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PubMed1998

Reactivity of human trophoblast monoclonal antibodies with marmoset monkey trophoblast cultures.

The aim of this study was to determine whether cultured trophoblast tissues, derived from the trophectoderm of marmoset monkey blastocysts, contain homologues of human trophoblast antigens. This is an essential prerequisite to determine whether the marmoset may be a suitable model for preclinical testing of a human antitrophoblast antigen for fertility regulation. Previously evaluated monoclonal antibodies from the Flinders University laboratory, which reacted with human trophoblast with a high degree of specificity, were tested for immunohistochemical reactivity using an immunoperoxidase detection method on both frozen and paraformaldehyde-fixed sections of the cultured marmoset monkey trophoblast. All monoclonal antibodies raised against human placenta reacted positively, when compared to controls, suggesting that human and marmoset trophoblast cells share common epitopes. The specificity of the monoclonal antibodies was investigated by determining whether there was cross-reactivity with other marmoset monkey tissues, including adrenal, spleen, kidney, liver, muscle, ovary and testis. The specificities of the monoclonal antibodies on these marmoset tissues were similar to those previously found on the corresponding human tissues. We have concluded that marmoset monkey trophoblast exhibits homologues of human trophoblast antigens. The findings also suggest that marmoset monkeys should be evaluated further as a primate model to test suitable target antigens for antitrophoblast vaccines that may be useful contragestation agents in humans.

Animals↗
PubMed1999

Antibodies to human ZP3 induce reversible contraception in transgenic mice with 'humanized' zonae pellucidae.

The initial spermatozoon-egg interaction of mammalian fertilization is mediated by the zona pellucida, an extracellular matrix composed of three glycoproteins (ZP1, ZP2, ZP3). These proteins are sufficiently conserved between human and mouse to form chimeric zonae pellucidae, and genetically engineered mice in which the endogenous mouse ZP3 has been replaced by human ZP3 have 'humanized' zonae, but normal fertility. Administration of monoclonal antibodies to mouse ZP3 does not affect fertility in these animals, but administration of antibodies to human ZP3 results in long-term, reversible contraception. The antibodies coat the zonae pellucidae surrounding growing oocytes within the ovary and their presence in the zona matrix inhibits, but does not eliminate, sperm binding. The contraceptive effect is attributed to steric hindrance that decreases sperm binding and prevents penetration through the zona pellucida. The resumption of fertility is associated with the disappearance of antibodies from the zona matrix. No adverse effect on mating behaviour, ovarian histology or fetal development (if administered after fertilization) is detected in treated females. These results suggest that transgenic mice expressing human proteins will prove useful in assessing contraceptive efficacy of zona epitopes in the rational design of immunocontraception directed at the human zona pellucida.

Animals↗
PubMed2004

Blocking of the placental immune-modulatory ferritin activates Th1 type cytokines and affects placenta development, fetal growth and the pregnancy outcome.

BACKGROUND: Placenta immunomodulatory ferritin (PLIF) cDNA was recently cloned from the human placenta, where it is expressed in syncytiotrophoblast and decidual mononuclear cells. PLIF and its subcloned bioactive domain (C48), expressed in Escherichia coli, are immunosuppressive proteins and induce pronounced IL-10 production in vitro and in vivo. METHODS AND RESULTS: PLIF serum level, measured by enzyme-linked immunosorbent assay, was elevated in pregnant mice throughout gestation and declined towards delivery. Blocking of PLIF activity by vaccination of mice with C48 prior to mating inhibited pregnancy development. Passive transfer of anti-C48 immunoglobulin (Ig) starting at 3.5-12.5 days post coitum (dpc) resulted in high rate of embryo resorption. Furthermore, treatment with anti-C48 Ig resulted in placental and embryonal growth restriction. At gestation day 13.5, growth retardation was especially notable in the placentae, while at 16.5 dpc it was pronounced in the embryos. Histopathological examination revealed that experimental placentae were globally hypoplastic and the labyrinth was strikingly pale and contained less maternal blood compared with control. Immune-activated spleen cells harvested at 13.5 dpc from anti-C48 Ig-treated pregnant mice secreted in vitro increased level of Th1 cytokines (IL-2, TNF-alpha, IL-12) and decreased level of Th2 cytokines (IL-10, IL-4, IL-5, IL-6) as compared with the level of the respective cytokines secreted by spleen cells from control pregnant mice. CONCLUSION: This study provides the first in vivo evidence that PLIF plays a major role in placentation and embryonic growth.

