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Albino mice were immunized with a purified capsular antigen isolated from the S. aureus strain 1193/74. The presence of specific anticapsular antibodies in the sera of animals were determined by two methods: 1) by conversion of diffuse growth of a homologous strain into compact one, and 2) by determination of opsonic index in phagocytosis of homologous staphylococci by human neutrophils. It was revealed that antibodies converting the microbical growth were absent in the sera of normal mice and reached the highest level after the second antigen injection; opsonins were present in the sera of normal mice in widely varying quantities; their maximal level was noted after the 3rd immunization.
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This study investigated the generation of primary tumor-specific CTL activity in vitro to several mouse tumors. We report that the development of optimal primary tumor-specific CTL to the P815 mastocytoma, the EL4 thymoma, and the Lewis lung carcinoma is dependent on tumor Ags, on enhancement of T cell costimulation by B7.1, and on exogenous T helper activity in the form of IL-2 and IL-4. A relatively low concentration of IL-2 and IL-4 was required to limit the induction of lymphokine-activated killer cells. In the case of P815, the CTL were directed toward molecularly defined tumor rejection Ags. These primary cultures yielded long term T cell lines that were heterogeneous in fine tumor Ag specificity and in cytokine production.
Radioimmunoprecipitation (RIP) analyses performed on 125I-surface-labeled Treponema pallidum cells using various immune sera revealed the presence of six major surface antigens (immunogens) with apparent molecular weights of 47 K, 36 K, 34 K, 32 K, 29 K, and 13 K. Among these, the 47 K surface antigen was most abundant. Radioimmunoprecipitation assays using 125I-labeled T. phagedenis biotype Reiter or immunoblot analyses using the same strain, failed to reveal the presence of the 47 K mol wt antigen in the representative nonpathogenic treponeme. Preabsorption of anti-T. pallidum immune rabbit serum (IRS) with the Reiter organism did not remove anti-T. pallidum antibodies from immune serum that reacted with the 47 K mol wt immunogen or other immunogens of T. pallidum present in the characteristic antigenic profile. Monoclonal antibodies (mAb) directed specifically against the 47 K mol wt immunogen of T. pallidum also failed to react with an analogous 47 K mol wt component in Treponema phagedenis biotype Reiter, further suggesting the unique presence of this antigen in pathogenic treponemes. The presence of the 47 K mol wt surface immunogen in pathogenic treponemes other than T. pallidum subspecies pallidum was also observed (43). Anti-47 K immunogen mAb was nonreactive against rabbit IgG or IgM. mAb directed specifically against the 47 K mol wt immunogen of T. pallidum was examined for strategic functional activities. It was found to be reactive in the microhemagglutination assay for T. pallidum antibodies, the T. pallidum immobilization test, and was found to be capable of significant blockage of attachment of virulent T. pallidum to host cells in tissue culture. Additional significant biological activity for the anti-47 K mol wt immunogen mAb was revealed through results of the in vitro-in vivo neutralization test of Bishop and Miller, in which a 99% or 100% neutralizing activity was demonstrated. The combined data of this study suggest that the 47 K mol wt immunogen of T. pallidum represents an abundant, immunodominant, surface-exposed immunogen possessing potential biological importance in the pathogenesis and immunology of T. pallidum infection. These studies serve to establish the first functionally defined immunogen for T. pallidum, which may represent the major immunogen of the organism.
The extreme variability of HIV-1 immunogenic regions has hampered attempts to design immunogens capable of inducing broadly reactive neutralizing anti-HIV antibody responses. We have begun to study the immune responses generated to a polyvalent mixture of HIV envelope gp120 synthetic peptides, and to determine the ability of each component of a polyvalent immunogen to prime and boost immune responses to each immunogen component. A major concern regarding the use of a polyvalent mixture of HIV-1 immunogens is that the phenomenon of "original antigenic sin," or HIV-1 primer-induced suppression of antibody responses to a subsequent boost by a second HIV-1 variant, may occur and prevent effective anti-HIV immune responses. Using a prototypic four-valent HIV peptide envelope immunogen in BALB/c mice, we observed two types of primer-induced antibody suppression: "original antigenic sin" with primer-induced suppression of antibody responses to only the boosting immunogen, and a second, novel form of primer-induced antibody suppression, with inhibition of antibody responses not only to the priming immunogen but also to all other immunogens in the polyvalent immunogen mixture as well. Importantly, either reversing the sequence of administration of the immunogens or administration of all four components as a polyvalent mixture completely overcame both forms of HIV-1 primer-induced antibody suppression.
