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PubMedDate not supplied

Manipulating the immune response; applications in livestock breeding.

There are many opportunities for the use of immune modulation techniques in livestock that offer the potential to reduce the requirements for chemical usage and surgical intervention in standard management practices. While vaccination has been used for many years for disease control, there are areas in which vaccination has not been very successful, including the induction of mucosal responses, the induction of cellular responses, and the ability to induce extended duration of protection after a single administration of antigen. In addition, new areas of immunological intervention such as immunisation against reproductive hormones offer new opportunities to modify not only reproductive performance, but also growth, metabolism, carcass quality and behaviour in livestock. These new techniques bring increased need for enhanced efficacy and duration of response. While extensive studies in vaccination have shown that many of the desired immunological responses can be induced in experimental conditions, effective application in the field is dependent upon the development of vaccine delivery methods that are practical within the confines of an effective livestock management system. This paper outlines restrictions that may be imposed on vaccine delivery to livestock and introduces controlled antigen delivery as a potential method for single dose vaccination.

Animal Husbandry↗

PubMed2005

Testicular development, ultrasonographic and histological appearance of the testis in ram lambs immunized against recombinant LHRH fusion proteins.

Sixteen native ram lambs weaned at 10 wk of age were divided into two groups. Eight animals were immunized against LHRH with a mixture of two fusion proteins: ovalbumin-LHRH-7 and thioredoxin-LHRH-7. The immunized lambs received a primary immunization plus two booster immunizations at 4 and 12 wks. Animals in the control group (n=8) were not treated. Scrotal measurements and blood samples were taken at 2-week intervals. Beginning at 25 wk of age, semen was collected and sexual behaviour was evaluated on a weekly basis. At 35 and 37 wk of age testes and accessory glands of all animals were subjected to ultrasound scanning. At 37 wk of age animals were slaughtered and testes were evaluated histologically. Serum LHRH antibodies (P<0.01) were detected in animals of the immunized group which had reduced serum testosterone concentrations (P<0.01). Testicular development was suppressed in the immunized animals (P<0.01). Immunized animals exhibited mounting activity 5 wks later than control animals. No mature spermatozoa containing ejaculates were collected from immunized animals. Control animals had moderately echogenic ultrasonographic appearance at 37 wk age, whereas immunized animals had hypoechogenic images. Mean seminiferous tubule diameter in immunized lambs was significantly smaller than that in control lambs. Basal membrane was thickened and hyalinized; there was an increase in peritubular connective tissue. No proliferating spermatogonia or mature spermatozoa were present in the tubules in these animals. There were no differences in the ultrasonographic appearance of prostate and vesicular gland between control and immunized animals. The LHRH recombinant fusion proteins were effective in immunological castration in ram lambs when started at 10 wk of age as noted by differences in serum testosterone, testicular histology and ultrasonographic appearance of testis and weight of accessory sex glands. Determining the effects of immunization on ultrasonographic appearance of the testis related to time after immunization requires further investigations.

Aging↗

PubMed1994

Biology and structure of the zona pellucida: a target for immunocontraception.

Although reversible interference of sperm-egg interactions with pharmacological agents has not yet been achieved, animal models have provided increasing evidence that immunological reagents directed against mammalian gametes can effectively inhibit fertilization. One potential target of immunocontraception is the zona pellucida, an extracellular matrix that surrounds the growing oocyte and ovulated egg. Recent advances in our knowledge of the biosynthesis and molecular biology of the zona pellucida have provided much information useful in the rational design of immunocontraceptive vaccines. There remain, however, major obstacles to using immunological reagents to prevent fertilization, including potential toxic side effects, the lack of adequate delivery systems and the possibility of incomplete reversibility. This review summarizes current understanding of the production of the zona pellucida during folliculogenesis, the structure of the conserved proteins and genes in the zona pellucida, and the progress made in the development of immunocontraceptive strategies that focus on this oocyte-specific structure.

Animals↗

PubMed1999

Vaccines and passive immunological approaches for the control of fertility and hormone-dependent cancers.

