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Immunocontraception of mammalian wildlife: ecological and immunogenetic issues

Australian and New Zealand Conservation Laboratories, School of Biological, Earth and Environmental Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia

Correspondence should be addressed to D W Cooper; Email: des.cooper{at}unsw.edu.au

	Abstract

Top Abstract Introduction Target species Immune responses to self... Variation in response and... Immunogenetic issues Acknowledgements References

 
Immunocontraception involves stimulating immune responses against gametes or reproductive hormones thus preventing conception. The method is being developed for the humane control of pest and overabundant populations of mammalian wildlife. This paper examines three fundamental issues associated with its use: (1) the difficulties of obtaining responses to self-antigens, (2) the likely evolution of genetically based non-response to immunocontraceptive agents, and (3) the possible changes in the array of pathogens possessed by the target species after generations of immunocontraception. Our review of the literature demonstrates that the barriers to an effective immunocontraceptive are at present very basic. Should they be overcome, the effects of immunocontraception on the immunogenetic constitution of wildlife populations through the selection for non-responders must be examined. We suggest that the attempt to use the animal’s own immune system to modulate reproduction may be incompatible with the basic biological function of protection against infectious disease. Research programs on mammalian immunocontraception should involve measurement of the heritability of non-response and an assessment of the likely change in the response of the contracepted population to possible pathogens.

	Introduction

Top Abstract Introduction Target species Immune responses to self... Variation in response and... Immunogenetic issues Acknowledgements References

 
The regulation of human and animal population numbers constitutes a difficult and largely unsolved contemporary problem. In the developed world, steroid contraceptives for humans are both widely used and efficacious. Elsewhere they are too costly. The development of less expensive methods is considered necessary (Aitken et al. 1993). One such method is immunocontraception, i.e. the vaccination against sperm, eggs, or reproductive hormones to prevent either fertilization or the production of gametes. Attempts to design human immunocontraception have a long history (Joshi 1973, Stevens 1975, Basten 1988, Gupta & Talwar 1994). The targets include sperm antigens, oocyte antigens, especially zona pellucida proteins (PZP), gonadotropin riboflavin carrier protein, gonadotropins and gonadotropin releasing hormones (Delves et al. 2002). The most advanced method involves immunization against human chorionic gonadotropin, in reality a method of very early pregnancy termination (Baird 2000). It now seems likely that problems associated with autoimmune disease and variability of response will prevent any widespread use of immunocontraception in humans in the foreseeable future (Rao 2001, Aitken 2002). Women’s health advocates have objected to all forms of immunocontraception because of perceived health risks and the potential for political abuse of the vaccine (Richter 1994). Human male immunocontraceptives have received much less attention and do not appear to be feasible in the near future (Delves et al. 2002).

Immunocontraceptives for wild animals have a different objective than those for humans. Their main aim is to check population growth rather than to contracept particular individuals. If some animals are irreversibly sterilized so much the better whereas such an effect in human medicine would be ethically most undesirable. Immunocontraceptives for animals are ostensibly humane and could potentially be used on the large scale required for wildlife population regulation. Research progress to date has been reviewed in Tyndale-Biscoe (1991, 1994), Barber & Fayrer-Hosken (2000), Barlow (2000), and Cooper & Herbert (2001). Three fundamental questions remain to be addressed: (1) Can sufficiently strong immune responses be provoked against the antigens (immunogens) of gametes or reproductive hormones to cause contraception in a proportion of animals large enough for effective population management? (2) How rapidly will variation in these responses lead to the evolution of failure to respond to the immunocontraceptive agent? (3) What will be the ecological consequences of the likely changes to the immunogenetic constitution of the population as a result of selection for non-responders? In particular, will the endemic pathogens of the species change? There is considerable information which allows us to answer at least in part the first two questions. The third is of fundamental importance but even a preliminary answer is not possible at present.

	Target species

Top Abstract Introduction Target species Immune responses to self... Variation in response and... Immunogenetic issues Acknowledgements References

 
Population control of native and exotic mammals is generally justified by environmental degradation, competition with and predation on native wildlife, conflicts with humans over food production, potential spread of pathogenic infectious diseases and the possibility of population crashes of over-abundant fauna or of wildlife populations near urban areas. Although still in its infancy, immunocontraception is regarded as being more humane than the traditional methods of wildlife population control, such as shooting, trapping, poisoning, or pathogenic agents and its use has strong support from influential animal welfare agencies worldwide (Oogjes 1997, Grandy & Rutberg 2002). Table 1 lists mammalian species for which immunocontraception is being investigated and for which the method could be applied. In all these species, there are at present no completely efficacious, cost-effective, or socially acceptable methods for population regulation available.

