patient. T cells from the patient with CVID showed an impaired response to recall antigens (tetanus toxoid, E. coli), whereas his IgA-deficient sister and his two healthy histoidentical brothers responded normally. Cross-mixing experiments using isolated monocytes and T cells from the CVID patient and one histoidentical brother revealed that the patient's monocytes were fully functional in processing and presenting antigen to resting T cells of his brother, and provided normal accessory cell function for superantigen-induced activation of his brother's resting T cells. In contrast, the patient's T cells were unable to respond to antigen presented by the brother's monocytes and failed to respond with an increase in intracellular free Ca++ to stimulation with superantigen, which is known to bind to the TCR V beta-chain outside the antigen-binding groove. However, stimulation with a combination of PMA and IM, directly activating protein kinase C and increasing intracellular free Ca++ by bypassing membrane receptors, induced normal Ca++ flux. These data indicate that the patient with CVID has a defect in TCR-mediated signalling at the level of the T cells which is not present in his histoidentical healthy brothers or in his haploidentical IgA-deficient sister.

Adolescent↗
PubMed1994

T cell differentiation and generation of the antigen-specific T cell repertoire in man: observations in MHC class II deficiency.

The circulating T cell pool of an MHC class II-deficient patient was shown to lack the MHC class II-specific T cell functions. This was demonstrated by the absence of MHC class II-specific alloreactive T cells and a substantially decreased number of circulating CD4+ lymphocytes. The patient's T cells did respond to an allostimulus, although the restriction pattern of this reaction remains speculative. The function and distribution of peripheral T cell subsets from the patient resemble findings in MHC class II-deficient mice, which also lack interaction of T cell precursors with MHC class II-bearing accessory cells during thymic differentiation. Our data support the concept that T cell differentiation in humans is similar, and that the human MHC-restricted T cell repertoire depends on prior interaction of T cell precursors with self MHC.

Base Sequence↗
PubMed1994

The costimulatory signal CD28 is fully functional but cannot correct the impaired antigen response in T cells of patients with common variable immunodeficiency.

A wide spectrum of different immunologic abnormalities have been postulated as being responsible for the impairment of specific antibody production and the decrease in all or selected immunoglobulin isotypes present in common variable immunodeficiency (CVID). These abnormalities include impaired B cell differentiation and/or function, defective macrophage function, and significant T cell defects. The aim of the present study was to delineate whether the accessory molecule CD28 is involved in the impaired antigen response of T cells from patients with CVID. Our results demonstrate that CD28 costimulation was functional in T cells stimulated with anti-CD3 or anti-TCR MoAb, but could not correct the impaired response of patients' peripheral blood T cells to tetanus toxoid. Analysis of patients' long-term cultured T cells further confirmed these results. Exogenous rIL-2, another costimulus, augmented but did not correct the defective proliferation and lymphokine production in patients' antigen-driven peripheral blood T lymphocytes or in long-term cultured T cells. These findings indicate that the CD28 signalling pathway in these patients' T cells is unimpaired, and that costimulation via CD28 cannot correct the defect occurring in the course of TCR-mediated T cell activation.

Adolescent↗
PubMed1994

The anti-inflammatory effect of an oral immunoglobulin (IgA-IgG) preparation and its possible relevance for the prevention of necrotizing enterocolitis.

An exaggerated release of inflammatory mediators has been implicated in the pathogenesis of necrotizing enterocolitis (NEC). Oral administration of a human immunoglobulin preparation (serum IgA-IgG) has been demonstrated to be an effective prophylaxis for NEC. The aim of the present study was to examine the regulatory effect of a human IgA-IgG preparation on the release of inflammatory cytokines in human monocytes. Our results indicate that the immunoglobulin preparation inhibits TNF-alpha and IL-6 release in monocytes following stimulation with heat-inactivated Hib in a dose-dependent manner. This might have a biological relevance in infants receiving oral immunoglobulin prophylaxis for NEC, since modulation of the release of inflammatory mediators at the level of the gastrointestinal mucosa could interfere with the development of noxious sequelae of acute and/or chronic inflammation initiated by microbial pathogens or their toxins that finally lead to the pathologic changes associated with NEC.