Reviewed here is the development of a vaccine against the human chorionic gonadotropin that prevents pregnancy in sexually active women without impairment of ovulation or derangement of menstrual regularity. Also reviewed are the vaccines inducing antibodies against the luteinizing hormone-releasing hormone, which have immunotherapeutic potential in prostatic hypertrophy and other sex hormone-dependent male and female cancers. The adoption of passive immunization using humanized recombinant antihormone antibodies is advocated for assured efficacy and safe, prompt therapeutic action.

Animals↗

PubMed1989

Effects of long-term immunization against LHRH and androgen treatment on gonadal function.

The possibility of immunological suppression of spermatogenesis while normal libido is maintained by exogenous androgen supplementation was tested in male rats. Neither short- nor long-term treatment with androgen (testosterone-17-trans-4-N-butyl-cyclohexane carboxylate) alone influenced fertility. Active immunization against LHRH administered simultaneously with exogenous androgen supplement caused infertility in 100% of the tested animals, all of which displayed normal sexual behavior. The atrophy of the testes and accessory sex organs was reversible.

Animals↗

PubMed1997

Designing an effective immunocontraceptive.

The immunological inhibition of fertilization is the goal of gamete immunocontraception. To achieve this goal a gamete-specific antigen target must be defined and the presentation of the immunogen to the immune system must be clearly understood in order to elicit a defined immune response which will target the native gamete molecule. Almost 20 years ago C.B. Metz suggested six studies which would answer the questions necessary for the development of a successful immunocontraceptive, and although much work has gone into answering each of these questions, none has been completed. Hyaluronidase is an example of a well studied sperm antigen whose native, membrane bound form (PH-20) is a successful immunocontraceptive in female guinea pigs. However, it remains to be demonstrated that a successful native antigen can be a successful synthetic or recombinant gamete immunocontraceptive (GAMICON). The problem of converting a successful native contraceptive antigen into an effective synthetic or recombinant GAMICON is at the heart of the problem of GAMICON design. If the epitopes of native and synthetic immunogens are not the same, then can a conversion ever be made? One approach to understanding how to make this conversion is to use defined, synthetic B- T-cell epitopes as specific B-cell epitopes on native antigens affect fertility.

Amino Acid Sequence↗

PubMed2005

Vaccines for the control of reproduction--status in mammals, and aspects of comparative interest.

The objective of producing vaccines which target elements of the reproductive system to control fertility has been pursued for many years. Of the many targets for such vaccines, several sperm-associated antigens have been proposed for antibody-mediated intervention before fertilization but the very abundance of antigen to be neutralized has been a barrier. Zona pellucida antigens associated with the surface of the oocyte have also been targeted and used successfully for control of 'wild' elephant populations but worries concerning immunopathologically-mediated tissue damage have been mooted. Vaccines using human chorionic gonadotropin (hCG) which is required for the implantation and maintenance of the fertilized egg, although of interest for the development of fertility control in human populations, has no relevance in the context of the present conference because external fertilization of fish eggs is independent. The pathways by which gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus promote release of luteinizing (LH) and follicle-stimulating hormone (FSH) which govern the physiological maturation and maintenance of the reproductive organs, provide many targets for immunological intervention. Most consistent success has been reported using GnRH-based vaccines which are immunosterilizing in a variety of mammalian species such as pigs, rodents and white-tailed deer. The fact that the structure of the decapeptide, GnRH, has been maintained over so many years of evolution and been conserved across so many animal species, encourages the view that a strategy for control of sexual maturation in fish based upon stimulation of GnRH antibodies may well prove to be a practical proposition, provided the formulation of an appropriate highly immunogenic vaccine can be achieved.

Animals↗

PubMed2003

Immunocontraception is induced in BALB/c mice inoculated with murine cytomegalovirus expressing mouse zona pellucida 3.

Immunocontraception, the prevention of oocyte fertilization through immunological means, could potentially be used to control plaguing mouse populations in Australia. This paper describes the construction of a mouse-specific betaherpesvirus, murine cytomegalovirus, which has been engineered to express the murine zona pellucida 3 (ZP3) gene. A single inoculation of this recombinant virus resulted in almost complete infertility, persistent anti-ZP3 antibody production, and profound changes to ovarian morphology in BALB/c mice in the absence of significant virus replication during the acute phase of infection. Murine cytomegalovirus may prove to be useful as a vector for the delivery of a mouse-specific immunocontraceptive agent to target populations of wild mice in the field.