Animals↗
PubMed1995

Development of contraceptive vaccines for humans using antigens derived from gametes (spermatozoa and zona pellucida) and hormones (human chorionic gonadotrophin): current status.

Contraceptive research has entered a new phase of development with the advent of hybridoma and DNA recombinant technologies. During the past 5 years, significant advances have been made in this area and now it seems that realistic prospects exist for the development of contraceptive vaccines for use in humans and animals (veterinary, wild and domestic), applicable to both the female and male sexes. Contraceptive vaccines will be valuable supplements to the presently available methods of family planning, and, due to high specificity, the occurrence of limited side-effects if any, low cost and infrequent administration, contraceptive vaccines may have greater acceptability than the currently available methods. Mammalian reproduction starts with the unison of gametes contributed by the male and female partners. Both spermatozoon and oocyte have antigens on the cell surface that are unique, tissue-specific, immunogenic and accessible to antibodies, and binding of the antibodies to these antigens can cause inhibition of gamete function, resulting in a failure of fertilization. Fertilization is followed by embryogenesis, with the early embryo producing several proteins, some of which, e.g. human chorionic gonadotrophin (HCG), have a vital role in the establishment and maintenance of early pregnancy. Again, these proteins are accessible to antibodies, and their immunoneutralization can cause anti-fertility effects with loss of early embryo. Thus, the antigens derived from proteins on spermatozoa, oocyte and early embryo, especially HCG, constitute interesting molecules for the development of contraceptive vaccines. The aim of the present article is to review the current status of development of contraceptive vaccines based on antigens derived from sperm cell, oocyte zona pellucida and HCG, and to discuss their relative merits and future development.

Acrosome↗
PubMed1995

Mechanisms of autoimmune disease in the testis and ovary.

This article reviews recent research on autoimmune diseases of the testis and ovary based on two experimental approaches for induction of autoimmune diseases of the gonads (immunization with testis or ovary antigen, usually with adjuvant, and deliberate alteration of the immune system in normal animals, without injecting antigen or adjuvant). It has been found that the local testicular immunoregulatory environment partially impedes autoimmune responses to ontogenic testis antigens and regulatory T cells usually control pathogenic T cells that are found in the normal peripheral immune system. If the clonal balance of these CD4+ T cell subsets is tipped in favour of pathogenic T cells, autoimmune diseases of the gonads could ensue. Loss of regulatory T cells may occur through aberrant T cell development, or oophoritogenic T cells can be activated by non-ovarian peptides that crossreact with self peptides at the level of the T cell receptor. The inflammatory CD4 (Th1) T cell mechanism has been established to be a critical pathway for autoimmune orchitis and autoimmune oophoritis; tumour necrosis factor has been shown to be required for amplification of the pathogenic T cell response. Histopathology has suggested tissue locations wherein pathogenic T cells encounter testicular and ovarian target antigens. Antibodies bind to both testicular and ovarian target antigens during the development of autoimmune orchitis and autoimmune oophoritis, but the precise role of the antibodies has not been determined. Resolution of this role may influence the clarification of the mechanism whereby autoantibody may access ejaculated human spermatozoa to cause infertility and the future of contraceptive vaccine development based on ovarian antigens. A novel mechanism of autoantibody induction and an immunogenetic approach to autoimmune oophoritis and orchitis, based on molecular linkage analysis of inbred mice, are also reviewed.

Animals↗
PubMedDate not supplied

Fertility regulating and immunotherapeutic vaccines reaching human trials stage.

