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Biomedical subjects

T B Nutman

Publications and source records attributed to T B Nutman.

At least 127 records · Page 7Linked to original sources
PubMed1991

Loiasis in endemic and nonendemic populations: immunologically mediated differences in clinical presentation.

To define the clinical spectrum of loiasis more precisely and to begin to assess the immunologic basis for the difference in clinical manifestations between visitors to endemic areas and natives of these areas, 51 West African patients with loiasis were evaluated and compared with 42 infected expatriates. Microfilaremia was present in 90% and Calabar swellings in only 16% of the endemic patients. Conversely, only 10% of the expatriates were microfilaremic while 95% complained of Calabar swellings. The endemic population showed significantly decreased levels of peripheral blood eosinophils, parasite-specific IgG, and lymphocyte proliferation to parasite antigens compared with the nonendemic population. These findings support the hypothesis that differences in the modulation of the immune response to parasite antigen are responsible for the observed differences in clinical presentation between expatriate and endemic populations with loiasis.

Adolescent↗
PubMed1991

Immunologic responses to repeated ivermectin treatment in patients with onchocerciasis.

To assess the effect of ivermectin treatment on the immunologic status of individuals with onchocerciasis, 27 patients from Guatemala were studied before and at 6-month intervals during 2 years of repeated semiannual treatment with ivermectin. T cell proliferative responses to onchocercal antigen increased transiently by 6 months (mean stimulation index [SI] rising from 4.17 to 12.81) but returned to preivermectin levels thereafter. Changes in SI to nonparasite antigen paralleled those induced by parasite antigen. There were also significant decreases in levels of blood eosinophils, polyclonal IgG and IgE, parasite-specific IgG antibody, and IgG subclass antibodies by the end of the study. This study emphasizes the apparent long-term safety of ivermectin by demonstrating the absence of immunopathogenic responses induced by repeated ivermectin treatments.

Adolescent↗
PubMed1991

Immunoregulation in onchocerciasis. Functional and phenotypic abnormalities of lymphocyte subsets and changes with therapy.

To help define the immunoregulatory defects in patients with onchocerciasis, flow cytometric analysis of circulating lymphocyte subpopulations was performed in parallel with functional assays. No significant differences in CD4/CD8 ratios were seen when microfilariae-positive individuals from Guatemala were compared with Guatemalan controls. However, the infected individuals had significantly increased numbers of circulating CD4+CD45RA+ lymphocytes (mean 38.3%) when compared with controls (mean 16.0%). Coexpression of the activation marker HLA-DR was significantly increased on CD4+ cells from infected individuals. In contrast, no up-regulation of HLA-DR was seen on CD8+ or CD19+ cells. At 1 year after initiation of treatment with semiannual doses of the microfilaricide ivermectin, there were significant increases (P less than 0.05) in the percentage of CD4+CD45RA- cells, the percentage of CD4+HLA-DR+ cells, and mitogen-induced lymphokine production (IL-2, IL-4). Despite these changes, parasite-specific IL-2 and IL-4 production which had been undetectable before treatment did not manifest itself even by the 2-yr follow-up. Defects in the T-cell activation pathway in Onchocerca volvulus-infected individuals may thus exist at several independent points; a state of parasite antigen-specific tolerance appears to remain even after the relative reversal of other generalized immunoregulatory defects.

Adolescent↗
PubMed1991

Interleukin-5 and the posttreatment eosinophilia in patients with onchocerciasis.

