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PubMed2000

Interferon beta neutralizing antibodies in multiple sclerosis: neutralizing activity and cross-reactivity with three different preparations.

The presence and titer of neutralizing antibodies (NABs) was evaluated by an antiviral biological assay in 387 samples of 111 multiple sclerosis (MS) patients treated with one of the three commercial preparations of interferon beta (IFNbeta). Fifty NAB positive samples were found in 19 patients: 11 treated with IFNbeta-1b (Betaferon(R)) and eight with IFNbeta-1a (five with Avonex(R) and three with Rebif(R)). All the 38 NABs+ samples of patients treated with IFNbeta-1b cross-reacted with IFNbeta-1a of both commercial types. The median level of neutralizing units (NUs) of the sera was higher when tested against IFNbeta-1a than against IFNbeta-1b (p=0.000 vs. Avonexr(R) and p=0.003 vs. Rebif(R)). In line with these data, the NABs+ sera of patients treated with IFNbeta-1a cross-reacted with IFNbeta-1b and the level of NUs were lower when tested against IFNbeta-1b than against IFNbeta-1a (p=0.003). The different amount of NUs against IFNbeta types 1a and 1b could be due to the presence of aggregates in the IFNbeta-1b preparation. The different levels of cross-reactivity of NABs could reduce the bioavailability and therapeutic efficacy of IFNbeta in NABs+ patients switching from IFNbeta-1b to IFNbeta-1a.

Adjuvants, Immunologic↗
PubMed1996

Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group.

Phase I studies of volunteers not infected with human immunodeficiency virus type 1 (HIV-1) have shown that immunization with envelope subunit vaccine products elicits antibodies that neutralize laboratory-adapted (prototype) HIV-1 strains in vitro. Prototype strains are adapted to grow in continuous (neoplastic) cell lines and are more susceptible to neutralization than are primary isolates cultured in human peripheral blood mononuclear cells. In this study, 50 sera from nine phase I vaccine trials and 16 from HIV-1-infected persons were evaluated for neutralizing antibody activity against 3 laboratory-adapted and 5 primary HIV-1 isolates. Of 50 sera, 49 neutralized at least 1 of the prototype strains; however, none displayed neutralizing activity against primary isolates of HIV-1. Serum from most HIV-1-infected persons neutralized both laboratory-adapted and primary HIV-1 isolates. These data demonstrate a qualitative, or large quantitative, difference in the neutralizing antibody response induced by envelope subunit vaccination and natural HIV-1 infection.

AIDS Vaccines↗
PubMedDate not supplied

Adaptation of the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay for the determination of virus-neutralizing antibodies using the virus-neutralization assay.

The tetrazolium salt MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] has been widely used for bioassays. Herein is described the use of the MTT dye with a virus-neutralization (VN) assay to titer infectious bursal disease virus (IBDV)-neutralizing antibodies. A standard VN assay using chicken embryo fibroblasts (CEFs) and IBDV was used for the assessment of IBDV-neutralizing antibodies. The percent of CEF killing due to IBDV was quantitated using MTT, and the absorbance (A) data were used to calculate the VN antibody titer. This method of calculation offers the expression of VN titer in terms of units of activity per unit of volume.

Animals↗
PubMedDate not supplied

The role of neutralizing antibodies in HIV infection.

Neutralizing antibodies against HIV-1 play an important role in preventing viral infections. Less clear is their role in the containment of viral replication in infected individuals. However, evidence is accumulating that neutralizing antibodies may help the cellular arm of the immune response to prevent or delay the progression to AIDS. Detection of neutralizing antibodies depends on the in vitro neutralization assays used, and standardization of the assays is essential in order to be able to compare the magnitude and quality of a neutralizing antibody response in sera or other fluids from HIV-infected patients, uninfected HIV-1 exposed persons, or vaccinated animals/persons. Viral mechanisms to prevent neutralization include high variability and extensive glycosylation of the Envelope proteins, Envelope trimerization and shedding as well as late exposure of functionally important entry domains by conformational changes induced upon CD4 binding. These are also the difficulties encountered in the design of immunogens able to induce neutralizing antibodies upon vaccination.

AIDS Vaccines↗
PubMed2001

The relationship between poliovirus multiplication, the sIgA antibody response and the serum neutralizing antibody titers after trivalent oral polio vaccination.

