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Biomedical subjects

T B Nutman

Publications and source records attributed to T B Nutman.

At least 145 records · Page 8Linked to original sources
PubMed1989

Protective immunity in bancroftian filariasis. Selective recognition of a 43-kD larval stage antigen by infection-free individuals in an endemic area.

There is little information about naturally occurring protective immunity in individuals living in areas endemic for lymphatic filariasis, though an immunologically hyperresponsive, uninfected group of "endemic normal" individuals that may be immune has been previously recognized. To analyze the nature of the hyperresponsiveness and its potential relation to a state of protective immunity in such individuals, strict clinical, parasitological, and serological criteria were applied to select seven "infection-free" endemic normal individuals (ENs) from a population of 459 persons resident in an area heavily endemic for bancroftian filariasis. Immunoblot analysis was used to compare the qualitative antigen recognition patterns of these endemic normal individuals to those of a group of 12 clearly infected microfilaremic individuals (MFs) from the same endemic area. Though immunoblot analysis using microfilarial and adult stage filarial antigens revealed no distinct differences in antigen recognition patterns between the two groups, when responses to infective larval stage antigens were assessed, 7/7 (100%) of the ENs were found to recognize a 43-kD antigen that was recognized by only 1/12 (8%) of the MFs. These findings are consistent with the concept that recognition of unique larval antigens may induce protective immunity to human filarial parasites and they identify a candidate immunogen for further functional assessment.

Adult↗
PubMed1989

Lymphocyte subpopulations in Bancroftian filariasis: activated (DR+) CD8+ T cells in patients with chronic lymphatic obstruction.

To examine the relationship between lymphocyte phenotypes and states of activation in patients with Bancroftian filariasis, dual colour flow cytometry and concurrent in vitro cell culture were performed on normal individuals (NV; n = 15), and on patients with either asymptomatic microfilaraemia (MF; n = 12) or elephantiasis (CP; n = 11). In contrast to findings by others in a population with Brugian filariasis, the percentages of total B lymphocytes (CD19), T lymphocytes (CD3), helper/inducer T lymphocytes (CD4), and suppressor/cytotoxic T lymphocytes (CD8) in both patient groups were found to be within the range defined by clinically normal individuals. Furthermore, there were no differences among the groups in the expression of the IL-2 receptor (CD25) on T cells. There was, however, a significantly greater proportion (P less than 0.01) of 'activated' cytotoxic/suppressor lymphocytes (defined by co-expression of CD8 and HLA-DR) in patients with elephantiasis (16.4 +/- 8.6%) than in the MF (8.9 +/- 2.6%) or NV (8.3 +/- 2.9%) groups. Further, when the expression of this activation antigen was examined in parallel with in vitro mitogen responsiveness, an inverse correlation between the percentage of CD8+ HLA-DR+ lymphocytes and pokeweed mitogen-induced proliferation was seen (r = -0.54; P less than 0.001). These data provide further definition of the immunoregulatory abnormalities seen in human filarial infections and suggest that activated CD8+ T lymphocytes may be involved in the pathogenesis of the chronic obstructed lymphatic form of this disease.

Adult↗
PubMed1989

Serologic evidence of Cryptosporidium infection in US volunteers before and during Peace Corps service in Africa.

To obtain prevalence data on Cryptosporidium infection in healthy US adults and to determine how often Cryptosporidium infection occurs after relocation to a situation of potentially great exposure, an enzyme-linked immunosorbent assay for anti-Cryptosporidium IgM or IgG was used to examine serum from 75 US Peace Corps volunteers before overseas service and after up to two years in West Africa. Of the volunteers, 32% had detectable anti-Cryptosporidium IgG initially, suggesting that infection sometime in life is common. After six weeks, one year, or two years overseas, 5% (1/19), 14% (8/56), and 13.6% (3/22), respectively, became newly IgG positive. This implies that the risk of acquiring Cryptosporidium infection and its associated diarrhea is real for travelers and temporary workers in endemic areas. Persistence of IgG and/or IgM response for 12 months or more occurred in some volunteers, although the significance is unclear.

Adult↗
PubMed1988

Diethylcarbamazine prophylaxis for human loiasis. Results of a double-blind study.