The progress and current status of vaccines which induce antibodies against human chorionic gonadotrophin (HCG) and luteinizing hormone-releasing hormone (LHRH) are reviewed. Three vaccines devised against HCG have undergone phase I clinical trials documenting their safety, and reversibility. One of these, the heterospecies dimer (HSD)-HCG vaccine has also completed phase II efficacy trials in sexually active women of proven fertility. Immunization with the vaccine prevents pregnancy, as long as the antibody titres remain > or =50 ng/ml HCG bioneutralization capacity. There is no disturbance of menstrual regularity and women continue to ovulate normally. The antibody response is predominantly against an epitope in the core part of beta-HCG. Fertility is regained at titres <35 ng. These observations have laid the scientific foundations of a birth control vaccine. Research suggests the feasibility of making a cost-effective recombinant vaccine. The carriers tetanus toxoid (TT) and diptheria toxoid (DT) can be advantageously replaced by peptide determinants recognizing T, not B cells. In addition to optional fertility control, HCG vaccines may have tumour growth inhibition potential in lung cancers which produce HCG. The vaccine against LHRH can be used in both males and females. As it is a structurally conserved molecule, the same vaccine is applicable to both animals and humans. Antibodies against LHRH block the generation of gametes and sex steroids, with the result that the vaccine can be used for fertility control (domestic pets, prolongation of lactation amenorrhoea); as well as for sex hormone-dependent cancers. Phase I/phase II clinical trials have been conducted with the LHRH vaccine in advanced metastazing carcinoma of prostate patients with encouraging results. Bioeffective monoclonal antibodies have been developed against both LHRH and HCG. These can be 'humanized' and produced cost-effectively in bacteria and plants, thus paving the way for passive use of such antibodies for immunotherapy of cancers and fertility control.

Chorionic Gonadotropin↗
PubMed1999

Antigenic and immunogenic properties of totally synthetic peptide-based anti-fertility vaccines.

In this study we describe the results of experiments in which a variety of totally synthetic luteinizing hormone releasing hormone (LHRH) vaccines were assembled and examined for their abilities to elicit antibody responses and induce sterility in mice. It is shown that totally synthetic vaccines consisting of a 15 residue-defined T cell epitope and the 10 residue LHRH epitope not only induced high titers of antibody but also induced sterility. This effect did not appear to correlate with antibody titer, antibody isotype or comparative antibody affinity, but may be related to the length of time for which antibodies are present to exert their influence.

Amino Acid Sequence↗
PubMed1997

Characterization and isolation of SOB2, a human sperm protein with a potential role in oocyte membrane binding.

G12 monoclonal antibody (mAb), one of a library of constructed mAb directed against human sperm proteins, was found by immunoperoxidase staining to label the post-acrosomal and neck regions of fixed human cauda epididymal and ejaculated spermatozoa. Epithelium and fluid of caput epididymis were strongly labelled while there was no staining on testis and efferent ducts. Western lot analysis revealed that G12 antibody reacted with proteins of 17.5, 18 and 19 kDa in human spermatozoa. This pattern seems to be specific for mature human spermatozoa, as it has not been observed either in other human tissues tested, or in spermatozoa from different animals. SOB2, the corresponding protein, was isolated from NP40-extracted human spermatozoa by using preparative electrophoresis, followed by isoelectrofocusing according to its isoelectric point of 6.4 G12 Fab fragments strongly inhibited binding of human spermatozoa to zona-free hamster oocytes (up to 86% inhibition at 200 micrograms/ml). Impairment of binding was dependent on the concentration of purified G12 immunoglobulin (Ig)G1, and significant even at 10 micrograms/ml. There was no inhibitory effect of G12 antibody on sperm motility parameters or triggering of the acrosome reaction and it did not inhibit binding to human zona pellucida. These results indicate that SOB2 is likely to participate in membrane oocyte binding, and my be potential candidate for the development of a contraceptive vaccine.

Animals↗
PubMed1999

Design and evaluation of a ZP3 peptide vaccine in a homologous primate model.