The time kinetics of poliovirus and secretory IgA (sIgA) antibody titers were examined in fecal samples from four vaccinees immunized with two doses of trivalent oral polio vaccine (TOPV) from 1996 to 2000. Poliovirus types 1 and 2 multiplied in the human intestine after the first vaccination, and poliovirus type 3 multiplied after the second vaccination. Additionally, poliovirus type 3 multiplied for several days in two cases after the first vaccination, and poliovirus types 1 and 2 multiplied for before and after a week in one case after the second vaccination. Poliovirus type 2 multiplied most efficiently in the human intestine and stimulated the sIgA antibody response. The sIgA antibody titers are required to be > or = 1:4 for poliovirus types 1 and 3, and > or = 1:8 for poliovirus type 2 in 10% fecal suspension for adequate TOPV protection against reinfection. Serum neutralizing antibody titers against poliovirus type 3 were 1:6 and 1:8 for the shorter periods of 16 and 13 days, respectively, and 1:60 and 1:45 for 36 days in multiplication of poliovirus type 3 after the second vaccination. For double infection of poliovirus types 1 and 2, only the higher titers were obtained. These results suggest that poliovirus multiplication induces the sIgA antibody in the human intestine and the induced sIgA antibody defends the subject from poliovirus infection, and that the duration and the amount of virus multiplication tend to correlate with the levels of the serum neutralizing antibody titers.

Autoantibodies↗
PubMed2004

Neutralizing antibodies to interferon beta: implications for the management of multiple sclerosis.

PURPOSE OF REVIEW: Antibodies against interferon-beta (IFN-beta) can appear in a relevant number of patients. The subset of antibodies that can neutralize IFN-beta activity are called neutralizing antibodies. This review focuses on their impact both on therapeutic efficacy and on bioactivity of IFN-beta, and on the management of antibody-positive patients. RECENT FINDINGS: When IFN-betas were first used, neutralizing antibodies were not considered important. However, recent clinical, biologic, and immunologic data have demonstrated that they reduce or abolish the therapeutic efficacy of IFN-beta in 10-20% of patients. Quantification of antibodies using various biologic methods make it difficult to compare among different laboratories, and hence, standardization of assay procedures is necessary. Despite these technical difficulties, data consistently show differences in immunogenicity among the different IFN-beta products and the negative effects of neutralizing antibodies on the clinical efficacy of IFN-betas. Because the therapeutic action of IFN-beta depends on activation of IFN-inducible genes, new methods for the quantification of the biologic activity of IFN-beta have been developed, and a good correlation has been found between the presence of neutralizing antibodies and abrogation of IFN-beta bioactivity. SUMMARY: Quantification of neutralizing antibodies and the in-vivo bioactivity of IFN-beta through IFN-beta-inducible gene products such as Myxovirus protein A, offer valuable information on IFN-beta therapy. Important questions such as the optimal therapeutic strategy for managing neutralizing antibodies positive patients require further study in clinical trials.

Antibodies↗
PubMedDate not supplied

Enzyme therapy of gaucher disease: clinical and biochemical changes during production of and tolerization for neutralizing antibodies.

The clinical impact of neutralizing antibodies directed against the therapeutic enzyme was investigated in patients with Gaucher disease. Two patients with Gaucher disease type 1 were followed for their clinical progression during antibody development and clinical changes during tolerization. Patient 1 developed neutralizing antibodies to imiglucerase (GCase) at the 10th month of enzyme therapy. Tolerization was achieved within a 42-month period with a short course of cyclophosphamide and then higher dose enzyme (60 IU/kg/week) alone. Patient 1 continues to improve up to 100 months of enzyme therapy despite the presence of low level in vitro neutralizing antibodies. Patient 2 developed neutralizing antibodies to GCase at the 29th month of enzyme therapy that correlated with clinical deterioration. Clinical stabilization has been observed with increased enzyme therapy (60 IU/kg/week) even in the presence of the neutralizing antibodies. Patient 2 is the first to develop neutralizing antibodies after 12 months of enzyme therapy. Plasma chitotriosidase activities were not well correlated with the clinical course in either patient. The presence of neutralizing antibodies should be suspected in Gaucher disease patients on enzyme therapy who experience diminished response or deterioration. The persistence of minimal amounts of in vitro neutralizing antibodies does not interfere with the therapeutic effectiveness. Chitotriosidase is not a sensitive marker for the severity of disease or disease progression.

Alleles↗
PubMed2005

The detection of anti-erythropoietin antibodies in human serum and plasma: part II. Validation of a semi-quantitative 3H-thymidine uptake assay for neutralizing antibodies.