To understand the role of the eosinophilopoietic cytokine IL-5 in humans, the posttreatment eosinophilic response in a group of microfilaria (mf)-positive patients with onchocerciasis (n = 10) was examined before and after treatment with diethylcarbamazine (6 mg/kg for 7 d). Sequential blood samples were assessed at 24 and 1 h before treatment (baseline values), then at frequent intervals over the next 14 d. Symptom scores, skin microfilariae (mf), and peripheral blood eosinophil counts were recorded as a function of time after treatment, and serum levels of IL-5 were quantitated by a highly sensitive (sensitivity greater than or equal to 20 pg/ml) monoclonal-based ELISA. Pretreatment eosinophil counts ranged from 240 to 1,186 eosinophils/microliter (geometric mean, 675), and the mf counts from 10 to 218 per mg skin (geometric mean, 79). After an initial decline in the peripheral eosinophil count to 28 +/- 8% of pretreatment levels at 8 h after beginning treatment, the eosinophil counts steadily increased over the next 2 wk, reaching a maximum at 14 d (257 +/- 38% of pretreatment levels). Serum levels of IL-5 rose sharply from pretreatment levels to a peak of 70.5 +/- 11 pg/ml by 24 h after treatment. Serum IL-5 remained elevated over the next 2-3 d and declined toward baseline by approximately 6 d after treatment, at which time the eosinophil levels were steadily increasing. IL-3 and granulocyte macrophage colony-stimulating factor, two other cytokines implicated in eosinophilopoeisis, were not detectable in the serum at any time before or after treatment. The rise in serum IL-5 before the posttreatment eosinophilia seen in this group of patients with onchocerciasis demonstrates a temporal relationship between IL-5 and the subsequent development of eosinophilia and implicates IL-5 as an important mediator of eosinophilia in humans.

Adolescent↗
PubMed1990

B cell responses to paramyosin. Isotypic analysis and epitope mapping of filarial paramyosin in patients with onchocerciasis.

To examine the fine specificity of the human immune response to filarial paramyosin, the antigenicity of an expressed rcDNA (2.55 kb) of Dirofilaria immitis paramyosin was detailed by ELISA. Using sera from patients infected with Onchocerca volvulus, we analyzed both the entire paramyosin molecule and six subcloned fragments for their IgG, IgG subclasses, and IgE responses. Patients from both Guatemala (64% positive) and Ghana (100% positive) reacted to paramyosin with specific IgG levels above normal controls. Although there was no anti-paramyosin subclass restriction common to all patients, the IgG3 response in the Ghananians was significantly greater than that of Guatemalans (p less than 0.001). IgE anti-paramyosin responses showed positive correlations with IgG2 (p less than 0.001), IgG4 (p less than 0.002), and IgG1 (p less than 0.04) responses. Epitope mapping using the IgG response to the six subclones demonstrated preferential recognition of the amino terminal end of the molecule (nucleotides 1 to 360). IgG2 reactivity was clearly localized to the most amino-terminal 120 amino acids, and the IgG4 antibodies recognized amino acids immediately adjacent to this fragment. These studies examining the fine specificity of anti-filarial immune reactions should provide a method for understanding how parasites either evade or induce host immune responses.

Adolescent↗
PubMed1990

The identification of an Onchocerca-specific recombinant antigen containing a T cell epitope.

Recombinant Onchocerca volvulus Ag have been derived from expression libraries and examined for their ability to stimulate PBMC from patients infected with O. volvulus. Ten clones producing recombinant Ag were selected and plaque purified; lysogens were produced and found to express beta-galactosidase fusion proteins ranging in molecular mass from 115 to 138 kDa. When ammonium sulfate-precipitated lysates of these recombinant phage clones were examined for their ability to stimulate PBMC from a patient with onchocerciasis, all 10 recombinants produced stimulation above that to nonrecombinant phage. When individual fusion proteins, affinity purified on anti-beta-galactosidase linked to agarose, were used to stimulate PBMC from patients with onchocerciasis, only one of the recombinant Ag induced PBMC proliferation (stimulation index greater than 4) above that to Ag from nonrecombinant phage. Characterization of the DNA coding for this Ag showed it to be 1.2 kb in length with a small (90 bp) open reading frame; furthermore, it appears to be Onchocerca specific (on genomic dot blots) and single copy. Using overlapping peptides encompassing the entire open reading frame, one T cell epitope has been localized.

