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PubMed1999

Vaccine for contraception targeting sperm.

Development of a vaccine(s) based on sperm antigens represents a promising approach to contraception. The utility of a sperm antigen in immunocontraception is contingent upon its tissue specificity, involvement in fertility and on raising high antibody titer, especially locally in the genital tract, that is capable of inducing reversible infertility. Several sperm antigens, such as lactate dehydrogenase C4, PH-20, sperm protein (SP)-10, fertilization antigen (FA)-1, FA-2, cleavage signal (CS)-1, NZ-1, and NZ-2 have been proposed as potential candidates for the vaccine development. Spermzona pellucida (ZP) binding is a pivotal tissue- and mostly species-specific event in the fertilization process, and the molecules involved in this site constitute the most exciting candidates for immuno-contraception. FA-1 is a sperm-specific glycoprotein having receptor activity for ZP recognition and binding. Complementary DNA encoding for FA-1 antigen has been cloned and sequenced. Active immunization of animals with recombinant FA-1 antigen causes a long-lasting reversible inhibition in fertility by raising a sperm-specific immune response. This antigen is also involved in human immunoinfertility. The exciting findings from the recent trial in immunoinfertile couples indicate that the FA-1 antigen may have clinical application in the treatment of male infertility. A vaccine having most appropriate tissue-specific and effective recombinant and/or synthetic epitopes of various sperm antigens, such as the FA-1 antigen, in a single formulation may provide a highly immunogenic and efficacious antisperm vaccine for contraception. The advances made during the last 5 years suggest that it may be a realistic proposition.

Animals↗
PubMed1999

Evidence for a unique N-linked glycan associated with human infertility on sperm CD52: a candidate contraceptive vaccinogen.

A major objective in developing a sperm antigen-based contraceptive vaccine for humans is the discovery of sperm surface immunogens that are functionally relevant and sperm specific. The latter criterion is deemed essential to avoid the possibility of inducing autoimmune disease upon vaccination. This review presents evidence that a unique carbohydrate epitope is synthesized in the human epididymis, is attached to the core peptide of CD52, a lymphocyte differentiation marker, and is subsequently inserted into the sperm membrane via a glycosylphosphatidylinositol anchor. This unique CD52 glycoform is localized to the entire sperm surface, functions as a potent target for agglutinating and cytotoxic antibodies, and is one of the few well-defined sperm surface glycoproteins indicated in human antibody-mediated infertility.

Antibodies, Monoclonal↗
PubMed1983

Effects of long-term immunization against the beta-subunit of ovine luteinizing hormone on circulating immune complex formation and on arterial changes in rhesus monkeys.

A major safety issue of contraceptive methods based on long-term immunization is the possible effect of circulating immune complexes (CIC) on the arterial wall. We have measured CIC's in 24 monkeys, immunized against the beta-subunit of ovine luteinizing hormone (oLH beta), emulsified with Freund's complete adjuvant, and in 7 nonimmunized controls by Raji assay, Clq assay, and an assay for rheumatoid factor. Eleven of the 24 immunized monkeys had CIC concentrations that were more than two standard deviations above the mean for controls in at least one of the assays. There was no correlation between antibody titer and CIC. Nine immunized and eight control animals on low-fat diets were killed to evaluate the effects of immunization on the artery wall. The cross-sectional intimal area was measured at several sites from projected microscopic images using a sonic digitizer. No statistically significant differences between test and control groups were found. However, when we compared the upper half of the distribution of test and control animals, we found that the mean intimal area of the thoracic aorta of immunized monkeys was twice that of controls and that that of the abdominal aorta was three times as large. These data indicate that long-term immunization against oLH beta induced CIC's in rhesus monkeys. Small increases in the intimal area were found in about half of the immunized animals. The results of this study suggest the need for a larger, more definitive study in which the diet is manipulated so that plasma lipids mimic those of human females in Western society.

Animals↗
PubMed1985

Reversible immunosuppression of fertility in the rat following immunization by a liposome incorporated spermatozoal polypeptide fraction.

A rat spermatozoal polypeptide with 40 amino acid residues and an N-terminal amino acid residue of Lys was purified to homogeneity by recycling high pressure liquid chromatography. Following incorporation of the peptide into pure phosphatidylcholine liposomes and immunization of female Wistar rats, a significant reduction in fertility rate occurred (chi 2 = 6.4, p less than 0.01). Following a 4-month recovery period after immunization, fertility rates returned to normal. No adverse effects of the immunization on vital organs could be detected.

Animals↗
PubMed1985

On the immunogenicity of the beta subunit of ovine luteinizing hormone (oLH beta) and equine chorionic gonadotropin (eCG) in the chimpanzee (Pan troglodytes): effect of antiserum on monkey cycle and early pregnancy.

