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T B Nutman

Publications and source records attributed to T B Nutman.

At least 109 records · Page 6Linked to original sources
PubMed1993

In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma.

The immunological mechanisms underlying the susceptibility to disseminated visceral parasitism of mononuclear phagocytes in patients with kala-azar remain undefined. Resistance and susceptibility are correlated with distinct patterns of cytokine production in murine models of disseminated leishmanial disease. To assess lesional cytokine profiles in patients with kala-azar, bone marrow aspirates were analyzed using a quantitative reverse transcriptase PCR technique to amplify specific mRNA sequences of multiple Th1-, Th2-, and/or macrophage-associated cytokines. Transcript levels of IL-10 as well as IFN-gamma were significantly elevated in patients with active visceral leishmaniasis; IL-10 levels decreased markedly with resolution of disease. These findings suggest that IL-10, a potent, pleiotropic suppressor of all known microbicidal effector functions of macrophages, may contribute to the pathogenesis of kala-azar by inhibiting the cytokine-mediated activation of host macrophages that is necessary for the control of leishmanial infection.

Adolescent↗
PubMed1993

Cytokine control of parasite-specific anergy in human lymphatic filariasis. Preferential induction of a regulatory T helper type 2 lymphocyte subset.

The immunological mechanisms involved in maintenance of an asymptomatic microfilaremic state (MF) in patients with lymphatic filariasis remain undefined. MF patients have impaired filarial antigen (Ag)-specific lymphocyte proliferation and decreased frequencies (Fo) of Ag-specific T cells, and yet elevated serum IgE and antifilarial IgG4. To investigate the mechanism of Ag-specific anergy in MF patients in contrast to amicrofilaremic individuals with chronic lymphatic obstruction (CP), the Fo of Ag-specific lymphocytes from peripheral blood mononuclear cells secreting either IL-4 or IFN-gamma were assessed by filter spot enzyme-linked immunosorbent assay, and IL-10 and transforming growth factor-beta (TGF-beta) mRNA transcript levels were assessed by a semiquantitative reverse transcriptase polymerase chain reaction technique. The Fo of filaria-specific IL-4-secreting lymphocytes were equivalent in both MF (geometric mean [GM] = 1:11,700) and CP (GM = 1:29,300 P = 0.08), whereas the Fo of IFN-gamma-secreting lymphocytes were lower in MF (GM = 1:39,300) than in CP (GM = 1:4,200, P < 0.01). When the ratio of IL-4/IFN-gamma (T helper type 2 [Th2]/Th1)-secreting cells was examined, MF subjects showed a predominant Th2 response (8:1) compared with a Th1 response in CP individuals (1:4). mRNA transcript levels of IL-10 were also significantly elevated in MF compared with CP individuals (P < 0.01). Further, IL-10 and TGF-beta were shown to have a role in modulating the Ag-specific anergy among MF subjects, in that neutralizing anti-IL-10 or anti-TGF-beta significantly enhanced lymphocyte proliferation response (by 220-1,300%) to filarial Ags in MF individuals. These findings demonstrate that MF subjects respond to parasite antigen by producing a set of suppressive cytokines that may facilitate persistence of the parasite within humans while producing little clinical disease.

Adult↗
PubMed1993

The biology of interleukin-5 and its receptor.

IL-5 is primarily a T-cell-derived cytokine that has multiple regulatory functions on eosinophils and (in the mouse) on antibody-secreting B cells. A complex network of cytokines appear to control transcription of the gene for IL-5 and its production. Abnormally high levels of this cytokine are associated with infections with tissue-dwelling parasites and a diverse group of hypereosinophilic conditions of no known etiology. Our understanding of the biological role of IL-5 in the regulation of Ig production and the development of immunity to parasites is far from complete, but basic knowledge of its action at the cellular level is accumulating and will be critical for the intelligent application of immunotherapy with IL-5 or antibodies to IL-5 in infectious, neoplastic, and possibly other diseases.

Animals↗
PubMed1993

Cytokines and immediate hypersensitivity in protective immunity to helminth infections.