Animals↗

PubMed1994

Double immunogold labelling demonstrating expression of recombinant genes for production of an anti-fertility vaccine.

The multiple antibody technique for double immunogold labelling for the simultaneous localization of two antigens with negative staining was utilized to demonstrate the expression of recombinant genes in bacteria, with the primary antibodies being raised in different host species. For the production of a vaccine for immunological control of fertility, a multi-functional plasmid vector was introduced into the bacterium Pseudomonas aeruginosa containing the Dichelobacter nodosus fimbrial subunit gene with a grafted amino acid sequence of luteinizing hormone releasing hormone (LHRH) peptide. Fimbriae of this recombinant, when run on a SDS-polyacrylamide electrophoresis gel, gave a single broad band for LHRH peptide/D. nodosus subunit and were harvested to produce the anti-fertility vaccine which, when injected into mice, produced atrophy of the testes with absence of sperm, resulting in reversible castration. Double immunogold labelling of the recombinant P. aeruginosa bacteria demonstrated fimbriae with strong expression of the LHRH-peptide, expression of the D. nodosus subunit and absence of host fimbriae.

Animals↗

PubMed1996

Progress in the development of human chorionic gonadotropin antifertility vaccines.

Prototype human chorionic gonadotropin (hCG) vaccines have demonstrated the feasibility of effectively eliciting antibodies in women and inhibiting fertility in both humans and nonhuman primates. Also, no serious side-effects due to immunization against self antigens have been revealed to date. However, the formulations so far tested in clinical trials are not suitable for widespread applications due to problems associated with complexities in production, burdensome application procedures, the need for frequent booster immunizations or cost of manufacture. Current research efforts involve the development of delivery systems to permit annual or biannual intervals between immunizations for protection from pregnancy, procedures for mucosal immunizations, methods to reduce hypersensitivity and local reactions, and procedures for reducing the cost of production. Recent progress in understanding the crystalline structure of the hCG molecule has stimulated further studies to define immunological epitope sequences that might constitute immunogens in future vaccines. The incorporation of vaccine components into biodegradable microspheres has resulted in formulations that elicit elevated antibody levels in rabbits for more than one year. Preclinical and clinical studies with such formulations are planned. Studies using totally synthetic peptide immunogens constituting hCG B-cell epitopes and "promiscuous" T-cell epitopes from bacterial or viral proteins have been shown to be equally immunogenic as conjugates of hCG peptides with macromolecular carriers. Still other peptide immunogens have been developed that can elicit antibody production without detectable proliferation of helper T cells. Some of these peptides can induce systemic immunity from oral immunization or systemic injections. Alternative vehicles for administering vaccine components with reduced local reactivity show promise for new vaccine formulations.

Animals↗

PubMed1994

Identification of sperm antigen targets for immunocontraception: B-cell epitope analysis of Sp17.

The selection of immunological targets present on gametes is an important first step in the successful production of animal or human vaccines for immunocontraception. One strategy with regard to sperm antigens is to select antigens with physiological roles in gamete interaction, obtain the mRNA sequence for such an antigen, and then determine which region or domain of the molecule is available to the immune system when spermatozoa are presented to the female reproductive system. To illustrate this strategy, we have used the rabbit sperm antigen Sp17 (RSA-3), which has been cloned and sequenced. The peptide pin-block method of Chiron Mimotopes, Australia, has been used to analyse the 146 amino acids of Sp17 with various homologous and heterologous antisera. This study demonstrates that such an analysis can lead to the identification of a B-cell epitope with strong immunocontraceptive potential.

Amino Acid Sequence↗

PubMed1998

Immune response to immunization with sperm antigens in the macaque oviduct.