To determine whether infection with Loa loa could be prevented in temporary residents of endemic areas, we conducted a randomized, double-blind, placebo-controlled trial of diethylcarbamazine as a chemoprophylactic agent. Diethylcarbamazine (300 mg) or placebo was taken orally once a week by Peace Corps volunteers serving in Gabon, Cameroon, and the Central African Republic. The participants were assessed clinically and with serologic and parasitologic testing before and yearly during their two years of service. One hundred one persons satisfactorily completed the study. In Gabon (where exposure to the parasite was heaviest), 6 of 20 volunteers (30 percent) in the placebo group had clinical disease, as compared with none of 16 (0 percent) in the diethylcarbamazine-treated group (P less than 0.02). Of those taking placebo, 10 of 20 (50 percent) became seropositive for antifilarial IgG antibody, as compared with 2 of 16 (12 percent) in the drug-treated group (P less than 0.02). Exposure to the parasite appeared to be much lower among the 65 Peace Corps volunteers in Cameroon and the Central African Republic. No volunteer in either group in these countries had overt loiasis; 2 of 40 (5 percent) in the placebo groups in Cameroon and the Central African Republic seroconverted, as compared with none of 25 (0 percent) of those receiving diethylcarbamazine. Occasional nausea was the only symptom significantly associated with the prophylactic drug regimen. We conclude that diethylcarbamazine given orally once weekly can be an effective, acceptable chemoprophylactic agent to prevent loiasis in temporary residents of regions of Africa where Loa loa is endemic.

Adult↗
PubMed1988

Enhanced solubilization of immunoreactive proteins from Brugia malayi adult parasites using cetyltrimethylammonium bromide.

To determine an optimal method for extracting immunoreactive proteins from filarial parasites, we have subjected Brugia malayi adult worms to a variety of solubilization regimens and compared the results. The parasites were extracted in one of seven detergents (including anionic, cationic, nonionic, and zwitterionic compounds) under varying conditions of pH, detergent concentrations, and incubation time. The individual antigen preparations were then compared both by one-dimensional SDS-PAGE and by immunoblotting analysis using a serum pool from individuals resident in an area endemic for lymphatic filariasis. The cationic detergent cetyltrimethylammonium bromide (CTAB) at 1.0% concentration, pH 7.2, consistently solubilized more proteins immunoreactive with the sera tested. Additionally, CTAB never failed to solubilize immunoreactive proteins solubilized by those other detergents or combinations of detergents studied.

Animals↗
PubMed1988

Onchocerciasis and immunity in humans: enhanced T cell responsiveness to parasite antigen in putatively immune individuals.

To identify possible immune mechanisms in human onchocerciasis, we compared a group of 12 individuals who had no clinical or parasitological evidence of infection, despite ongoing exposure to the parasite, with a group of 16 individuals from the same area who had active Onchocerca volvulus infection. Despite having less parasite-specific serum antibody, the infection-free ("putatively immune") individuals showed greater lymphocyte responsiveness, especially interleukin-2 (IL-2) production, to O. volvulus antigen (OVA) than did the infected subjects; lymphocyte responses (including IL-2 production) to mitogens and nonparasite antigen in both study groups were equivalent and normal. Our findings define differences in parasite-specific T cell subpopulations between infected and putatively immune subjects that could be a central element in developing or maintaining protective immunity to O. volvulus infection.

Adolescent↗
PubMed1988

Immunologic correlates of the hyperresponsive syndrome of loiasis.

The usual clinical picture of loiasis in long-term visitors to endemic areas differs from that in residents of these areas, with allergic symptoms, hypergammaglobulinemia, profound hypereosinophilia, and increased serum levels of IgE being more prominent. In further analyzing the immunologic correlates of this apparent hyperreactivity in 20 patients, we have found the following: (1) parasite-specific IgG (in all) and IgE (in some) were extremely elevated in the patients; (2) qualitative analysis by immunoblotting indicated multiple antigens recognized by both IgG and IgE antibodies in these patients; (3) filaria antigen-specific, lymphocyte proliferative immune responses were vigorous in all patients and, in each individual, exceed the response to other soluble antigens; (4) spontaneous and antigen-driven, parasite-specific antibody production in vitro was elevated in all six patients studied; (5) there was a significant increase in the ratio of CD4/CD8+ T cells. These observations suggest that both specific dysregulation of the immune response to the parasite antigen, as well as nonspecific immune activation, accounts for the clinically apparent hyperresponsive state seen in expatriates acquiring loiasis.

Animals↗
PubMed1987

T-cell-derived IgE-binding factors. I. Cloned and transformed T cells producing IgE-binding factors.

In order to derive T cell clones that can produce factors that specifically regulate the IgE response, Fc epsilon receptor (Fc epsilon R)-positive T cells were isolated from two patients with hyper-IgE states (either the tropical pulmonary eosinophilia syndrome or the hyper-IgE syndrome) and transformed using the human T cell leukemia/lymphoma virus. After infection, these T4-positive, Fc epsilon R-positive T cells manifested a fourfold increase in the surface interleukin 2 receptor, a 10-fold increase in Fc epsilon R, and acquired viral markers not present in the uninfected cells. Cloning soon after transformation allowed for the isolation of 17 distinct T cell clones producing IgE-binding factors. The levels of these binding factors released in supernatant fluid from these clones ranged from 10 to 98 U (negative less than 1 U) using a radioimmunoassay. Furthermore, the presence and kinetics of production of these binding factors also could be demonstrated by metabolic labeling studies. These cells should prove potent immunologic tools for dissecting the various regulatory mechanisms involved in IgE production both in the normal state and in pathologic conditions.