Neutralizing antibodies to erythropoietin (EPO) can cause a loss of response to recombinant human EPO (rHuEPO) and lead to rare cases of sudden, unexplained, severe anemia in chronic renal failure patients treated with rHuEPO. An assay for neutralizing anti-EPO antibodies has been validated that is based on the inhibition of proliferation of human UT-7/EPO cells, an immortalized cell line, by neutralizing antibodies in serum test samples using 3H-thymidine as a marker for proliferation. The dependence of the human cell line on EPO for growth and proliferation in a concentration-dependent manner enabled the validation of a rHuEPO standard curve for cell proliferation that can be used to determine the presence of neutralizing anti-EPO antibodies in serum samples. Proliferation of the cells increases with increasing concentrations of EPO, forming an S-shaped standard curve, which is fit with a 4-parameter logistic model, between 2.5 and 50 mU/mL rHuEPO, with a percent coefficient of variation (% CV) from 8.7% to 22.1% and a % accuracy of 103.5% to 109.5%. Anti-EPO antibodies and serum with anti-EPO antibodies neutralize UT-7/EPO proliferation by 10 mU/mL rHuEPO in a concentration- or dilution-dependent manner with < or = 25% CV. Percent neutralization is calculated by determining the amount of EPO recovered from the original 10 mU/mL added using the formula [((10-concentration recovered)/10)x100%]. Stem cell factor (SCF) stimulated cell proliferation, but not as effectively as rHuEPO. Antibodies to SCF were not able to inhibit the proliferative response induced by EPO and vice versa, confirming the specificity of the assay for antibodies to EPO. High EPO levels can impact both the radioimmunoprecipitation and neutralization assays to produce a false negative result. However, the impact can be mitigated by the large dilutions used in the neutralization assay.

Antibodies↗
PubMed1988

Application of immunoassay of encephalomyocarditis virus in cell culture with enzyme-labeled virus-specific monoclonal antibodies for rapid detection of virus, neutralizing antibodies, and interferon.

Encephalomyocarditis virus (EMCV)-specific monoclonal antibody UM 21.1 labeled with horseradish peroxidase was used to detect EMCV in L-cell monolayers. This direct enzyme immunoassay of EMCV, performed in wells of 96-well plates, could be applied for various purposes, such as early detection of virus multiplication, determination of 50% tissue culture infective doses, and rapid titration of interferon and EMCV-neutralizing antibodies. Multiplication of EMCV is indicated by a rapid increase of the absorbance values measured against EMCV-infected L cells starting as early as 4.5 h after virus inoculation. The early rise of absorbance (i.e., virus multiplication) is inhibited by interferon, allowing its rapid titration. Preincubation of the virus inoculum with neutralizing antibodies also yielded decreased absorbance values. With the latter enzyme immunoassay for neutralizing antibodies, performed after an infection period of 8 h, antibody titers measured were comparable to those obtained with a conventional plaque reduction test. We assume that similar assays could be developed for other picornaviruses (e.g., polioviruses).

Animals↗
PubMed1989

Foot-and-mouth disease virus-neutralizing antibodies induced in mice by anti-idiotypic antibodies.

A neutralizing monoclonal antibody (nmAb) to foot-and-mouth disease virus (FMDV) was used as antibody-1 (AB1) to induce anti-idiotypic antibodies (a-IdAb) in rabbits. The rabbit a-IdAb (AB2) were isolated on protein A-Sepharose, followed by cycles of separation on idiotype and isotype affinity columns. The specificity of the AB2 for the paratope of AB1 was determined by direct binding to AB1 in solid-phase radioimmunoassay (SP-RIA), and by competition RIA (C-RIA) with virus for binding to the AB1. The AB2, termed a-2PD11, was utilized to immunize six groups of female Swiss mice at weekly intervals with either one of three formulations, in doses of 50 micrograms or 5 micrograms, given in single subcutaneous (s.c.) spots. Anti-viral antibody (AB3) was first detected by RIA at the fifth week in the 50 micrograms/dose groups, and maximum levels were reached at the sixth week in the 50 and 5 micrograms/dose groups. The AB3 levels were at least three times higher for mice given 50 micrograms doses. In addition, the AB3 were also shown to neutralize FMDV infectivity in tissue culture and in a suckling mouse protection assay. Overall, mice exhibited variable responses to immunization with AB2. In a subsequent trial, mice received multispot s.c. and footpad injections of 50 micrograms of a-2PD11 coupled to keyhole limpet haemocyanin (KLH) on a weekly basis. In these mice, AB3 was detected earlier than in mice immunized with single s.c. injections. These results support the use of a-IdAb as potential surrogates of critical determinants for FMD vaccines.