The concept of a safe, immunocontraceptive vaccine using the zona pellucida glycoprotein 3 (ZP3) as an immunogen has been marred by the appearance of ovarian dysfunction in several species. However, careful selection of epitopes on mouse ZP3 have demonstrated that it is possible to segregate contraceptive bone marrow-derived (B)-cell epitopes from the cytotoxic thymus-derived (T)-cell epitopes thought to be responsible for inducing ovarian disease. B-cell epitopes on marmoset ZP3 (mstZP3) were identified by epitope mapping studies. Using a panel of polyclonal antibodies against recombinant mstZP3, an immunodominant epitope mstZP3(301-320) was identified. A chimeric peptide was co-linearly synthesized incorporating this sequence with a promiscuous tetanus toxoid T-helper cell epitope. Using the common marmoset (Callithrix jacchus) as an animal model, we have compared the consequences of active immunization with homologous recombinant mstZP3 and mstZP3(301-320) chimeric peptide vaccine. Long-term infertility was achieved using mstZP3 but at the expense of ovarian function. In contrast, no disruption to ovarian function was observed following mstZP3(301-320) immunization. Antibodies to this peptide immunolocalized to the zona pellucida of both marmoset and human ovarian sections and inhibited human sperm-zona binding by approximately 60% in vitro. However, in-vivo studies indicated that targeting a single ZP3 epitope was insufficient to reliably and consistently achieve a contraceptive effect.

Animals↗
PubMed2005

Immunocontraceptive effects on female rabbits infected with recombinant myxoma virus expressing rabbit ZP2 or ZP3.

Recombinant myxoma viruses expressing rabbit zona pellucida 2 (rZP2) or rabbit zona pellucida 3 (rZP3) glycoproteins were constructed and tested in domestic rabbits to assess their potential to induce autoimmune infertility. The recombinant virus expressing rZP2 had no effect on fertility or ovarian histology, despite all animals developing antibodies against the rZP2 antigen. However, recombinant viruses expressing rZP3 induced infertility in 70% of animals at the first breeding. Serum antibodies were relatively short-lived, but antibody was bound to zona pellucida of all rabbits from Day 10 onward. There was no obvious correlation between infertility and rZP3 antibody titer. There was a transient inflammatory response in the ovaries of rZP3-immunized rabbits at Day 15 but no T-cell response to rZP3 could be detected at any time. Dysfunctional follicular formation was present in ovaries from rabbits infected with rZP3-expressing viruses 15-40 days postinfection but this had disappeared at later time points. A recombinant myxoma virus expressing a modified rZP3 antigen with the C-terminal hydrophobic putative anchor sequence deleted was also tested. This virus did not induce either infertility or an antibody response against the zona pellucida. Thus, the context of antigen presentation was crucial for an autoimmune response.

Animals↗
PubMed2006

The effects of immunizing sheep with different BMP15 or GDF9 peptide sequences on ovarian follicular activity and ovulation rate.

The aims of these studies were to determine the abilities of antisera against different regions of ovine bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) to inhibit ovarian follicular activity, estrus (mating), and ovulation in sheep. The 9-15-mer peptides were conjugated to keyhole limpet hemocyanin (KLH) and used to generate antibodies against the flexible N-terminal regions of the mature protein as well as against regions in which dimerization of the protein or interaction with a type 1 BMP or a type 2 TGFB or BMP receptor was predicted to occur. Ewes (n = 10 per treatment group) were vaccinated with KLH or the KLH-BMP15 (n = 9 different peptides) or KLH-GDF9 (n = 10) peptides in Freund adjuvant at five consecutive monthly intervals. Overall, antisera generated against peptides that corresponded to amino acid residues 1-15 of the N-terminus of the BMP15 or GDF9 mature protein or GDF9 amino acid residues 21-34 were the most potent at inhibiting ovulation following primary and single booster vaccination. Several other BMP15 (8/9) or GDF9 (6/10) treatment groups, but not KLH alone, also produced significant reductions in the numbers of animals that ovulated, although 2, 3 or 4 booster vaccinations were required. Anovulation was commonly associated with the inhibition of normal ovarian follicular development and anestrus. The in vitro neutralization studies with IgG from the BMP15 or GDF9 immunized ewes showed that the mean inhibition of BMP15 plus GDF9 stimulation of (3)H-thymidine uptake by rat granulosa cells was approximately 70% for animals without corpora lutea (CL), whereas for animals with one to three CL or more than three CL, the inhibition was 24%-33% or 27%-42%, respectively. In summary, these data suggest that reagents that block the biological actions of BMP15 or GDF9 at their N-termini have potential as contraceptives or sterilizing agents.