Antigens, Viral↗
PubMed1987

T-cell-derived IgE-binding factors. II. Purification and characterization of IgE-binding factors produced by human T cell leukemia/lymphoma virus-1-transformed T lymphocytes.

We previously described human T cell leukemia/lymphoma virus-1-transformed T cell clones expressing surface molecules binding to monoclonal antibodies against lymphocyte Fc epsilon receptor (Fc epsilon R) and releasing soluble factors binding to both IgE and to monoclonal antibody to lymphocyte Fc epsilon R. In this study, one such clone (HE1-11) was tested for the presence of mRNA hybridizing with a cDNA probe coding for Fc epsilon R on B cells. Northern blot analysis revealed the presence of the same 1.7 kb Fc epsilon R mRNA in HE1-11 and in RPMI 8866 cells as well as in the macrophage cell line U937, expressing Fc epsilon R. The IgE binding factors (BF) released by HE1-11 cells appeared to be identical to those released by RPMI 8866 cells as shown by 1) one- and two-dimensional sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis and 2) tryptic peptides analysis. IgE-BF are microheterogeneous containing molecules with molecular mass of 25 to 27 kDa and with isoelectric point ranging from 4.5 to 5. Some preparations further contained 16-kDa fragments of IgE-BF. These findings suggest that the gene coding for both Fc epsilon R and IgE-BF may also be expressed on some human T cells.

Antibodies, Monoclonal↗
PubMed1987

Brugia malayi antigens associated with lymphocyte activation in filariasis.

Filarial parasites induce immune response in humans which are still poorly characterized. To define the antigens responsible for inducing lymphocyte responses, fast protein liquid chromatography was used to fractionate the antigens of Brugia malayi adult worms which were then tested on lymphocytes from patients with filariasis and normal controls. From an anion exchange column (Mono Q), three peaks of lymphocyte-stimulating activity were eluted which were further fractionated by gel filtration (Superose-12). Peak I induced both a proliferative response as well as the production of filaria-specific antibody in patient lymphocytes. Peak II, capable of inducing only a proliferative response (without antibody production) in patient lymphocytes, was a glycoprotein with phosphocholine as one of the antigenic determinants. Peak III induced proliferative responses in both patient and normal lymphocytes and thus appears to be mitogenic. Two-dimensional gel electrophoresis was then used to identify changes in the major cellular proteins associated with the activation of patient lymphocytes by these partially purified antigens. Stimulation of patient lymphocytes with peak I resulted in increased synthesis of immunoglobulin heavy, light, and J chains. Further, these were the only major secreted proteins found in the culture supernatants. Peak II resulted in quantitative changes in proteins associated with T and not B lymphocyte stimulation. Further analysis of these antigens should help to elucidate the mechanism of host-parasite interaction at both the cellular and molecular levels.

Animals↗
PubMed1987

An analysis of in vitro B cell immune responsiveness in human lymphatic filariasis.

The immunoregulatory mechanisms involved in B cell function in patients with varying clinical manifestations of bancroftian filariasis were examined by studying the ability of peripheral blood mononuclear cells (PBMC) or PBMC subpopulations from patients with elephantiasis, asymptomatic microfilaremia (MF), and acute tropical pulmonary eosinophilia (TPE) to produce polyclonal and parasite-specific antibody in vitro, both spontaneously and in response to a mitogen (PWM) and to parasite antigen. When the spontaneous or mitogen-driven polyclonal responses were examined, all groups produced significant amounts of IgM and IgG; those with TPE produced extremely high levels. However, when in vitro parasite antigen-specific responses were examined, those with MF were unable to produce filaria-specific antibody either spontaneously or in response to PWM or parasite antigen; in contrast, patients with chronic lymphatic obstruction or TPE produced large quantities. Removal of neither adherent cells nor T8+ T cells affected the parasite-specific B cell anergy seen in those with MF. This absent or severely diminished capacity to produce antibody on parasite antigenic stimulation in patients with MF is likely responsible for the low levels of parasite-specific antibody seen in this most common clinical manifestation of bancroftian filariasis. Its inability to be reversed by the removal of "suppressor elements" suggests a state of B cell unresponsiveness to the parasite.