YBA, a Moloney virus-induced leukemia in CBA mice, and a relatively weak immunogenic tumor, was screened for the presence of immunogenic antigens. The tumor was subjected to homogenization and subcellular fractionation on sucrose gradients; the immunogenic subcellular fractions underwent further separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The immunogenicity of the subcellular fractions and the SDS-PAGE-isolated molecular species were tested by (their) subcutaneous injection into syngeneic mice and examination of their splenocytes examined against tumor cell and normal cell targets by the chromium release cell-mediated lympholysis assay. Tumor cell homogenates were also separated by SDS-PAGE and tested for immunogenicity without prior fractionation. Splenocytes from mice that had received injections of certain SDS-PAGE-isolated epitopes derived from YBA tumor homogenate or its light and heavy subcellular fractions generated effective cytotoxic responses against YBA target cells after 6 days in vitro cultivation. In contrast, intact YBA tumor cells or non-separated tumor homogenates failed to induce an efficient cytotoxic response. The effector cells induced with the immunogenic SDS-PAGE-isolated epitopes of YBA tumor were specific, since they cytolysed the homologous target cells more efficiently than unrelated target cells or syngeneic normal cells. The activity of these effector cells was affected by varying the effector: target ratio. Augmentation of the cytotoxic responses was obtained when the splenocytes of mice immunized with SDS-PAGE-isolated epitopes of YBA tumor were restimulated in vitro, with the homologous neoplastic cells. Immunogenic SDS-PAGE epitopes were isolated from YAC tumor also (YAC is a Moloney-induced tumor of A mice). The effector cells induced with these separated epitopes were characterized as thymus-derived cells and not as natural killer cells. The results suggest that (1) the molecular repertoire of YBA and YBA tumors contain immunogens that can induce a specific antitumor cell-mediated response; (2) the isolated molecular species injected are more efficient immunogens than the entire, unseparated homogenate sample or a dose of 10(8) intact inactivated tumor cells; and (3) the gel matrix may be responsible for the enhanced cell-mediated response induced against the weakly immunogenic tumor.
Seven polymeric forms and conjugates of purified principal postsynaptic neurotoxins of Naja naja siamensis (NNS), Ophiophagus hannah (OH) and Bangarus fasciatus (BF) have been synthesized by controlled polymerization in which only 29-60% of the toxins were allowed to react. A carbodiimide (ECDI) and glutaraldehyde (GA) were used as coupling agents while BSA and tetanus toxoid (TT) were used as carriers. The antigenic mosaic of these immunogens was: NNS-ECDI, NNS-BF-OH-ECDI, NNS-BSA-ECDI, NNS-TT-ECDI, NNS-BF-OH-TT-ECDI, NNS-GA and NNS-BF-OH-GA. By using SDS-PAGE and radioactive toxin, each immunogen preparation was characterized in terms of molecular size and abundance of protein components, percent toxin reacted and toxin density. The relative immunogenicities of the immunogens along with those of NNS venom and pure NNS neurotoxin were evaluated in groups of eight rats. The levels of specific antibody against each of the neurotoxins were determined by ELISAs. Multiple comparisons between antibody responses to these immunogens were made. All the chemically modified immunogens were at least as immunogenic as NNS venom. NNS-TT-ECDI gave the highest antibody response (2.7-6.2-fold higher than that induced by NNS venom). All three multispecific immunogens induced comparable specific antibodies to BF, OH and NNS neurotoxins. The results showed that the presence of TT carrier and the relative degree of toxin density affected the immunogenicities. Some of the immunogens reported here should be useful for the production of potent, polyvalent antivenoms against elapid snakes.
