Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021359 (infertility)
 26,075 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Female golden hamsters were immunized with solubilized porcine zona pellucida (s-PZP) or ZP4 glycoprotein family isolated from s-PZP by preparative SDS-PAGE. Both antigen preparations induced production of antibodies which reacted not only with porcine zona pellucida but also with the hamster zona pellucida. The hamsters immunized with solubilized porcine zona pellucida mainly produced antibodies reactive to ZP3, while the hamsters immunized with ZP4 mainly produced antibodies reactive to ZP4. The former animals became permanently infertile but the infertility in the latter animals was temporary and they became pregnant later. Histological studies revealed that the ovarian follicles in hamsters immunized with s-PZP were completely destroyed leaving only atrophic follicle-like cell clusters, while in the ovaries of hamsters immunized with ZP4 a number of small follicles with oocytes remained intact. These observations are encouraging for the further characterization of the ZP4 antigens as candidates for the development of a contraceptive vaccine.
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PMID:Antifertility effect of active immunization with ZP4 glycoprotein family of porcine zona pellucida in hamsters. 150 Dec 6

Certain sperm antigens are auto- or isoimmunogenic, and naturally occurring sperm antibodies have been implicated in 10-15% of unexplained human infertility. Thus, efforts to develop an immunocontraceptive for human application have targeted sperm antigens. The World Health Organization Task Force on Contraceptive Vaccines designated the human sperm SP-10 as a primary vaccine candidate. The presence of SP-10 mRNA was demonstrated in baboons and macaques, and it is an ideal primate model for evaluating human efficacy. At a workshop on worldwide research on all monoclonal antibodies against sperm, HS-11 and HS-63 were selected for further evaluation because of their high specificity and significant anti-fertility effects. Isoenzyme LDH-C4 is a primary sperm antigen: it provokes antibodies that are absolutely cell specific and do not cross-react with somatic LDH isozymes. Immunization of both males and females with purified LDH-C4 results in an immune response and antibodies suppress fertility in female mice, rabbits and baboons. The PH-20 protein from guinea pigs has a required function in sperm-zona binding, and a 100% effective contraception is obtained when either male or female guinea pigs are immunized with purified PH-20. Regarding zona pellucida antigens (ZP), the porcine zona pellucida contains the major glycoprotein families identified as ZP1, ZP2 and ZP3. In a human in vitro fertilization system, only antibodies against ZP3 completely suppressed sperm-egg interaction. Passive administration of anti-zona pellucida antibodies results in long-term reversible contraception. The development of antigens capable of evoking an immune response, thereby preventing fertility without ovarian histopathology, is under way. A zona pellucida contraceptive vaccine containing 8-cell, but not T-cell, zona pellucida epitopes may prevent ovarian pathology.
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PMID:Anti-sperm and anti-ovum vaccines: the selection of candidate antigens and the outcome of preclinical studies. 151 25

We have undertaken a comparative analysis of the contraceptive activity of antibodies directed against the porcine sperm receptor zona pellucida antigen (ZP3) and its Mr = 32,000 polypeptide core (DGZP-32). The strategies employed for this analysis included the induction of active immunity in a primate, the common marmoset, and an in vitro fertilization protocol involving the use of viable human ova. In both experimental situations, antibodies against ZP3 were shown to exhibit contraceptive activity, leading respectively to the induction of long-term infertility in the primate model and to the complete inhibition of human fertilization in vitro. The in vivo studies also revealed that the induction of high titer antibodies against ZP3 was inevitably associated with the appearance of an ovarian pathology characterized by the progressive depletion of the primordial follicle pool within one to two years. This side effect could not be alleviated by the use of DGZP-32 as antigen since the induction of immunity against this polypeptide was also associated with the eventual appearance of an ovarian pathology identical to that observed with ZP3. Furthermore, the DGZP-32 peptide was less effective than ZP3 in inducing the formation of antibodies capable of inhibiting the fertilization of human ova in vitro. We conclude that significant problems remain with the use of deglycosylated zona peptides for the development of contraceptive vaccines and that their potential will not be realized until the epitopes responsible for the induction of infertility and the primordial follicle depletion have been identified and segregated.
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PMID:Analysis of the contraceptive potential of antibodies against native and deglycosylated porcine ZP3 in vivo and in vitro. 157 51

