Hannesdottir, Solveig Gudrun; (2002) Immunosterilisation affecting the functional level of reproductive hormones. Doctoral thesis (Ph.D.), University College London.

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Abstract

Immunosterilisation in males is aimed at inhibiting the production of sperm by eliciting antibodies capable of neutralising the hormones that control spermatogenesis, gonadotrophin-releasing hormone (GnRH), luteinising hormone (LH), follicle- stimulating hormone (FSH) and testosterone. This approach is attractive as an alternative to surgical procedures for companion animals and animals bred for food purposes. Traditional castration can be time consuming and have a risk of infection and mortality. Additionally, immunosterilisation can improve meat and carcass characteristics in cattle, sheep, goats and boars, improve feed efficiency relative to castrates and reduce male aggressive behaviour and male-associated odours. Although immunosterilisation is unlikely to be used for fertility control in humans, there is great interest in using active immunisation against GnRH as means of treating steroid- dependent pathologies such as prostate cancer. The work described in this thesis explores a number of design strategies aimed at producing an improved GnRH-based vaccine for male animals that would cause effective and irreversible sterilisation. Preliminary studies investigating the feasibility of increasing the efficacy of a GnRH vaccine by additionally neutralising another component in the hormonal reproductive pathway, LH, are also presented. GnRH or a GnRH-analogue (GnRH-D6-Lys) were chemically coupled to the carrier molecules tetanus toxoid (TT) and heat shock protein 70 (Hsp70). Alternatively, they were expressed on the surface of bacteriophage particles or synthesised as part of a multiple antigen peptide (MAP) system along with a T helper cell epitope. These different carrier-antigen complexes in either Ribi adjuvant or without active adjuvant (in Freund's incomplete adjuvant) were used to immunise groups of male Balb/c mice repeatedly from 3 weeks of age to 12 weeks of age. Hormone-specific antibodies and serum testosterone levels were measured. In addition, the testes and the accessory reproductive organs were analysed for histological and morphological changes. The level of the testosterone-dependent relaxin-like factor (RLE) mRNA in the testes was also determined. All the groups immunised with GnRH or ovine LH (oLH) conjugates mounted a hormone-specific antibody response, albeit at levels which varied between groups and between individual animals. Animals immunised with GnRH coupled to Hsp70 produced the highest level of specific antibodies. Although serum testosterone levels also varied, signs of testosterone reduction were apparent in histological analysis of the testes, involution of the seminiferous vesicles and prostate gland, and in the RLF expression in the testes following immunisations with most GnRH conjugates. We hypothesised that targeting more than one component of the hormonal pathway (e.g. GnRH and LH) would achieve a more effective immunosterilisation than seen in experiments following immunisation with either one of the hormones alone. We did not, however, see such an additive effect in animals immunised with both GnRH constructs and oLH. Although the animals mounted an appreciable GnRH response, they produced very little oLH-specific IgG compared to mice immunised with oLH alone. These observations are discussed in relation to antigenic competition, carrier determinants and adjuvanticity.

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