Amino Acid Sequence↗
PubMed1990

Enumeration of IgE secreting B cells. A filter spot-ELISA.

To assess the frequency of IgE producing cells in humans a filter immunoplaque assay has been developed to detect IgE secretion from individual B lymphocytes in unfractionated peripheral blood mononuclear cells (PBMC). PBMC were incubated in microfilter plates containing nitrocellulose membranes coated with polyclonal anti-human IgE antibody, and the IgE production by a single cell was detected using a specific anti-human IgE monoclonal antibody followed by enzymatic development. The products of the enzymatic reaction were visualized as blue plaques on the membranes. The assay was both sensitive and specific as determined by: (1) a near 1:1 correlation between direct cell counts of an IgE producing myeloma cell line (U266) and the number of plaques in the filter immunoassay; and (2) the absence of detectable plaques generated by human B cells transformed by Epstein-Barr Virus (EBV) and producing only IgG or IgM. The presence of other cell types in PBMC did not affect the ability to detect IgE secreting cells. Replicate cultures of highly purified B lymphocytes, first transformed with EBV and then stimulated with recombinant human interleukin-4, produced IgE levels in culture supernatants that correlated closely with the number of IgE producing cells (r = 0.93; P less than 0.001). Furthermore, using the same transformed cells, the number of IgE secreting cells assessed by the immunoplaque assay was significantly correlated (r = 0.94; P = 0.002) with the number of IgE producing cells assessed by immunofluorescence staining of intracytoplasmic IgE. This assay provides a simple and direct method to assess the frequency of IgE producing lymphocytes in humans.

B-Lymphocytes↗
PubMed1990

Regulation of parasite-induced eosinophilia: selectively increased interleukin 5 production in helminth-infected patients.

Production of the eosinophilogenic cytokines interleukin 3 (IL-3), granulocyte/macrophage colony-stimulating factor (GM-CSF), and IL-5 by mitogen-stimulated peripheral blood mononuclear cells was compared between 11 noneosinophilic individuals and seven patients with helminth-induced eosinophilia. Both the kinetics and quantities of IL-3 and GM-CSF were similar in the two groups. In contrast, IL-5 production at both the protein and the mRNA level was markedly greater in the eosinophilic patients, an observation suggesting that IL-5 may be particularly important in mediating the selective eosinophilia seen in filarial and other helminth infections.

Adult↗
PubMed1990

Changes in antibody profile after treatment of human onchocerciasis.

To define the changes in antibody response to Onchocerca volvulus antigens after treatment of patients with onchocerciasis, IgG and IgE antibodies were examined quantitatively and qualitatively in 21 patients and 3 control individuals before and sequentially for 14 days after treatment with diethylcarbamazine. The quantitative levels of IgE and IgG responses (both polyclonal and O. volvulus-specific) remained essentially unchanged for all patients, but 9 of the 21 patients showed intensified responses to one or more parasite-specific antigens, and 8 of 21 developed antibodies to previously undetected antigens. There was a significant correlation between the intensities of infection and the development of newly recognized anti-O. volvulus antibodies. These studies demonstrate that O. volvulus-specific IgE and IgG antibody responses are, at least transiently, enhanced by treatment with diethylcarbamazine and that after treatment, parasites possibly release antigens previously hidden from the host's immune response.

Adolescent↗
PubMed1990

Cytokine regulation of antigen-driven immunoglobulin production in filarial parasite infections in humans.