Opening a small aperture in the zona pellucida of mouse oocytes by using micromanipulation and a stream of acidified Tyrode's solution (zona drilling) improved the efficiency of in vitro fertilization at low sperm concentrations without adversely affecting development to the blastocyst stage. Zona drilling also permitted in vitro fertilization and development when sperm penetration through the zona was blocked by a monoclonal antibody to the protein core of the zona glycoprotein, ZP3. These results provide a direct demonstration that sperm entry occurs through the aperture and also suggest that zona drilling of human oocytes may offer a therapeutic approach when autoantibodies to the zona pellucida are suspected as a cause of infertility.
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PMID:Fertilization of zona-drilled mouse oocytes treated with a monoclonal antibody to the zona glycoprotein, ZP3. 305 64

The present study was conducted to investigate the molecular identities, nature of interaction, and tyrosine phosphorylation activity of the sperm-zona pellucida binding proteins in humans. Sperm proteins belonging to four major molecular regions, namely 95, 63, 51, and 14-18 kDa, reacted with zona pellucida proteins in the Western blot and immunoprecipitation procedures. In these procedures, zona pellucida protein that reacted strongest with the sperm proteins belonged to the molecular region of 55 kDa (ZP3), besides weakly reacting proteins in the 110-kDa (ZP1/ZP2) and 14-18-kDa molecular regions. The major forces involved in the sperm-zona protein interactions were of hydrophobic and ionic in nature. Three (95, 51, and 14-18 kDa) of the four molecular regions of sperm proteins that bound to the zona pellucida proteins also seem to involve o-phospho-L-tyrosine residues in their interaction, and these proteins demonstrated the presence of phosphotyrosine residues, and the 51-kDa protein also showed autophosphorylating activity in the in vitro kinase assay. The sperm binding zona protein of 55 kDa also demonstrated autophosphorylating activity. Using specific monoclonal antibody to the well characterized sperm-specific glycoprotein, designated FA-1, and the competitive inhibition in the immunoprecipitation procedure, it was found that the 51 kDa protein is indeed FA-1 antigen. Besides elucidating the molecular nature of the sperm-zona interaction, these antigens will find application in the development of a multivalent contraceptive vaccine, and may also help in specific diagnosis and treatment of infertility mediated through defective gamete (sperm or oocyte) function.
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PMID:Molecular identities of human sperm proteins that bind human zona pellucida: nature of sperm-zona interaction, tyrosine kinase activity, and involvement of FA-1. 753 65

The 3 primary candidates for the development of a contraceptive vaccine are: a) human chorionic gonadotropin (hCG), b) the zona pellucida, and c) the sperm surface. The most advanced approach involves the induction of immunity against hCG. Completed Phase I clinical trials have revealed that such preparations are capable of stimulating the production of anti-hCG antibodies. Phase 2 studies are about to commence. Vaccines are being engineered based on conjugates which incorporate tetanus or diphtheria toxoid linked to a variety of hCG-based peptides centered on the beta-subunit of this molecule. However, the longterm safety of efficacy of such immunity is unknown. The remaining 2 vaccine development approaches aim to prevent conception by interfering with the interactive events that characterize the union of male and female gametes of fertilization. The zona glycoprotein, ZP3, is a prime candidate for such a vaccine, in the view of its important role in the recognition and activation of spermatozoa and its unique antigenic composition. A major problem with this approach involves the loss of primordial follicles observed in the many in vivo studies in which active immunity against this protein has been induced. The possibility that this problem can be overcome by identifying B-cell epitopes that will avoid the T-cell responses thought to be responsible for the appearance of ovarian dysfunction is now being actively investigated. Disruption of fertilization through the induction of immunity against sperm surface antigens is a third approach, for which there is clinical support as patients have exhibited infertility associated with the appearance of spontaneous immunity against sperm antigens. Potential targets are constrained by considerations of immunogenicity, specificity, antigen density, and location.
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PMID:Contraceptive vaccines. 832 18

Mammalian oocytes synthesize and secrete a zona pellucida that surrounds the growing oocytes, ovulated eggs and preimplantation embryos. The extracellular zona matrix is composed of three glycoproteins (ZP1, ZP2, ZP3) that are involved in folliculogenesis, species-specific fertilization, and passage of the early embryo down the oviduct. We have established a mouse line in which Zp3 has been inactivated by homologous recombination with an insertional mutation. Neither Zp3 transcripts nor ZP3 protein was detected in female mice homozygous for the mutation (Zp3-/-), whereas both ZP1 and ZP2 were present in mutant oocytes. Homozygous mutant Zp3-/- mice had follicles with germinal-vesicle-intact oocytes but that lacked a zona pellucida matrix and had a disorganized corona radiata. Although mutant oocytes underwent germinal vesicle breakdown (GVBD) prior to ovulation, the cumulus-oocyte complex was markedly disrupted and the oocytes were often separate from the cumulus cells. After hormone-induced ovulation, cumulus masses were present in the oviducts of homozygous mutant mice, but zona-free eggs were observed in only half of the females and, in these, less than 10% of the normal number [correction of mumber] of eggs were detected. No zona-free 2-cell embryos were recovered from homozygous mutant Zp3-/- female mice after mating with males proven to be fertile, and none became visibly pregnant or produced offspring. These results demonstrate that a genetic defect in a zona pellucida gene causes infertility and, given the conserved nature of the zona pellucida, a similar phenotype is expected in other mammals.
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PMID:Mice homozygous for an insertional mutation in the Zp3 gene lack a zona pellucida and are infertile. 878 63