The oviduct of most mammalian species is the site where spermatozoa first encounter the oocyte and the process of fertilization is initiated. It should therefore be considered an important focus of study for the development of an effective gamete immunocontraceptive with the goal of immunologically interfering with spermatozoon function. The study reported here used the cynomolgus macaque as a nonhuman primate model in which to analyze the serum and oviductal fluid immune response to immunization with the human sperm protein Sp17 and synthetic peptides derived from Sp17. Human and macaque Sp17 were shown to share a very high degree of identity (96.7%), confirming this species as a suitable model in which to study the antibody response and recognition of spermatozoa. The oviductal fluid antibody titer varied with respect to serum titer both over time for individual monkeys and between different monkeys. In all cases, however, the antibody response was restricted solely to the immunoglobulin G class. Finally, both serum and oviductal fluid antibodies were directed against identical Sp17 B-cell epitopes and both recognized native macaque Sp17 in spermatozoa.

Amino Acid Sequence↗

PubMed1998

Construction and immunological assessment of Salmonella typhimurium expressing fox sperm LDH-C4.

This study examined immune responses of foxes to oral doses of recombinant Salmonella typhimurium expressing fox sperm-specific lactate dehydrogenase (fLDH). The cDNA for fLDH was cloned into the expression plasmid pKK233.2 (pKKfLDH). Salmonella typhimurium aroA- (SL3261) was transformed with either the pKK233.2 plasmid alone (SpKK) or the pKKfLDH construct (SpKfLDH). The fLDH expressed by SpKfLDH retained enzymatic activity and was recognized by human LDH-C4-specific antibody. Male European red foxes (Vulpes vulpes) were given an initial oral dose of 1 x 10(11) cfu of either SpKK (control, n = 3) or SpKfLDH (test, n = 6), followed four weeks later with a further dose of 1 x 10(11) cfu. Antibodies to Salmonella lipopolysaccharide (LPS-04) and fLDH were measured in plasma and saliva for eight consecutive weeks after the initial doses. Both LPS-04 IgG- and IgA-specific antibodies as well as fLDH-specific IgG antibodies were detected in plasma and saliva. However, there was a marked fLDH-specific IgA response in saliva consistent with induction of the common mucosal immune system. The antibody measurements demonstrated the feasibility of using recombinant Salmonella as an oral vaccine to elicit gamete antigen-specific mucosal immune responses in foxes.

Amino Acid Sequence↗

PubMed1979

The investigation of immunological infertility.

Immune reactions to spermatozoa may interfere with fertility in both males and females. These mechanisms may operate in a small, but significant, proportion of infertile couples, particularly when the duration of infertility is greater than three years. Antibodies to sperm may appear both in the blood and in genital tract secretions and their presence should be sought in both sites. The most suitable screening test for circulating anti-sperm antibodies in either partner is a method based on the complement-dependent antibody immobilization of sperm. This test may also be applied to cervical mucus as a routine in females. In males the detection of sperm immobilizing antibodies in blood serves as a reasonable guide to the existence of antibodies in seminal plasma where their presence may be confirmed using a gelatin agglutination test. Further information about the presence of locally secreted antibodies either in cervical mucus or in semen may be gained by using the sperm-cervical mucus contact (SCMC) test in which cross-testing with donor mucus or sperm will identify the site of local antibody production. Results based on immunofluorescence and sperm microagglutination methods are unreliable and lacking in correlation with continuing infertility and the routine use of these tests is not recommended.

Agglutination Tests↗

PubMed1976

Attempt at "immunological castration" as an approach to the problem of the involvement of testosterone in control of expression of certain mouse antigens.

Adult male mice of the strain B10.A were immunized with a testosterone-protein conjugate, testosterone 3-(O-CARBOXYMETHYL)-oxime-bovine serum albumin which contained 27-75 steroid residues/mol BSA. Two different immunization doses of the conjugate were used, respectively, 2 x 40 mug and 2 x 200 mug in complete Freund's adjuvant or in alum adjuvant. There were two groups of control males, non-immunized and immunized with BSA in adjuvant. In the pooled immune sera, antibodies to testosterone were determined by radioimmunoassay; their titre ranged between 7 and 10. On histological sections of testes, inhibition of spermatogenesis (manifested by a sower frequency or even absence of tubules producing mature sperm, reduced frequency of tubular cells and their degenerative changes) was observed in almost all males immunized with the higher dose of the conjugate. In such animals, increased frequency of interstitial cells (except vascular elements) and enlarged nuclei of Leydig cells were found. In spite of these signs of a hyperproduction of testosterone by the Leydig cells, the product seemed to have lacked its normal biological activity as suggested not only by the low activity of spermatogenesis, but also by a significantly subnormal level of the androgen-dependent serum protein Ss.