Administration, Oral↗
PubMed1994

Inhibition of receptor-dependent and receptor-independent generation of the respiratory burst in human neutrophils and monocytes by human serum IgA.

An important feature of the role of IgA in protection against infection and disease at the level of the mucosal surfaces might be the elimination of pathogens without induction of a strong inflammatory reaction. In the present study we addressed the question whether IgA has a regulatory effect on the generation of reactive oxygen intermediates in human neutrophils and monocytes (i.e. the respiratory burst). Cells were stimulated with heat-inactivated Haemophilus influenzae type b or phorbol myristate acetate, stimuli known to use different recognition structures or signal transduction pathways. Concentrations of IgA as low as 10 mg/L significantly inhibited the receptor-dependent Haemophilus influenzae-induced respiratory burst in granulocytes, as assessed by measuring luminol-enhanced chemiluminescence. Furthermore, IgA had a dose-dependent inhibitory effect on the receptor-independent induction of the respiratory burst, as examined by flow cytometry in monocytes and granulocytes activated with phorbol myristate acetate. Our results therefore indicate that inhibition of receptor-ligand interaction is not a sufficient explanation for the IgA-mediated modulation of the respiratory burst in human phagocytic cells. In addition, IgA might directly regulate the activation of the respiratory burst at the level or downstream of protein kinase C activation. By modulating the release of mediators of inflammation such as reactive oxygen intermediates, the inflammatory response could be down-regulated at the level of the mucosal surfaces, thereby preventing the development of sequelae of an exaggerated inflammatory response potentially leading to local or systemic pathology.

Adolescent↗
PubMed1993

Defective interleukin-2 and interferon-gamma gene expression in response to antigen in a subgroup of patients with common variable immunodeficiency.

Patients with common variable immunodeficiency (CVID) are heterogeneous in the clinical manifestations of the disease and in the underlying mechanisms leading to the immunodeficiency. The impairment of B-cell function can be due to an intrinsic defect of the B cells, a deficiency in the function of the antigen-presenting cell, or a dysfunction in the course of T-cell activation. In the present report we have focused our attention on T-lymphocyte activation in three patients with CVID. Numbers of T and B cells, as well as CD4 and CD8 T cell subsets, were within the normal range. The patients' B cells secreted IgM but did not secrete IgG and IgA in response to B-cell stimuli in vitro. Addition of allogeneic T cells was followed by an increase in IgM production but had no effect on the other immunoglobulin isotypes. Examination of T-cell function revealed impaired proliferative response, interleukin-2 (IL-2) and interferon-gamma gene expression and IL-2 release after antigenic stimulation, whereas T-cell proliferation, as well as IL-2 gene expression and release in response to stimulation via anti-CD3, were comparable to those of healthy control subjects. Anti-CD3-induced IFN-gamma gene activation in T cells from two patients was comparable to that of control subjects, whereas T cells from the third patient showed reduced expression of IFN-gamma mRNA. In contrast to the decreased IL-2 and IFN-gamma mRNA levels, IL-2R transcripts examined in parallel were normal in CVID T cells on stimulation with antigen. The defect in IL-2 and IFN-gamma mRNA expression after stimulation with antigen, but not with anti-CD3, suggests an abnormality confined to T-cell activation by the T-cell receptor.

Adult↗
PubMed1993

Activation of CVID patients' T cells with conventional antigens and superantigens.