Animals↗
PubMed1993

Anti-C5a receptor antibodies. Characterization of neutralizing antibodies specific for a peptide, C5aR-(9-29), derived from the predicted amino-terminal sequence of the human C5a receptor.

Results obtained indicate that a site-directed polyclonal antibody specific for a synthetic peptide based on the predicted amino-terminal sequence of human C5aR (anti-C5aR(9-29)) is capable of binding to both normal human and transfected cells bearing C5aR. Flow cytometric analysis of stable murine L cell transfectants (C5aR-neo), human neutrophils, and human monocytes indicated that these cells bound anti-C5aR(9-29) in a specific manner. Moreover, F(ab')2 fragments of anti-C5aR(9-29) specifically neutralized proinflammatory and immunoregulatory activities induced by natural human C5a. This antiserum was found to block, in a dose-dependent manner, 1) zymosan-induced neutrophil chemotaxis, 2) C5a-induced enzyme release from neutrophils, and 3) C5a-induced cytokine production (IL-6 and IL-8) from human monocytes in vitro. These results suggest that this site-directed polyclonal antiserum specifically interacts with the human C5aR molecule. To the best of our knowledge, none of the existing reports in the literature provided evidence for a site-directed antiserum to C5aR that was capable of specifically blocking C5a-mediated inflammatory/immunoregulatory activities in vitro. Studies conducted with anti-C5aR(9-29) indicated that this antiserum effectively blocked C5a-mediated cell activation but by itself did not activate either neutrophils or monocytes. Combined, these data suggest that this antiserum does not interact with the C5a "effector" site but sterically interferes with C5a binding to its receptor by interacting with the extracellular amino-terminal region of the receptor.

Amino Acid Sequence↗
PubMed1991

Immunizations of monkeys with synthetic peptides disclose conserved areas on gp120 of human immunodeficiency virus type 1 associated with cross-neutralizing antibodies and T-cell recognition.

Site-directed immunization was employed to identify sites on the envelope glycoprotein gp120 for antibody-mediated neutralization of human immunodeficiency virus type 1 (HIV-1). Antisera were raised in monkeys (Macaca fascicularis) against a series of 40 overlapping synthetic peptides covering the entire amino acid sequence of gp120 from the HTLV-IIIB strain of HIV-1. Immune sera against 12 of these peptides were reactive with gp120 by immunoblotting analysis, and antisera raised against 5 peptides, corresponding to amino acids (aa) 152-176, 193-218, 206-230, 248-269, and 307-330, were highly efficient in neutralizing HIV-1 (HTLV-IIIB) infectivity in vitro. Admixture of individual neutralizing anti-peptide monkey sera resulted in increment in neutralizing antibody titer. Antisera with reactivity to the relatively conserved regions defined by aa 152-176, 193-230, and 248-269 also neutralized to different extents the infectivity of the five Swedish clinical isolates of HIV-1 tested. Only a few HIV-1-infected people were found to make antibodies to these three conserved domains of gp120 as judged by ELISA using synthetic peptides as antigens. Three of the peptides (aa 152-176, 248-269, and 307-330) that induced neutralization antibodies also induced interleukin 2 production and lymphocyte proliferation when added to cultures of peripheral blood mononuclear cells from monkeys immunized with the corresponding peptides, indicating that these domains accommodate T-cell recognition sites. The results have obvious implications for the rational design of subunit vaccines against HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Neutralizing antibody responses to human herpesviruses 6 and 7 do not cross-react with each other, and maternal neutralizing antibodies contribute to sequential infection with these viruses in childhood.

Seroprevalence of human herpesvirus 6 (HHV-6) and HHV-7 infections is very high throughout the world, and almost all people are exposed first to HHV-6 and second to HHV-7 in their childhood. However, it is not clear whether the neutralizing (NT) antibody response between each virus is cross-reactive or not. To elucidate the NT antibody response between each virus, 55 serum samples from an adult group (subjects 22 to 88 years old) and 60 serum samples from a young group (subjects 2 to 18 years old) were examined by a dot blot method for detecting viral late antigen. Thirty-nine serum samples obtained from cord bloods and a few serum samples obtained from pediatric patients with exanthem subitum were also examined to assess the maternal transferred NT antibodies against each virus. The NT antibody titers against HHV-7 in the adult group remained high throughout all the individuals, and none were negative. Those against HHV-6 were high values in the young group but low values, including negative values (three samples), in the adult group. These results suggested that the NT antibody response to either HHV-6 or HHV-7 in each individual was specific to each virus and did not cross-react with each other. In the adult group, the NT antibody response to HHV-6 decreased, while that to HHV-7 remained high throughout all the individuals. Maternal transferred NT antibody titers against HHV-7 were higher and remained longer after birth than those of HHV-6, and these findings were in accord with the clinical observation that HHV-6 infection usually occurs earlier than HHV-7 infection.