Antibody to ovine LH beta (oLH beta) subunit and equine chorionic gonadotropin (eCG) were produced in adult male chimpanzees and evaluated for cross reactivity with oLH, human chorionic gonadotropin (hCG) and eCG by in vitro and in vivo methods. Chimpanzee antiserum to eCG failed to cross-react with hCG, but antibody raised against oLH beta subunit effectively neutralized not only exogenously administered hCG but also endogenous pituitary LH and monkey (Macaca radiata) chorionic gonadotropin. Chimpanzee antiserum to oLH beta when administered early in pregnancy reduced progesterone levels and terminated gestation in bonnet monkeys. Our data suggest that active immunization of chimpanzee, an ape that is very close to human, with oLH beta subunit leads to production of antibodies that are likely to affect both normal cycle as well as pregnancy.

Animals↗
PubMed1985

A candidate carrier protein for beta-human chorionic gonadotropin: 54,000-molecular-weight fragment of tetanus toxin.

As an alternative to intact tetanus toxoid as a carrier for beta-human chorionic gonadotropin (beta-hCG), a fragment of tetanus toxin was sought that had a relatively low molecular weight, yet was highly immunogenic. Purified culture filtrate tetanus toxin was subjected to limited enzymatic digestion with papain, and the resulting fragments separated by column chromatography on Sephadex G-150. Four fractions were thus identified. Fraction II was found to have a molecular weight of 54,000 by SDS-polyacrylamide gel electrophoresis. This fragment was covalently linked to the beta-subunit of hCG (beta-hCG-TTII) using carbodiimide hydrochloride. The ability of beta-hCG-TTII to stimulate production of anti-hCG sera in rabbits was measured by 125I-hCG radioimmunoassay. At sera dilutions of 1:40,000, an average 125I-hCG binding capacity of 34.7 +/- 5.86% (mean +/- SD) was observed 8 weeks after the final immunization. Tetanus toxin Fragment II has the potential for future application in active immunization studies involving hormone-carrier conjugates.

Animals↗
PubMed1987

Sex difference of antifertility effect by passively immunized monoclonal sperm antibodies.

Sperm-specific monoclonal antibodies (MS 204, MS 207, HS 11, and HS 63) that had been shown to inhibit fertilization of mouse oocytes in vitro were used to passively immunize male and female mice. In vitro and in vivo fertilization experiments were performed to compare the efficacy of resulting antifertility effects owing to the presence of circulating sperm antibodies. When the sperm from the antibody-treated mice were recovered for insemination, a partial inhibition of fertilization of mouse oocytes in vitro was observed. However, under the same antibody dose that effectively inhibits the in vivo fertilization of treated female mice the fertilization rate of the treated male was not significantly reduced, when they were mated with normal superovulated females followed by in vitro embryo culture. Similarly, on day 9 after mating with the antibody-treated males, the number of fetuses in mated females was not significantly different from that of the control. In contrast, when the antibody-treated females were mated with the proven fertile males, the number of fetuses was significantly reduced in response to the antibody treatment. When I-125-labeled monoclonal sperm antibodies were used to passively immunize male mice, the percentage of antibodies recovered from epididymis (relative to that of blood) was not much different from that of other organs, except for lower percentages detected in brain and testis. In treated females, oviduct and uterus revealed the presence of relatively high percentages of antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Long-term immunization against the beta-subunit of ovine luteinizing hormone (oLH beta) has no adverse effects on pituitary function in rhesus monkeys.

One postulated safety hazard of contraceptive methods based on immunization against gonadotropic hormones is the possibility that circulating antibodies which crossreact with pituitary hormones may impair pituitary function through the deposition of immunoglobulin and/or complement suggesting immune complexes. In order to evaluate this possibility in rhesus monkeys actively immunized against the beta-subunit of ovine luteinizing hormone (oLH beta), we used three approaches to study the effects of long-term immunization on pituitary function: a) evaluation of pituitary responsiveness to challenge with a GnRH-agonist; b) examination of pituitary histology and immunostaining with gonadotropin antisera; and c) examination of pituitary cells for deposition of immune complexes. Our results indicate that circulating anti-oLH beta antibodies did not result in significant impairment of pituitary function in rhesus monkeys.

Animals↗
PubMed1988

Ovarian histopathology of bitches immunized with porcine zonae pellucidae.