Animals↗

PubMed1994

Immunization against HCG.

The possibility of using the immune system to provide protection against an unwanted pregnancy has been postulated since the very early days of modern immunology. During the past two decades or more, a major goal-directed research effort, involving several independent groups of investigators, has been underway with the objective of developing birth control vaccines suitable for use by men and women at all stages of their reproductive lives. The most advanced work in this area is concerned with the development of a vaccine directed against human chorionic gonadotrophin (HCG), a hormone that is produced by the peri-implantation embryo and that is essential for successful implantation and the establishment of early pregnancy. These studies have reached the stage of clinical testing of a number of prototype vaccines based on different parts of the HCG molecule. No adverse side effects have been observed or reported in these clinical trials and larger scale clinical studies are being planned to assess further the safety, efficacy and acceptability of these preparations. Research is also underway to develop improved versions of these HCG vaccines that will offer 12-18 months protection following a single injection. The stage is set for the introduction, by the turn of this century, of the first totally new method of family planning in four decades.

Amino Acid Sequence↗

PubMed1978

Immunological control of fertility: measurement of affinity of antibodies to human chorionic gonadotrophin.

Four baboons were primed with diazotized beta human chorionic gonadotrophin and boosted with diazotized C-terminal beta human chorionic gonadotrophin peptide, and the changes in antibody amount and affinity determined using a double isotope modified Farr assay, using labelled human chorionic gonadotrophin as the antigen. The degree of cross-reaction with human luteinizing hormone was also determined. Although appreciable reactivity with luteinizing hormone was observed soon after immunization, this declined rapidly during the response. At the time intervals studied, there was a progressive increase in affinity of antibodies to human chorionic gonadotrophin until day 248 after priming. At day 313, in two of the animals, there was a decrease in affinity from 1.04 X 10(11) to 6.80 X 10(10) and 1.05 X 10(11) to 4.93 X 10(10) l/mol, whereas in the other two baboons there was a further increase in antibody affinity. At corresponding time intervals, there was a steady decrease in values of total antibody binding sites. To determine the overall effect of the maturation of affinity with a decrease in antibody amount on biological efficacy, the theoretical amount of chorionic gonadotrophin that would be neutralized was calculated. We computed that in all instances, over 99% of a peak concentration of chorionic gonadotrophin that could be in circulation in a pregnant baboon would be neutralized. This was in excellent agreement with results of mating experiments in these baboons. In over forty cycles studied, none of the matings resulted in a sustained pregnancy.

Animals↗

PubMedDate not supplied

Prospects of riboflavin carrier protein (RCP) as an antifertility vaccine in male and female mammals.

Riboflavin carrier protein (RCP) is obligatorily involved in yolk deposition of the vitamin, riboflavin, in the developing oocyte of the hen. The production of this protein is inducible by oestrogen. It is evolutionarily conserved in terms of its physicochemical, immunological and functional characteristics. It is the prime mediator of vitamin supply to the developing fetus in mammals, including primates. Passive immunoneutralization of the protein terminates pregnancy in rats. Active immunization of rats and bonnet monkeys with avian RCP prevents pregnancy without causing any adverse physiological effects of the mother in terms of her vitamin status, reproductive cycles or reproductive-endocrine profile. Denatured, linearized RCP is more effective in eliciting neutralizing antibodies capable of interfering with embryonic viability either before or during peri-implantation stages. Two defined stretches of sequential epitopes, one located at the N-terminus and the other at the C-terminus of the protein have been identified. Active immunization with either of these epitopes conjugated with diphtheria toxoid curtails pregnancy in rats and monkeys. Immunohistochemical localization of RCP on ovulated oocytes and early embryos shows that the antibodies cause degeneration only of early embryos. RCP is produced intra-testicularly and becomes localized on acrosomal surface of mammalian spermatozoa. Active immunization of male rats and monkeys with denatured RCP markedly reduces fertility by impairing the fertilizing potential of spermatozoa. These findings suggest that RCP, or its defined fragments, could be a novel, first generation vaccine for regulating fertility in both the sexes.

Amino Acid Sequence↗