To define the immunoregulatory mechanisms underlying serum IgE levels found in patients with filariasis, we studied polyclonal IgE production by peripheral blood mononuclear cells (PBMC) from 15 patients with filarial infections, with a focus on the role of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) in the generation and regulation of the response. Spontaneous in vitro IgE production was elevated in 10 of the 15 patients (836-6,464 pg/ml; normals, less than 500 pg/ml). Addition of filarial parasite antigen to PBMC cultures significantly stimulated polyclonal IgE production in an antigen dose-dependent manner in 10 of 12 patients tested (P less than 0.001). The essential role of IL-4 in the generation of this response was demonstrated when simultaneous addition of anti-IL-4 completely inhibited antigen-stimulated IgE production in all 10 patients studied. An inhibitory role of endogenously produced IFN-gamma was also indicated when the addition of anti-IFN-gamma to the cultures significantly augmented filarial antigen-stimulated IgE production by 33-1,238% in these same patients. Addition of 10-1,000 U/ml of recombinant human IFN-gamma to PBMC completely inhibited parasite antigen-induced IgE production. This study demonstrates that filarial antigen-stimulated IgE production in patients with filariasis is mediated by IL-4 and down regulated by IFN-gamma and suggests that the amount of IgE produced depends on the relative quantity of IL-4 and IFN-gamma generated by parasite-specific T cells.

Antibody Formation↗
PubMed1990

Phosphocholine-containing antigens of Brugia malayi nonspecifically suppress lymphocyte function.

The immunosuppressive effect of Brugia malayi antigen (BmA) on phytohemagglutinin (PHA) driven T cell proliferation was evaluated in patients with filariasis (n = 14) and compared to control individuals (n = 12). When peripheral blood lymphocytes were co-cultured with BmA and PHA, BmA markedly suppressed the T cell proliferative response to PHA in both filarial patients and control individuals in a dose-dependent manner. The suppression resulted neither from any direct toxicity of BmA nor from nonspecific absorption of the PHA mitogenic activity by BmA. The major suppressive component appears to be phosphocholine (PC), an immunodominant molecule present in abundance on filarial parasites and on circulating filarial antigen. Both purified PC as well as PC-containing antigens affinity purified from BmA were capable of suppressing the proliferative responses of co-cultured autologous lymphocytes to PHA. The suppressive activity was not abolished by mitomycin-C treatment and was greater in patients with filariasis than in normal controls, suggesting that levels of PC-containing antigens determines the magnitude of the suppressive effect of PC-antigen. Further, as induction of the suppressive activity was completely abrogated when antigen pre-treated cells were T cell-depleted, the suppressive effect appears to be mediated primarily by T cells.

Adult↗
PubMed1989

Selective up-regulation of endothelial cell class I MHC expression by cytokines from patients with lymphatic filariasis.

Local host immune responses to the lymphatic-dwelling filarial parasite Wuchereria bancrofti are important in the pathogenesis of the lymphangitis that leads to filarial elephantiasis. That the lymphatic endothelial cells may be important in this inflammatory process was shown by the ability of supernatants generated from filarial Ag-driven PBMC of individuals with filarial elephantiasis caused by W. bancrofti infection to up-regulate class I MHC expression on human umbilical vein endothelial cells when compared to unstimulated control supernatants from the same individual (relative fluorescence intensity = 159% +/- 13.5; p less than 0.001). In contrast, individuals with the same filarial infection but manifesting no lymphatic disease were unable to generate, in response to filarial Ag the cytokines required for this activation (relative fluorescence intensity = 93% +/- 2.6). Supernatants induced by a non-filarial Ag (purified protein derivative) were able to effect class I MHC up-regulation in both patient groups. The same filarial Ag-driven supernatants did not cause detectable class II MHC staining on human umbilical vein endothelial cells. These results suggest a likely role for parasite Ag-driven, cytokine-mediated endothelial cell activation in the pathogenesis of lymphatic inflammatory/obstructive filarial disease.

Adult↗
PubMed1989

Human T-cell stimulation, molecular characterization and in situ mRNA localization of a Brugia malayi recombinant antigen.