The ovarian histopathology of bitches immunized with crude (cPZP) or partially purified (pPZP) porcine zona pellucida proteins was examined in order to determine the cause of abnormal estrous cycles. The majority of immunized bitches had ovarian cytes. Those immunized with cPZP had follicular cysts lined with a thin layer of granulosa cells, while in those immunized with pPZP, the cysts were lined by a basement membrane with a clump of luteinized cells. In two bitches immunized with cPZP, oocytes were present only in primordial follicles. Similar abnormalities were not found in a bitch immunized with human serum albumin or in 12 untreated bitches. Oocytes flushed from the oviducts of mated, immunized bitches were degenerating, which may have been a primary cause of infertility in such bitches. Ovaries studied 2-6 weeks after immunization showed no loss of gap junctional communication between oocytes and granulosa cells, nor was any inflammatory reaction seen. IgG was bound to the zona as revealed by fluoresceinated protein A staining of frozen sections of those ovaries. Abnormal estrous cycles in PZP-immunized bitches appear to result from follicular dysgenesis or cyst formation, but the etiology of these conditions is unresolved.

Animals↗
PubMedDate not supplied

Bioneutralization capacity of the antibodies generated in women by the beta subunit of human chorionic gonadotropin (beta hCG) and beta hCG associated with the alpha subunit of ovine luteinizing hormone linked to carriers.

Data is presented on the bioneutralization capacity per unit immunoactivity of 30 serum samples of women immunized with the beta-subunit of human chorionic gonadotropin (beta-hCG) or beta hCG associated noncovalently with the alpha-subunit of ovine luteinizing hormone (alpha-oLH), to form a heterospecies dimer (HSD), which were linked to carriers. The bioassays utilized were inhibition of radioiodinated hCG binding to rat testicular receptors in vitro and the inhibition of hCG induced testosterone production in mice. In both assays, antisera of women immunized with the HSD had a bioactivity to immunoactivity ratio that was about 25% higher, on an average, than antisera of women immunized with beta-hCG, suggesting a better bioneutralization capacity of sera raised by the HSD in women.

Adult↗
PubMed1990

Immunization of male but not female mice with the sperm-specific isozyme of lactate dehydrogenase (LDH-C4) impairs fertilization in vivo.

The goals of this study were to determine the site at which fertility is impaired in mice immunized with LDH-C4 and to determine whether immunization of both males and females would have a greater antifertility effect than immunization of one sex alone. Mice were immunized with LDH-C4 in two systemic doses in Freund's adjuvants and two gastric doses in bicarbonate buffer. The presence of anti-LDH-C4 antibodies in uterine fluid was confirmed. Male and female mice were assigned to four blocks in which either the males, the females, both, or neither were immunized. Oviducts were viewed directly 1 h after mating for the presence of sperm. No significant effect of immunization on sperm transport to the oviduct could be demonstrated. Fertilization was evaluated 4 h after mating. It was found that immunization of males, but not females, impaired fertilization (19.6% versus 50.8% of the oocytes penetrated in 17 and 19 females, respectively). Orchitis was found histologically in 43.8% of the immunized males and 10% of the control males.

Animals↗
PubMedDate not supplied

Active immunization against LHRH: I. Effects of conjugation site and dose.

UNLABELLED: Active immunization against LHRH is a promising method of contraception for men. In order to be acceptable, sufficient amounts of anti-LHRH antibodies must be induced rapidly after vaccination. In previously reported animal studies, we found that it took considerable time (up to 5 months) to obtain antibody titers (AT) that were sufficiently high for complete suppression of spermatogenesis. The possibility of accelerating the immune response to LHRH by increasing the dose of immunogen was investigated in the male rat. Six doses of LHRH conjugated to tetanus toxoid (TT) in the 10 position (LHRH10-TT), ranging from 2.5 to 612 micrograms, and three doses of LHRH1-TT (50 to 612 micrograms) were tested. The magnitude of the immune response did not depend on the dose of the antigen, provided a threshold dose had been surpassed. Antigenicity of LHRH conjugated to TT at either the 1-, 6-, or 10-position was compared in rats and rabbits. In both species LHRH1-TT induced sufficient antibody concentrations to suppress pituitary gonadotropins (LH and FSH) and, subsequently, serum testosterone (T) levels faster than either the 6- or 10-conjugates. Only materials permitted for use in humans were utilized in these experiments. CONCLUSION: Active immunization against LHRH conjugated to TT at the 1-position has potential as a fast, convenient method of male contraception.

Animals↗
PubMed1993

Antigenic stimulation and blocking of pregnancy in mice by an anti-idiotypic antibody to progesterone.