Adolescent↗
PubMed1987

Circulating parasite antigen(s) in lymphatic filariasis: use of monoclonal antibodies to phosphocholine for immunodiagnosis.

Hybridoma cell lines producing monoclonal antibodies (MAb) against a 200 kD antigen found circulating in the sera of microfilaremic patients infected with Wuchereria bancrofti were obtained by immunizing mice with a partially purified antigen preparation. A sensitive MAb (CA101)-based ELISA for measuring circulating parasite antigen was capable of detecting antigen in the sera of 93% of patients with microfilaremia, 46% of those with lymphatic obstruction, and 56% of patients with tropical pulmonary eosinophilia syndrome. Circulating antigen was absent from sera of normal controls, and "false positives" were recorded in only two of 17 patients with nonfilarial helminth infections. By ELISA and immunoblot analysis, it was shown that three of the monoclonals raised to this 200 kD antigen were directed to epitopes of phosphocholine (PC). Two MAb (CA86, CA101) were identified as having the T15 idiotype previously associated with antibodies to the PC of pneumococcal teichoic acid; one was untypeable. All three of these anti-PC MAb reacted with adult, microfilaria, and larval antigen preparations, and by immunoblotting showed multiple banding patterns that indicated the presence of PC determinants on many different antigenic molecules. On the other hand, target antigens of CA101 which were found in the circulation of infected patients were limited to three species with apparent m.w. of 200, 160, and 78 kD. The 200 kD antigen was seen more frequently than the other two antigens. Other T15 anti-PC MAb derived from mice not immunized with filarial antigen showed similar patterns of reactivity with circulating filarial antigen.

Animals↗
PubMed1987

Demonstration by immunoblotting of heterogeneity in the autoantibody response directed against fat cells in Graves' disease.

Guinea pig fat cell membranes (FCM) have been widely used in preference to thyroid membranes as a source of TSH receptors to investigate TSH receptor antibodies in Graves' disease, because FCM are ostensibly free of other thyroid antigens. However, by FCM immunoblotting we have found: 8 of 10 normal sera bound to determinants at 38 and 190 kDa; 17 other determinants were recognised by 60% of Graves' or Hashimoto sera and by 20% of normal sera; three determinants at 65-90 kDa were recognised by 5 of 13 Graves' but by none of the normal or Hashimoto sera; and none of the determinants recognised appeared to be related to the TSH receptor.

Adipose Tissue↗
PubMed1987

Heterogeneity of thyroid autoantigens identified by immunoblotting.

Autoimmune thyroid disease in man is commonly associated with autoantibodies against thyroglobulin, microsomes, and the TSH receptor, and the character and specificity of these antithyroid antibodies have been extensively utilized in investigating these conditions. In the present study we have asked whether other thyroid-related antigens exist, against which autoantibodies may be directed. A crude thyroid extract was separated by polyacrylamide gel electrophoresis followed by immunoblotting with serum obtained from patients with Graves' disease or Hashimoto's thyroiditis. Antibodies in sera from patients with Graves' disease and Hashimoto's thyroiditis reacted with many antigenic determinants in immunoblots of the thyroid membrane preparation (2000g supernatant). These determinants were disease specific in that sera from normals and patients with Addison's disease and rheumatoid arthritis did not react, but there was no difference between the patterns of reactivity with Graves' disease or Hashimoto's thyroiditis sera. Thyroglobulin produced two predominant bands of reactivity at 320 and 200 kDa, whereas purified microsomal antigen produced a triplet of bands around 105 kDa, when these preparations were reacted with appropriate autoimmune sera. Nonetheless, some sera produced additional bands with the microsomal antigen blots, indicating that some of the antigens which were detected using crude thyroid membrane remained in the microsome preparation to produce multiple antibody binding reactivities. We were unable to inhibit any of the antibody binding with TSH. Purification of individual thyroid antigens on the basis of their molecular weights should standardize current antibody assays and permit more detailed evaluation of the cellular immune responses in Graves' disease and Hashimoto's thyroiditis.

Adult↗
PubMed1987

Eosinophilia in Southeast Asian refugees: evaluation at a referral center.

We determined the cause of persistent eosinophilia in 128 Indochinese refugees for whom initial comprehensive routine screening had failed to yield an explanation. Intestinal parasitism with one or multiple organisms was the cause of eosinophilia in all but six of these patients. Hookworm and Strongyloides stercoralis were among the potentially pathogenic organisms most frequently implicated (55% and 38%, respectively). There was no correlation between the age or sex of the patients and the type of infecting organism. We also confirmed the usefulness of a previously described serological test for diagnosing infection with Strongyloides stercoralis and examined the test's ability to distinguish between infected and noninfected individuals and to determine parasitological cure.

Adult↗