Amino Acid Sequence↗
PubMed1987

Ovaries remain functional in squirrel monkeys (Saimiri sciureus) immunized with porcine zona pellucida 55,000 macromolecule.

Fifty female squirrel monkeys were each immunized with 200 micrograms of a purified preparation of the 55,000 macromolecule (ZP3) from porcine zona pellucida. The fertility status of these immunized monkeys, as well as the effect of ZP3 antibodies on ovarian function, was monitored. High anti-ZP3 titers were achieved (greater than 75% binding levels as determined by radioimmunoassay) and remained high (approximately 67% binding level) for the duration of this study. Hormonal evaluations indicated initial disturbances in normal ovarian steroid secretion and function that were confirmed by laparoscopic observation and oocyte production data. Histological examination of ovaries at 6-7 mo post-injection suggested an interference in folliculogenesis. No pregnancies were observed in the immunized monkeys during this period. By 10-15 mo post-immunization, hormonal and laparoscopic data indicated that ovarian function was recovering in injected monkeys despite the continued presence of high titers to ZP3. Collectively, these results demonstrate that although immunization with ZP3 initially produces disturbances in normal ovarian function that inhibit fertility, these effects are reversible. Such findings encourage the continued intensive investigation of purified porcine zona macromolecules for immunocontraceptive purposes.

Animals↗
PubMed1990

Reversible inhibition of fertility in mice by passive immunization with anticumulus oophorus antibodies.

The mucified cumulus oophorus represents an outer enveloping layer around ovulated mammalian oocytes. This coat in its definitive expanded form appears late in the preovulatory development as a result of intensive secretion of intercellular matrix by cumulus cells. We have shown recently that antibodies to the cumulus matrix inhibit human fertilization in vitro. This study was undertaken to assess, in an animal model, the effects of anticumulus oophorus antibodies on fertility by use of different passive immunization protocols. A purified anticumulus immunoglobulin fraction was prepared from hyperimmune rabbit serum and administered at different times before and after mating to mice superovulated with equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG). A dose-dependent negative effect of this anticumulus antibody preparation on the number of fertilized eggs recovered from the oviducts of treated animals was observed when the antibodies were given before mating. High antibody doses also interfered with oocyte maturation and ovulation if applied on the day of eCG treatment, but no effects on these processes were found when the antibodies were given on the day of hCG treatment. The antifertility effect of anticumulus antibodies was reversible and the antibodies did not affect postfertilization development. These findings make cumulus oophorus antigens serious candidates for the development of a contraceptive vaccine.

Animals↗
PubMed1991

Endocrine response in rabbits immunized with native versus deglycosylated porcine zona pellucida antigens.