Infection with tissue-invasive helminth infections characteristically induces immunological responses associated with immediate hypersensitivity such as IgE elevations, tissue and peripheral blood eosinophilia, and mast cell hyperplasia. Specific sets of cytokines appear to regulate these responses; the resulting responses reflect the balance of upregulatory and inhibitory signals these cytokines provide. The nature of these cytokines and their role in both protective immunity and pathogenesis in helminth infections of humans is the subject of this review.

Animals↗
PubMed1992

Biochemical and immunologic characterization of a major IgE-inducing filarial antigen of Brugia malayi and implications for the pathogenesis of tropical pulmonary eosinophilia.

A major allergen of the human filarial parasite Brugia malayi has been identified by two-dimensional immunoblot analysis using a serum pool from patients with tropical pulmonary eosinophilia. The allergen is composed of two Ag with M(r) 23 and M(r) 25 and acidic isoelectric point (Bm23-25). Immunoblots using affinity-purified IgE antibodies to BM23-25 indicated that Bm23-25 is expressed mainly in the microfilarial stage. Digestion of the allergen with endoglycosidases indicates that it has N-linked oligosaccharide chains. Analysis of the reactivity of T cells derived from patients with lymphatic filariasis revealed that the Bm23-25 allergen was capable of stimulating T cell proliferation; Bm23-25 was also shown to induce IgE production in vitro from PBMC derived from patients with either TPE or other filarial symptoms. Bronchoalveolar lavage fluid of patients with TPE contained IgE antibodies that recognized Bm23-25 strongly, an observation suggesting that the microfilarial allergen might be involved in the pathogenesis of the TPE syndrome.

Allergens↗
PubMed1992

Parallel regulation of IL-4 and IL-5 in human helminth infections.

To investigate the relationship between cytokine production and the increased levels of serum IgE and peripheral eosinophilia commonly accompanying human helminth infections, we studied the ability of PBMC of normal (N1) (n = 18) and eosinophilic individuals with helminth infections (H1) (n = 9) to produce IL-3, IL-4, IL-5, granulocyte-macrophage-CSF, and IFN-gamma in vitro after stimulation with PMA (50 ng/ml) and ionomycin (1 microgram/ml). The two groups differed in both the levels of serum IgE and eosinophilia. For mitogen-induced production of granulocyte-macrophage-CSF and IFN-gamma, there was no difference in cytokine production between the two groups. In marked contrast, supernatants from PBMC of infected individuals had significantly higher levels of IL-4 (mean = 213 pg/ml for N1 and 944 pg/ml for H1, p less than 0.02), IL-5 (mean = 180 pg/ml for N1 and 1118 pg/ml for HL, p less than 0.001), and IL-3 (mean = 13900 pg/ml for N1, 28029 pg/ml for H1, p less than 0.05). In addition, helminth-infected patients had approximately 5-fold greater numbers of T cells capable of producing IL-5 and 2.5-fold greater frequency of IL-4-secreting cells than did normal individuals; GM-CSF- and IFN-gamma-producing T cell numbers were not significantly different in the two groups. IL-3-producing cell frequencies could not be evaluated by this method. There was a direct correlation between IL-4 production and IL-5 production at the level of both protein production and frequency of T cells capable of producing these cytokines. These data indicate that individuals with reactive eosinophilia and elevated serum IgE have an expanded population of lymphocytes producing IL-4 and IL-5 and the association of the two suggests that the regulation of IL-4 and IL-5 may be linked.

CD4-Positive T-Lymphocytes↗
PubMed1992

Characterization of a muscle-associated antigen from Wuchereria bancrofti.

A recombinant clone, WbN1, isolated from a genomic expression library of Wuchereria bancrofti and showing restricted specificity at the DNA level (Southern and PCR analyses) for Wuchereria bancrofti and Brugia malayi has been previously described. Sequence analysis of WbN1 indicated that it had notable similarity to myosin. Further characterization using in situ hybridization has localized the mRNA in the muscle of the adult parasite and in the microfilariae. Rabbit polyclonal antiserum, raised against the recombinant WbN1 fused to the maltose-binding protein, recognized a 200-kDa polypeptide in immunoblots containing B. malayi antigen extracts. The same antibody also recognized myosin extracted from Brugia pahangi, Onchocerca volvulus, and Caenorhabditis elegans. Localization using the rabbit antiserum revealed the presence of the antigen in the adult muscle tissue and in the microfilariae; the same antibody inhibited the binding of a monoclonal antibody 28.2 (directed toward MHC B of C. elegans myosin) to the recombinant WbN1 antigen and also to purified C. elegans myosin. Based on homology data, structural location, competitive ELISA, and immunoblot we conclude that WbN1 is related to myosin or a similar myofibrillar protein.