PROBLEM: The present study was carried out to see if the anti-idiotypic (anti-Id) antibody (Ab2) to progesterone could mimic the immunogenicity of the steroid hormone by giving rise to antiprogesterone antibodies (Ab3) and whether these antiprogesterone antibodies (Ab3) were biologically active. METHOD: Twenty virgin female Balb/C mice were actively immunized with the anti-Id antibody (Ab2). The antiprogesterone antibody (Ab3) titres in the serum were determined and the animals were used for fertility studies. In the passive immunization studies Balb/C female mice were injected i.p. with 100 micrograms of anti-Id antibody to see its effect on pregnancy. RESULTS: The actively immunized animals when mated showed 80% reduction in their fertility rate. The duration of infertility (20-121 days) in these animals could be directly correlated with the concentration of antiprogesterone antibody (Ab3). The anti-Id antibody (Ab2) blocked pregnancy in 80% of the passively immunized mice. CONCLUSION: The studies show that anti-Id antibody to progesterone could mimic the immunogenicity of progesterone and give rise to antiprogesterone antibodies (Ab3). The anti-Id antibody successfully blocked pregnancy in mice both after active and passive immunization.

Animals↗
PubMed1993

Assay for recombinant and native human intraacrosomal antigen SP-10.

PROBLEM: To develop a method to measure a recombinant sperm protein, SP-10, during scale up and purification for a contraceptive vaccine formulation. METHOD: A quantitative assay method for the human intraacrosomal protein SP-10 was developed utilizing the format of indirect capture enzyme-linked immunosorbent assay (ELISA). A SP-10 specific monoclonal antibody mAb, MHS-10, was used as the capture antibody. Two recognition reagents, a rabbit polyclonal anti-SP-10 antisera (pAb) and a biotin-labeled mAb, MHS-10, were used as the recognition antibodies, respectively. A SP-10 recombinant fusion protein consisting of 125 SP-10 amino acids linked to glutathione transferase was used as a working SP-10 standard. The coefficient of variance for the assay system using the rabbit pAb was in the range of 0.099 to 0.157, and for the assay system using the biotinylated mAb MHS-10 was in the range of 0.081 to 0.084. RESULTS: Employing biotinylated MHS-10 as the recognition antibody, it was found that the native SP-10 molecule had more than one MHS-10 epitope. The concentration of SP-10 in a pool of human sperm extracts was found to be approximately 1% of the total proteins, assayed by both of the recognition antibody systems. CONCLUSIONS: The assay system described is useful to monitor the yield of recombinant SP-10 during scale-up production of the SP-10 vaccine.

Acrosome↗
PubMed1993

Immunoneutralization of heterodimeric FSH using FSH beta subunit as the immunogen.

PROBLEM: Immunization with beta subunit of gonadotropin may elicit antibody formation to endogenous heterodimeric gonadotropin and result in reproductive unresponsiveness. The objectives of this study were to determine if antibodies produced in rats following immunization with human follicle stimulating hormone beta-subunit (hFSH-beta) could bind to and immunoneutralize heterodimeric FSH, and to elucidate the immunoneutralizing epitope. METHOD: Mature female Sprague-Dawley rats received subcutaneous injections of 10 micrograms of hFSH-beta emulsified in complete Freund's adjuvant, while control animals received only adjuvant. Animals received 10 micrograms hFSH-beta booster injections emulsified in incomplete Freund's adjuvant 2, 4, 11, and 21.5 wk after the initial immunization. RESULTS: Immunization with hFSH-beta produced appreciable antibody titers against human FSH (hFSH) as measured in enzyme-linked immunosorbent assays (ELISA) of immunized rat sera. A more modest titer to rat (rFSH) and no antibody response to rat Luteinizing Hormone (rLH) was observed, thus confirming the specificity of the immune response. Titers against hFSH increased throughout the study. Rat anti-hFSH-beta sera was tested to determine its ability to inhibit binding (immunoneutralizing) of 125I-hFSH to the FSH receptor. Continued immunization resulted in all animals producing immunoneutralizing antibodies. Immunization of rats also resulted in disrupted estrous cycles, but only animals with subsequent titers high enough to completely block binding of FSH to its receptor failed to conceive. In order to assess the immunoneutralizing epitope, antisera were tested in a peptide ELISA. Peptides used in the ELISA corresponded to amino acids that spanned the entire hFSH beta sequence. It was found that antibodies from all rats immunized with hFSH beta bound to amino acids within hFSH-beta 33-53. CONCLUSIONS: Collectively, these data suggest that amino acids within hFSH-beta 33-53 are necessary but not sufficient to confer immunocontraception. Amino acids within this linear sequence appear in a variety of epitopes of hFSH-beta and hFSH, only some of which are immunoneutralizing. (Am J Reprod Immunol. 1993; 29:000-000.)

Amino Acid Sequence↗