Defects in T cell function are known to be present in a subset of patients with CVID, but the true nature of these defects still has to be revealed. In prior studies we described that T cells from these patients show an impaired proliferative response following activation with recall antigens (E. coli, Tet. Tox., TBE and PPD). Gene expression of IL2 and IFN-gamma in patients' T cells following antigenic stimulation was significantly reduced compared to controls, while IL-2R transcripts were normal. To further characterize the defect we examined T cell responses to bacterial enterotoxins, collectively termed superantigens. Following stimulation with optimal (10 ng/ml p < 0.05) as well as suboptimal (1 ng/ml p < 0.0025) concentrations of staphylococcal enterotoxin A (SEA), proliferative response and cytokine release (IL-2 and IFNg) were significantly decreased in patients' T cells as compared to controls'. When patients' T cells were stimulated with staph. enterotox. C3 (SEC3) an even more pronounced difference between patients' and controls' T cells could be observed (10 ng/ml p < 0.002, 1 ng/ml p < 0.0005). Our data indicate that, in addition to the defect in antigen-induced T cell activation, T cells of CVID patients express a broader impairment in the interaction between the antigen presenting cell and the TCR.

Antigens↗
PubMed1992

Impaired primary antibody responses after vaccination against hepatitis B in patients with breast cancer.

The response to hepatitis B (HBV) vaccination was studied in 32 breast cancer patients who were HBV antigen- and antibody-negative at the time of diagnosis. Ten of the patients included into the study received radical mastectomy without adjuvant therapy, 15 patients underwent breast-conserving surgery with subsequent irradiation with or without tamoxifen treatment, and 7 patients were treated by modified radical mastectomy plus adjuvant chemotherapy. Eight patients received the first dose of vaccine 3 months after irradiation therapy. Seven patients were first vaccinated 6 months following irradiation therapy. Seven healthy age-matched persons were vaccinated as controls. Antibody response in the patients was significantly delayed. Four weeks after the second vaccination 6 out of 7 controls showed a significant (> 10 IU/ml) HBs antibody titer, while only 6 out of 32 patients responded. In addition, HBs antibody titers were also significantly lower after the second vaccination even in those patients treated with surgery alone, although they were first vaccinated 3 months after surgery and had no residual tumors. This difference disappeared after the second booster immunization, at which time the frequency of significant antibody titers and the levels of HBs antibody titers were comparable between patients and controls. As the population of patients undergoing treatment for breast cancer is increasing, additional studies are needed to determine optimal immunization regimens in this group of patients.

Adult↗
PubMed1992

Cellular and humoral immune responses in haemophiliacs after vaccination against tick-borne encephalitis.

The primary immune response to a viral antigen (tick-borne encephalitis, TBE) has been determined in haemophiliacs. Twelve HIV-negative and four clinically asymptomatic, HIV-positive haemophiliacs as well as 16 age-matched healthy controls were included in the study. Antibody responses after TBE vaccination were comparable in HIV-negative haemophiliacs and controls; however, antibody titres in HIV-infected haemophiliacs were significantly lower after completion of the three-dose vaccination schedule (geometric mean reciprocal antibody titres (SEM): controls, 193 (1.37), HIV-positive haemophiliacs, 13 (2.18), P < 0.005). TBE vaccination failed to induce a T cell proliferative response in the HIV-positive haemophiliacs. While in HIV-negative patients the antigen-specific lymphoproliferative responses after primary and one booster vaccination were comparable to those of the controls, cellular responses were decreased in HIV-negative haemophiliacs following a second booster immunization 19 months after primary immunization (3H-thymidine incorporation, delta dpm, mean +/- SEM: controls, 34662 +/- 7129, HIV-negative haemophiliacs, 14339 +/- 7420, P < 0.005). As the protective mechanisms for TBE infection are not yet completely understood, further work will be necessary to determine whether the decreased capacity to mount a sufficient long-term cellular memory response in HIV-negative haemophiliacs might be important for the protective effect of TBE vaccination in this population.

Adolescent↗
PubMed1991

Immunization of chimpanzees with the HIV-1 glycoprotein gp160 induces long-lasting T-cell memory.