Adolescent↗
PubMedDate not supplied

Comparison of precipitin antibodies and virus-neutralizing antibodies to infectious bursal disease virus.

Three hundred twenty-two serum samples from commercial pullets and multiplier breeders were analyzed for agar-gel precipitin (AGP) antibodies and virus-neutralizing (VN) antibodies to infectious bursal disease virus. Two hundred thirty-four of these sera were AGP-positive, and 88 were AGP-negative. The geometric mean of the reciprocal of the VN titers for the AGP-positive sera was 208.7, and 232 (99.1%) had a VN titer of 1:16 or greater. In contrast, the geometric mean of the reciprocal of the VN titers for the AGP-negative sera was 6.1, but 53 (60.2%) had a VN titer ranging from 1:4 to 1:256. When the AGP test was compared with the VN test, the sensitivity and specificity, respectively, of the AGP test were 81.5% and 100%.

Animals↗
PubMed1993

Neutralizing antibodies to Haemophilus ducreyi cytotoxin.

Neutralizing antibodies against cytotoxin produced by Haemophilus ducreyi bacteria were studied in rabbits by an assay employing HEp-2 cells and diluted crude cytotoxin preparations from the organism. Antisera to 12 different H. ducreyi strains were prepared by immunization of rabbits with bacterial sonicates combined with Freund's adjuvant. The antibody response during infection with H. ducreyi was studied in two groups of rabbits which were infected with five live strains by either single or multiple intradermal injections. Neutralizing antibodies in hyperimmune sera to sonicates from 12 H. ducreyi strains tested against their homologous cytotoxin preparations were present with titers ranging from 1:80 to 1:640. Similar antibody titers against heterologous cytotoxin preparations were recorded, indicating immunological similarity or identity between cytotoxins from the various H. ducreyi strains. Three strains did not produce cytotoxin, and these strains did not induce toxin-neutralizing antibodies. Hyperimmune sera to other gram-negative bacteria had no detectable neutralizing capacity, indicating species specificity of the H. ducreyi cytotoxin. Cytotoxin-neutralizing antibodies were not detectable in rabbit sera before infection with H. ducreyi. Repeated single injections with live bacteria resulted in development of low levels of neutralizing antibodies. Multiple primary injection of live bacteria of the cytotoxin-producing strain CCUG 7470 resulted in a low immune response to the cytotoxin preparation from the same strain. A booster infection resulted in the development of neutralizing antibodies in all rabbits infected with cytotoxin-producing strains. The antibody titers determined against the homologous cytotoxin preparation were similar to those recorded for two heterologous cytotoxin preparations.

Animals↗
PubMed1975

Neutralizing antibody responses to varicella-zoster virus.

Neutralization of varicella-zoster (V-Z) virus by human sera and immune rhesus monkey sera was enhanced by fresh guinea pig complement. There was no marked difference in the degree to which complement enhanced neutralization by sera from current V-Z virus infections and sera from long-past varicella infections. Immunoglobulin G neutralizing antibody in sera from varicella cases was enhanced by complement to a slightly higher degree than was immunoglobulin M (IgM) antibody, and immunoglobulin G neutralizing antibody in immune monkey sera was enhanced to a much greater degree than was IgM antibody. There was a rapid decline in the complement requirement of IgM neutralizing antibodies over the course of immunization of the rhesus monkeys. V-Z neutralizing antibody titers in the presence of complement were higher than complement-fixing titers of the same sera in all groups of individuals studied. IgM neutralizing antibody for V-Z virus was demonstrable in all cases of varicella but in only 1 of 22 zoster cases, and V-Z IgM neutralizing antibody was not detectable in primary herpes simplex virus infections in which heterotypic antibody titer rises occurred to V-Z virus. Complement-fixing antibody for V-Z virus was absent in 19S serum fractions which contained IgM neutralizing antibody for the virus.

Animals↗