Amino Acid Sequence↗
PubMed1992

Tropical pulmonary eosinophilia.

Tropical pulmonary eosinophilia is one of the many PIE syndromes [pulmonary infiltrates with eosinophilia (of the peripheral blood)]. It is caused by immunologic hyperresponsiveness to the filarial parasites Wuchereria bancrofti or Brugia malayi. Its clinical presentation includes nocturnal cough, dyspnea, wheezing, fever, weight loss, fatigue, interstitial mottling on chest radiograph, predominantly restrictive but also obstructive lung function abnormalities, and peripheral blood eosinophilia of more than 3000 per microliter. It can be distinguished from other PIE syndromes by the patient's history of residence in the tropics, by the presence of extraordinarily high levels of both serum IgE and antifilarial antibodies, and by the dramatic clinical improvement after treatment with the antifilarial drug diethylcarbamazine. Recent studies indicate that the compromised lung diffusion capacity of patients with acute tropical pulmonary eosinophilia is a function of the degree of the eosinophilic alveolitis present and that, despite a 3-week course of diethylcarbamazine, low-grade alveolitis persists in almost half of such patients; this persistent alveolitis is likely to be the cause of the progressive interstitial fibrosis seen in many untreated or inadequately treated patients with tropical pulmonary eosinophilia.

Animals↗
PubMed1992

Pulmonary involvement in loiasis.

A 40-yr-old West African man presented acutely with pleural effusion. Cytologic evaluation of the pleural fluid revealed Loa loa microfilariae. No additional etiology for the pleural effusion could be identified, and antifilarial treatment with diethylcarbamazine led to a rapid resolution of the patient's symptoms and pulmonary abnormalities. Loa loa must be considered as a treatable cause of eosinophilic pleural effusions in persons from endemic areas of West and Central Africa.

Adult↗
PubMed1992

Immunologic tolerance in lymphatic filariasis. Diminished parasite-specific T and B lymphocyte precursor frequency in the microfilaremic state.

To explore the mechanisms of antigen-specific immune unresponsiveness seen in microfilaremic patients with bancroftian filariasis, T and B cell precursor frequency analysis was performed using PBMC from individuals with either asymptomatic microfilaremia (MF, n = 7) or chronic lymphatic obstruction (CP, n = 20). Highly purified CD3+ cells were partially reconstituted with adherent cells and their proliferative response to parasite antigens determined in cultures of T cells by limiting dilution analysis. A filter immunoplaque assay also assessed the frequency of both total and parasite-specific Ig-producing B cells. While the lymphocyte proliferation to mitogens and to a nonparasite antigen (Streptolysin-O, [SLO]) were similar in all groups of patients, the frequency of parasite-specific CD3+ T cells was significantly lower (geometric mean [GM], 1/3,757) in MF patients when compared to that in CP patients (GM 1/1,513; P less than 0.001). Similarly, the proportion of lymphocytes producing parasite-specific IgE or IgG was significantly lower in MF patients (IgE mean, 0.2%; IgG mean, 0.33%) compared with CP patients (IgE mean, 3.2%; IgG mean, 1.76%; P less than 0.05 for both comparisons). These observations imply that low numbers of parasite-specific T and B lymphocytes may be partially responsible for the severely diminished capacity of lymphocytes from patients with MF to produce parasite-specific antibody and to proliferate to parasite antigen in vitro. Such differences in parasite-specific lymphocyte responses suggest that tolerance by clonal anergy may be a critical mechanism for maintaining the microfilaremic state.

Animals↗
PubMed1991

Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1.