Cellular immune responses play a major role in lymphatic filarial infections. To further our understanding of the host-parasite interaction, we investigated T-cell stimulation by purified filarial recombinant antigens in peripheral blood mononuclear cells derived from filarial-infected individuals. One of a subset of cloned Brugia malayi antigens involved in the humoral immune response to filarial infection was found to be a T-cell-stimulating antigen. The fusion protein encoded by clone lambda Bm19 induced proliferation of human T cells in a parasite-specific, antigen dose-dependent manner. The deduced amino acid sequence from this cloned region revealed 4 predicted T-cell recognition sites. The lambda Bm19 DNA sequence hybridizes to a 3-kb transcript, and in situ mRNA hybridization analyses of the adult female worm demonstrated that this gene is expressed in developing uterine microfilariae. The native parasite protein is present in several developmental stages since clone lambda Bm19 was initially identified with antiserum directed against the infective larval stage; this protein is therefore a potential target for the host's immune system.

Adult↗
PubMed1989

Regulation of immunoglobulin production in hyperimmunoglobulin E recurrent-infection syndrome by interferon gamma.

The hyperimmunoglobulin E recurrent-infection (Job) syndrome (HIE) is a congenital disorder characterized by high serum IgE, chronic eczematoid dermatitis, and recurrent infections. We examined the effect of interferon gamma (IFN-gamma) on excessive IgE production in HIE patients. Spontaneous in vitro production of IgE by peripheral blood mononuclear cells from HIE patients was elevated compared to normal individuals and correlated with serum IgE. In 9 of 13 patients, IgE production by peripheral blood mononuclear cells was inhibited by 50% by IFN-gamma at 100-1000 units/ml, whereas inhibition by IFN-gamma at 10(4) units/ml ranged from 67 to 93% for these 9 patients. IFN-gamma also inhibited IgG1, IgG3, and IgG4 production by B lymphocytes without inhibiting IgG2 production. IFN-gamma was administered subcutaneously to 5 HIE patients. After 2 weeks of treatment with IFN-gamma (0.05 mg/m2) at three doses per week given on alternate days, peripheral blood mononuclear cells from all 5 HIE patients decreased spontaneous in vitro IgE production (27-62% decrease) with no change in IgG and IgM. One patient had a 58% decrease in serum IgE and another patient had a 50% decrease in serum IgE after the IFN-gamma was increased to 0.1 mg/m2 for three doses per week for a month. In both patients, serum IgE returned to pre-IFN-gamma-challenge levels 1-3 months after completion of treatment, and in vivo IFN-gamma did not affect serum IgG and IgM, although serum IgG4 decreased with changes in serum IgE. Our studies demonstrate that IFN-gamma can regulate production of IgE and some IgG subclasses in humans.

Antibody Formation↗
PubMed1989

Tropical pulmonary eosinophilia: analysis of antifilarial antibody localized to the lung.

Acute tropical pulmonary eosinophilia (TPE) is characterized by wheezing, pulmonary infiltrates, marked peripheral blood eosinophilia, and very high serum levels of filaria-specific antibodies. To evaluate the amount and character of the filaria-specific antibodies in the lungs in this disorder, bronchoalveolar lavage was carried out in individuals with acute TPE, in normal subjects, and in patients with elephantiasis or asthma. Striking elevations of total IgE were found in the lower respiratory tract epithelial lining fluid (ELF) of patients with TPE along with high levels of filarial-specific IgG, IgM, and IgE. When patients with acute TPE were treated with diethylcarbamazine and evaluated again 6-14 d later, there was marked reduction in ELF parasite-specific IgG and IgE, which paralleled a rapid clinical response. Immunoblot comparison of the antigen recognition patterns of ELF and serum antibodies demonstrated a general similarity in parasite antigens recognized, but the lung IgE and IgG antibodies appeared to recognize only a certain subset of the parasite antigens recognized by serum antibodies. Thus, a profound antibody response to filarial infection is found in the lungs of patients with TPE, suggesting that these filaria-specific antibodies play an important role in the pathogenesis of this disorder.

Acute Disease↗