Autoantibodies to ZP3, a major glycoprotein of the zona pellucida (ZP) with sperm receptor function, can block sperm/oocyte interaction. However, only mice of certain major histocompatibility complex (MHC) haplotype respond to the ZP3 peptide. Moreover, ZP3-specific T cells can mediate ovarian autoimmune disease. A chimeric peptide has been designed that induces antibody to native ZP3 regardless of the MHC haplotype of the inbred mice tested. This results in reduction in fertility that is reversible. Infertility correlates well with ZP antibody titer, and the mice do not develop concomitant autoimmune oophoritis. The vaccine contains (1) a promiscuous foreign T-cell peptide capable of eliciting a T-cell response regardless of the animals' MHC haplotype, and (2) a modified native B-cell peptide of ZP3.
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PMID:ZP3 peptide vaccine that induces antibody and reversible infertility without autoimmune oophoritis. 896 44

Previous studies have demonstrated the efficacy, in mice, of synthetic peptides derived from zona pellucida (ZP) glycoprotein in blocking fertility without ovarian dysfunction. This study used bonnet monkeys (closely related to humans in the primate evolutionary tree and less susceptible to summer amenorrhea than rhesus monkeys) to explore the design of an immunocontraceptive vaccine based on synthetic peptides, recombinant glycoproteins, or proteins corresponding to ZP. Immunization of female monkeys with pig ZP3 glycoprotein using adjuvants permissible for human use produced infertility. Although only half the animals conceived after antibody titres declined, monkeys that failed to conceive did not show any obvious ovarian changes. Mapping of the epitopes recognized by monoclonal antibodies against ZP3 alpha and beta and possessing contraceptive efficacy in vitro identified an N-blocked decapeptide from the N-terminus corresponding to 23-32 amino acids of the precursor protein of pig ZP3 beta. When DNA encoding bonnet monkey ZP3 was cloned and sequenced, the deduced primary amino acid sequence showed a 93.9% similarity with human ZP3. Bonnet monkey ZP3 corresponding to an internal 975 nucleotide fragment excluding the N-terminus signal sequence and the C-terminus transmembrane domain has been expressed in Escherichia coli.
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PMID:Strategies for designing an immunocontraceptive vaccine based on zona pellucida synthetic peptides and recombinant antigen. 898 75

Zona pellucida (ZP) glycoproteins possess sperm receptor-binding activities. Antibodies against ZP can block sperm-egg interaction and thereby prevent fertilization. The feasibility of developing a safe contraceptive vaccine based on the ZP has been hampered by the finding that active immunization with autologous or heterologous ZP proteins results in infertility that is associated with ovarian dysfunction. A mouse model was used to investigate mechanisms of the ovarian pathology that is induced by active immunization with a 13mer peptide derived from mouse ZP3 (mZP3(330-342)). This peptide includes one native B-cell epitope and two nested T-cell epitopes. Ovarian pathology could be transferred into naive recipients by CD4+ T cells, but not by antibodies, from immunized mice, suggesting the importance of T cells in the mechanism of ovarian pathogenesis. Moreover, immune responses, as well as disease induction, were restricted to H-2a,k,u,s,axb haplotypes. On the basis of this mouse model, a strategy to generate a contraceptive anti-ZP antibody response without a pathogenic T-cell response, irrespective of H-2 haplotype, is described. The B-cell epitope was modified by amino acid substitution to eliminate the overlapping oophoritogenic T-cell epitope, and was linked to a promiscuous foreign T-cell epitope, bovine RNase94-104. The resultant chimaeric peptide (CP2) induced anti-ZP antibodies in 100% of the eight strains of inbred mice with different H-2 haplotypes without significant disease induction. An antifertility trial in B6AF1 female mice immunized with CP2 showed that the anti-ZP antibody was associated with a reduction in fertility. This infertility was reversed with a decline in anti-ZP antibody titre. Preliminary data show that this strategy of vaccine design may also be applied to primates.
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PMID:Influence of autoimmune ovarian disease pathogenesis on ZP3 contraceptive vaccine design. 898 79


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