Many ligands of adhesion molecules mediate costimulation of T cell activation. The generality of this emerging concept is best determined by using model systems which exploit physiologically relevant ligands. We developed such an "antigen-specific" model system for stimulation of resting CD4+ human T cells using the following purified ligands: (a) major histocompatibility complex class II plus the superantigen Staphylococcus enterotoxin A, to engage the T cell receptor (TCR); (b) adhesion proteins vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1), to provide potential cell surface costimulatory signals; and (c) recombinant interleukin 1 beta (rIL-1 beta)/rIL-6 as costimulatory cytokines. In this biochemically defined system, we find that resting CD4+ T cells require costimulation in order to respond to TCR engagement. This costimulation can be provided by VCAM-1 or ICAM-1; however adhesion alone is not sufficient since ELAM-1 mediates adhesion but not costimulation. The cytokines IL-1 beta and IL-6 by themselves cannot mediate costimulation, but augment the adhesion ligand-mediated costimulation. Direct comparison with the model of TCR/CD3 engagement by CD3 monoclonal antibody demonstrated comparable costimulatory requirements in both systems, thereby authenticating the commonly used CD3 model. The costimulation mediated by the activation-dependent interaction of the VLA-4 and LFA-1 integrins with their respective ligands VCAM-1 and ICAM-1 leads to increased IL-2R alpha (CD25) expression and proliferation in both CD45RA+ CD4+ and CD45RO+ CD4+ T cells. The integrins also regulate the secretion of IL-2, IL-4, and granulocyte/macrophage colony-stimulating factor. In contrast the activation-independent adhesion of CD4+ T cell to ELAM-1 molecules does not lead to T cell stimulation as measured by proliferation, IL-2R alpha expression, or cytokine release. These findings imply that adhesion per se is not sufficient for costimulation, but rather that the costimulation conferred by the VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions reflects specialized accessory functions of these integrin pathways. The new finding that VLA-4/VCAM-1 mediates costimulation adds significance to observations that VCAM-1 is expressed on a unique set of potential antigen-presenting cells in vivo.

Antibodies, Monoclonal↗
PubMed1991

An immunogenic Onchocerca volvulus antigen: a specific and early marker of infection.

Onchocerciasis (river blindness) is a serious health problem and a severe obstacle to social and economic development, especially in Africa. A complementary DNA fragment coding for an Onchocerca volvulus antigen (OV-16) was cloned and expressed in the plasmid vector pCG808fx. Immune responses to this O. volvulus-specific recombinant antigen were detectable in patients with documented onchocerciasis; the antibody response was also detectable at 3 months and at more than 1 year before infection could otherwise be detected in humans and in chimpanzees experimentally infected with O. volvulus third-stage larvae.

Animals↗
PubMed1991

Frequency analysis of IgE-secreting B lymphocytes in persons with normal or elevated serum IgE levels.

The immunoregulatory mechanisms that determine the high serum IgE antibody levels in disorders such as helminth parasite infections and the hyper-IgE recurrent infection syndrome (HIE) remain poorly understood. To assess whether elevated serum IgE levels result from an increased number of B lymphocytes committed to IgE production, the proportion of IgE-producing B lymphocytes was determined by a filter immunoplaque assay using PBMC from persons with a broad range of serum IgE levels that included normal persons (n = 9) and patients with loiasis (n = 12), tropical pulmonary eosinophilia (TPE) (n = 6), lymphatic filariasis (n = 28), and HIE (n = 8). PBMC from these persons were assessed for production of in vitro IgE. The geometric mean number of IgE-secreting cells in 10(5) B lymphocytes in PBMC was 0.42 (range 0-2.2) in normal persons, 5.6 (range 0.1-35.5) among patients with loiasis, 9.4 (range 0-53.2) among patients with lymphatic filariasis, 52 (range 31.5-115) among patients with TPE, and 218 (range 56-1404) among patients with HIE. When all study subjects were grouped, there were significant correlations with serum IgE levels (r2 = 0.78; p less than 0.0001) and net spontaneous in vitro IgE production (r2 = 0.8; p less than 0.0001). Estimates of the amount of IgE production per B lymphocyte were similar among normal persons, patients with filarial infections, and patients with TPE (geometric means of 134, 96, and 141 pg/ml/cell, respectively); in contrast, for HIE patients, IgE production by individual B cells was significantly lower (geometric mean 28 pg/ml/cell; p less than 0.001). These observations demonstrate that clonal expansion of IgE-producing B lymphocytes is a major mechanism underlying the elevated serum IgE levels seen in persons with hyper-IgE states.