The goal of the present study was to investigate the antigen-specific T-cell response to the recombinant HIV envelope glycoprotein (gp160) and to test the effect of various adjuvant formulations on the efficiency of T-cell priming as well as on magnitude and longevity of the gp160-specific T-cell response. Our studies revealed that, in combination with an appropriate adjuvant (lipid-based adjuvant or mineral carrier complex), immunization with recombinant gp160 led to the appearance of gp160-primed T cells. The T-cell response obtained was substantial (proliferative response of greater than 100,000 delta dpm after one primary and two booster immunizations), gp160-specific (proliferation only in response to gp160, no proliferation after addition of a mock gp160 preparation), and long-lasting (T cell responses of greater than 50,000 delta dpm were observed more than one year after the last booster). The results presented here differ from those of previous studies in that they show the presence of substantial and long-lasting T-cell memory toward the immunogen gp160. Therefore further investigations on the use of these preparations as HIV candidate vaccines appear to be justified.

Adjuvants, Immunologic↗
PubMed1991

Phenotypes of peripheral blood lymphocytes during acute hepatitis A.

We investigated peripheral blood lymphocyte phenotypes of 74 patients at weekly intervals during the course of acute hepatitis A. In the second week after onset of jaundice, a significant elevation of total lymphocytes was observed (4,096 X 10(6) +/- 1,003 X 10(6)/l vs. controls 3,038 X 10(6) +/- 1,208 X 10(6)/l, p less than 0.005). However, no change in the relative percentage of B-cells (CD20+), T-cells (CD3+ or CD2+), or T-cell subpopulations (CD4+ helper cells and CD8+ suppressor cells) could be demonstrated during the course of the disease. Activated T-cells (CD3+ DR+) were elevated during the first week (204 X 10(6) +/- 134 X 10(6)l vs. normal 91 X 10(6) +/- 54 X 10(6)/l, p less than 0.005) and during the second week (202 X 10(6) +/- 82 X 10(6)/l, p less than 0.0005) after onset of disease and returned to normal values until the third week. Cells expressing phenotypes of lymphocytes capable of exerting non-MHC-restricted cellular cytotoxicity, i.e. Natural Killer cell activity (CD57+, CD16+, and CD56+) were significantly elevated in percentage in the first week of disease, as compared to controls (CD57: 14.5 +/- 7.0% vs. 9.3 +/- 5.8%, p less than 0.05; CD16: 13.4 +/- 7.3 vs. 9.5 +/- 5.1%, p less than 0.05; CD56: 10.5 +/- 3.5% vs. 8.0 +/- 1.5%, p less than 0.005). Also the absolute numbers of these lymphocyte subpopulations were found to be elevated during the first and second week. The increase in NK cells in the initial phase of acute hepatitis A suggests an important role of these cells in the first line of defence in this disease.

Acute Disease↗
PubMed1991

Cell-mediated immune functions in a patient with MHC class II deficiency.

This report focuses on cell-mediated immune functions in a patient with MHC class II deficiency. The patient described presented with a case of "classical" MHC class II deficiency (T and B cells within the normal range, normal lymphocyte proliferation in response to stimulation with mitogens, gene encoding for MHC class II present, no expression of MHC class II). The absence of MHC class II expression resulted in an incapability of the patient's antigen-presenting cells to function as accessory cells in the presentation of soluble protein antigens, while accessory functions required for the induction of alloantigen-induced lymphocyte proliferation or for the generation of cytotoxic T cells in response to an allostimulus were normal. The patient's T cells responded normally to alloantigenic stimulation and also had the capacity to develop antigen-specific cytotoxic functions. However, the T cells were completely naive with respect to activation by soluble protein antigens, even after presentation by accessory cells derived from the patient's healthy histoidentical brother. In this context it was interesting to note that the patient's CD4-positive cells showed a normal pattern of expression of the 4B4 marker, a marker generally present on memory T cells. These data make it tempting to speculate that in the absence of MHC class II, other cell surface structures may at least partially take over immune functions normally under the control of the MHC class II complex.

Antigens, CD↗