Immunization of macaques with the soluble oligomeric gp140 form of the SF162 envelope (SF162gp140) or with an SF162gp140-derived construct lacking the central region of the V2 loop (DeltaV2gp140) results in the generation of high titers of antibodies capable of neutralizing the homologous human immunodeficiency virus type 1 (HIV-1), SF162 virus (Barnett et al. J. Virol. 75:5526-5540, 2001). However, the DeltaV2gp140 immunogen is more effective than the SF162gp140 immunogen in eliciting the generation of antibodies capable of neutralizing heterologous HIV-1 isolates. This indicates that deletion of the V2 loop alters the immunogenicity of the SF162gp140 protein. The present studies were aimed at identifying the envelope regions whose immunogenicity is altered following V2 loop deletion. We report that the antibodies elicited by the SF162gp140 immunogen recognize elements of the V1, V2, and V3 loops, the CD4-binding site, and the C1 and C2 regions on the homologous SF162 gp120. With the exception of the V1 and V2 loops, the same regions are recognized on heterologous gp120 proteins. Surprisingly, although a minority of the SF162gp140-elicited antibodies target the V3 loop on the homologous gp120, the majority of the antibodies elicited by this immunogen that are capable of binding to the heterologous gp120s tested recognize their V3 loops. Deletion of the V2 loop has two effects. First, it alters the immunogenicity of the V3 and V1 loops, and second, it renders the C5 region immunogenic. Although deletion of the V2 loop does not result in an increase in the immunogenicity of the CD4-binding site per se, the relative ratio of anti-CD4-binding site to anti-V3 loop antibodies that bind to the heterologous gp120s tested is higher in sera collected from the DeltaV2gp140-immunized animals than in the SF162gp140-immunized animals. Overall, our studies indicate that it is possible to alter the immunogenic structure of the HIV envelope by introducing specific modifications.
A benzpyran derivative was linked to the lysines of bovine thyroglobulin (BTG) where 69% of the available lysines were modified. This derivative was designed to elicit antibodies that were directed towards the conserved epitopes of cannabinoid metabolites that appear in urine. Polyclonal antibodies from sheep and goats and murine monoclonal antibodies were generated using this immunogen. The cross-reactivity of the antibodies was compared with antibodies generated from the more traditional phenolic-linked or 9-linked immunogens. An ELISA assay was developed using delta 9-11-nor-9-carboxy-tetrahydrocannabinol (COOH-THC) to obtain a standard curve. The antibodies generated using the benzpyran immunogen showed an average of two to three times higher cross-reactivity towards 11-OH-delta 9-THC, 8 beta-OH-delta 9-THC, 8 alpha-OH-delta 9-THC, 11-OH-delta 8-THC, and 8 beta,11-di-OH-delta 9-THC than antibodies that were generated by traditional cannabinoid immunogens. The selectivity of the benzpyran-elicited antibodies was also compared with antibodies derived from traditional immunogens using clinical urine samples that were confirmed for cannabinoids by GC/MS. The total cross-reactive cannabinoid values obtained with the benzpyran-elicited antibodies were 49% higher than the values obtained using the traditional immunogen structures. The benzpyran immunogen-induced antibodies exhibited the same low cross-reactivity for non-structurally related compounds as antibodies derived from traditional immunogens. The novel benzpyran immunogen used in this study is the first non-cannabinoid immunogen used to generate cannabinoid-selective antibodies and demonstrates the usefulness of such a structure in developing broadly cross-reactive cannabinoid antibodies.
Testosterone 19-O-carboxymethyl ether (T19C) and 19-hemisuccinate (T19H) derivatives were synthesised, and coupled to bovine serum albumin (BSA) or porcine thyroglobulin (PT) for immunogens or to iodohistamine for radioligands. The immunogenicity of these conjugates in mice was compared with those of testosterone 3-O-carboxymethyloxime and 15 beta-thioethyl conjugates. Of 10 immunogens studied, those linked to PT gave the highest antiserum titres and more sensitive standard curves. The site of conjugation (19 or 3 position) had little effect on immunogenicity. Cross-reactivity with 5 alpha-dihydrotestosterone (DHT) was in the range 22-100%, for the 19-linked immunogens. Antisera to T19C and T19H conjugated to PT were then raised in rabbits and characterised with 4 radioligands. Homologous assay systems in which the chemical bridge was identical in immunogen and 125I-radioligand gave the highest antiserum titres but the poorest assay sensitivity while those heterologous with respect to bridge or site gave the most sensitive standard curves. Rabbit antisera to both T19C and T19H immunogens showed good specificities with respect to DHT (range of cross reactions 0.78-21.1%), androstenedione, AN (range 0.45-2.3%) and progesterone, Po (range 0.05-1.4%) with all radioligands. The best assay system employed an antiserum to the T19H-PT immunogen with heterologous radioligand [125I]T19C. It had a detection limit of 15pg/tube and low cross-reactivity with DHT (0.78%), Po (0.3%) and AN (0.43%). We conclude that 19-linked derivatives of testosterone conjugated to PT are good immunogens and the antisera when combined with [125I]testosterone radioligands which are heterologous with respect to the chemical bridge, provide highly specific assays for testosterone with potential for clinical application.