Adolescent↗
PubMed1991

Cloning and characterization of a species-specific repetitive DNA sequence from Loa loa.

A genomic DNA library of Loa loa was constructed in lambda gt11 using EcoRI-digested DNA from microfilariae isolated from two West African patients. Screening with labeled L. loa DNA yielded several potential repetitive DNA clones. An MboI fragment of one of these, LL3M9, was identified and characterized. Sequence analysis of LL3M9 revealed an 839-bp fragment with an unusual 356-bp region containing 37 copies of the hexamer CTTAGG, many of which are arranged in repeated motifs of 12, 27 and 63 bp. This region shares many of the characteristics of eukaryotic satellite DNA. A synthetic oligonucleotide corresponding to the 27-bp repeated motif, LL3M9REP, was found to be both sensitive and species-specific by dot hybridization. Species specificity of LL3M9REP was confirmed by amplification of the repetitive region using genomic DNA as a template in the polymerase chain reaction.

Animals↗
PubMed1991

A recombinant clone of Wuchereria bancrofti with DNA specificity for human lymphatic filarial parasites.

In order to understand the immune response to Wuchereria bancrofti and to aid in the diagnosis of W. bancrofti infections, recombinant antigens were identified from a W. bancrofti genomic expression library made in lambda gt11 using a pool of sera from infected Indian patients. One of the recombinant clones, lambda WbN1, containing a 2.5-kb insert, reacted strongly to a pool of sera from patients with lymphatic filariasis but not to normal human sera. In addition, this clone showed restricted specificity at the genomic level to the major lymphatic filarial parasites W. bancrofti and Brugia malayi but not to the closely related filarial parasite Brugia pahangi or to other filarial and non-filarial species tested. Nucleotide sequence analysis indicated the cloned DNA to have homology to myosin-like myofibrillar proteins. Polymerase chain reaction amplification initiated by specific synthetic oligomers amplified DNA in a species-specific manner from as little as 16 pg of isolated DNA or from one microfilaria.

Amino Acid Sequence↗
PubMed1991

Regulation of the immune response in lymphatic filariasis and onchocerciasis.

The persistence of microfilariae in the blood or skin accompanied by a prominent eosinophilia and elevated serum IgE levels are common features of human infection with filarial parasites. In this review Christopher King and Thomas Nutman discuss recent findings on the role of interleukin 4 (IL-4), IL-5 and gamma-interferon (IFN-gamma) in the induction of these immediate hypersensitivity responses. They discuss the role of hypersensitivity in immunity, the development of immune tolerance to filarial antigens and suggest that could explain the impaired immune response of some individuals to filarial infections and the persistence of the microfilaremic state.

Animals↗
PubMed1991

Immunity to onchocerciasis: recognition of larval antigens by humans putatively immune to Onchocerca volvulus infection.

Immunoblot analyses were done using sera from 12 individuals without evidence of onchocerciasis and 16 with active infection from an area of Guatemala holoendemic for onchocerciasis. For adult antigens from Onchocerca volvulus, no differences in antigen recognition could be identified between the two groups. In contrast, when infective larval (L3) antigen preparations derived from the related animal parasite Onchocerca lienalis were used, IgG from the "immune" individuals preferentially recognized a 45- to 50-kDa triplet and a 22-kDa L3 antigen. When L3 antigens of Brugia malayi were used, sera from putatively immune individuals identified a high-molecular-weight triplet/quadruplet plus several additional antigens of lower molecular weights that were recognized by sera from few (or none) of the infected patients. These findings define some differences in antibody specificity in onchocerciasis patients and therefore might define potential target antigens of humoral host defense. The exact nature of such defenses is unknown.

Adolescent↗