Previous studies evaluating porcine zona pellucida antigens for immunocontraceptive purposes have in some cases revealed altered ovarian function in association with antibody response. This study was undertaken in an attempt to identify zona immunogens that do not cause adverse endocrine effects. To this end, we investigated the effects of highly purified preparations of native and deglycosylated pig zona pellucida antigens on ovarian function and immune response in the rabbit. Thirty female rabbits were immunized, 5 per group, with 100 micrograms each of either 1) SIZP, solubilized isolated zonae pellucidae; 2) ZP3, a purified porcine zona preparation containing the two principle glycoproteins, ZP3 alpha and ZP3 beta, endo-beta-galactosidase-digested ZP3 glycoproteins (approximately 30% deglycosylated) termed 3) ZP3 alpha/EBGD and 4) ZP3 beta/EBGD; and chemically deglycosylated ZP3 alpha and ZP3 beta (greater than or equal to 92% deglycosylated), termed 5) ZP3 alpha/DG and 6) ZP3 beta/DG. Rabbits injected with saline (n = 2) or Freund's adjuvant alone (n = 3) served as controls. Serum LH, FSH, estradiol, and progesterone were measured at 5-day intervals during seven 20-day cycles of hCG-induced pseudopregnancy over 42 wk. Anti-ZP3 titers, determined by RIA, developed in all treatment groups and correlated directly with carbohydrate content. Animals immunized with SIZP, ZP3, and ZP3 beta/EBGD showed a significant elevation of LH and FSH and a significant decline of peak progesterone levels by the fourth pseudopregnancy cycle. In contrast, animals immunized with ZP3 alpha/EBGD, ZP3 alpha/DG, and ZP3 beta/DG showed no significant elevations of gonadotropins and continued to display cyclic progesterone secretion in response to hCG.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Monoclonal antibody to human fertilization antigen-1 (FA-1) inhibits bovine fertilization in vitro: application in immunocontraception.

A monoclonal antibody (mAb) to the human sperm plasma membrane protein, fertilization antigen-1 (FA-1), was tested for its reactivity with bovine spermatozoa and its effects on bovine fertilization in vitro. Western blot analysis revealed that the FA-1 mAb reacted with proteins of similar molecular mass (53 +/- 2 kDa) in human and bovine sodium deoxycholate (DOC)-solubilized sperm extracts. Indirect immunofluorescence, using epifluorescence microscopy and laser scanning confocal microscopy, revealed that the FA-1 antigen is present in the post-acrosomal region of bovine spermatozoa, which is similar to human FA-1 localization. In bovine in vitro fertilization (IVF) trials, using oocytes obtained from slaughterhouse ovaries, addition of 20, 40, or 80 micrograms/ml of FA-1 mAb to the IVF medium resulted in a linear decrease in the fertilization rate from 86.3% in the controls to 54.6%, 21.6%, and 1.8% in the respective experimental groups (p < 0.01). There was no inhibitory effect (p > 0.10) of the FA-1 mAb on percent sperm motility or other motility characteristics tested, suggesting that human FA-1 mAb inhibits bovine sperm cell function at some point after capacitation. In conclusion, the evolutionarily conserved antigen FA-1 has a molecular identity in bovine sperm similar to that in human sperm, and mAb to human sperm FA-1 inhibits fertilization of bovine oocytes. These results indicate that FA-1 is a promising candidate for the development of a contraceptive vaccine. The research also suggests that bovine species could be used as a model for investigating the use of FA-1 as an immunovaccine in ruminants.

Animals↗
PubMed1995

Oral immunization with attenuated Salmonella expressing human sperm antigen induces antibodies in serum and the reproductive tract.

Induction of immune responses in the reproductive tract will be crucial for a functional gamete antigen-based antifertility vaccine. Here we describe the construction and development of an avirulent Salmonella as an oral vaccine delivery vector to elicit sperm-specific immune responses in reproductive tract secretions. A cDNA sequence encoding the human sperm antigen SP10 was cloned on an asd+vector and expressed to a high level in an avirulent delta cya, delta crp, and delta asd vaccine strain of Salmonella typhimurium. Oral immunization of female BALB/c mice with this recombinant Salmonella elicited high-titer anti-SP10 IgG antibodies in serum and IgA antibodies in vaginal secretions. Anti-SP10 antibody titers could be increased by secondary and tertiary oral administrations of the recombinant Salmonella. Induction of sperm-specific antibodies in the reproductive tract following oral administration of a recombinant Salmonella could lead to the development of a simple, safe, efficient, and easy-to-use antifertility vaccine.

Acrosome↗