	Immune responses to self-antigens

Top Abstract Introduction Target species Immune responses to self... Variation in response and... Immunogenetic issues Acknowledgements References

Jackson et al.(2001) attempted to overcome the problem of lack of immune response to self-antigens in the absence of adjuvant by inserting the cytokine interleukin-4 into mousepox virus with the intention of increasing the humoral response. The virus was then inserted into the mice with the unwelcome outcome that the mice all died very quickly. This work caused alarm because of the possibility that this technology could lead to a method for simple conversion of relatively innocuous viruses into lethal ones, which could be used in biological warfare (Finkel 2001).

Another possible problem with virus-vectored immunocontraception is the potential for the horizontal transfer of the immunocontraceptive gene into viruses affecting other species (Becker 2000). While it may be possible to create genetically modified organisms without adverse effects on the target animals, the effects they might have on related species they come in contact with make any use of this approach questionable.

	Variation in response and genetic change

Top Abstract Introduction Target species Immune responses to self... Variation in response and... Immunogenetic issues Acknowledgements References

 
Variation in response to biocontrol agents is a widespread phenomenon. This variation has frequently led to evolution of a degree of resistance so that the agent is no longer useful. The evolution of resistance to insecticides has been reviewed by McKenzie (1996). He draws a distinction between biocontrol agents with responses within the phenotypic range and those with responses outside the phenotypic range of the target species. An agent which initially kills all members of the target species is acting outside the normal phenotypical range, while one which kills onlya fraction of the population is acting within the normal phenotypical range. He points out that when resistance appears in the former case it is frequently monogenic, while in the latter case a number of different genetic regions are involved, i.e. it is probably multi-factorial. The basic genetic parameter to be estimated in either case is heritability, i.e. the extent to which genetic variation is controlled by genetic as opposed to environmental factors. The relative fertility of the immunocontracepted animals in Table 2 is >10% in 27 out of the 32 data sets. A proportion of non-responders is characteristic of most species. Only three species (Tammar wallaby, Fallow deer and Norway rat) out of 14 had no non-responders (Table 2). Following McKenzie’s (1996) argument, this implies that non-response is likely to be multi-factorial in genetic terms. There are no data which will allow estimates of the heritability of non-response to immunocontraception in any of the species in Table 2. We are unable to predict the rate at which this characteristic will increase in any one of these populations under the selective influence of immunocontraception. However, some idea of the likely change per generation given the initial frequency of non-responders can be found using Falconer’s (1965) model for threshold characters (Table 3). Reproduction is a good example of a threshold character; it is an all-or-none attribute which can be affected by a variety of underlying genetic and environmental factors. If heritabilities are high, rapid selection occurs. This is shown by the high percentage of non-responders that occur within one generation (Table 3).

Zoo animals are convenient for immunocontraception studies of wild species, because of their long-term accessibility, although the small numbers usually available make controls hard to find. This is illustrated by an investigation involving 27 females from 10 felid species. Immunization with PZP and Freund’s Complete Adjuvant gave several kinds of adverse reaction but no convincing evidence of an effect upon fertility (Harrenstien et al. 2004).

Delves & Roitt (2005) review attempts to immunocontracept mammals and conclude that GnRH is the most promising target, because of its evolutionary conserved sequence.

	Immunogenetic issues

Top Abstract Introduction Target species Immune responses to self... Variation in response and... Immunogenetic issues Acknowledgements References

 
Infectious diseases are assumed to be one of the main classes of selective forces which act upon genes controlling immune responses (Klein et al. 1993). Immunocontraceptive agents also have the potential to influence the genetic constitution of a population with respect to the ability to mount immune responses. The two are similar in that pathogens which cause plagues and immunocontraceptive agents are both capable of exerting very strong selective pressure with the potential for rapid genetic change. However, they differ in two important respects. First, most pathogens are cellular and antigenically more complex than most immunocontraceptive agents, which consist of one or a few proteins and in some cases associated carbohydrate. Second, they have opposite directions of selection; resistance to a pathogen involves a positive response, whereas resistance to an immunocontraceptive involves non-response. The consequences of this kind of selection imposed by an immunocontraceptive agent require study. It seems likely that it will alter the immunogenetic constitution of the target species. The existence of genes governing response to pathogens is well documented in humans for malaria (Hill 2001), tuberculosis (Blackwell 1998, Bellamy 2003), and HIV (McNicholl & Cuenco 1999, Carrington & O’Brien 2003). Relevant examples are found in New Zealand Red Deer in which susceptibility to tuberculosis has high heritability (Mackintosh et al. 2000) and in the NRAMP1 association with the human response to leishmaniasis (Bucheton et al. 2003). The complexities of the co-evolution of pathogens and hosts and its biomedical significance are beginning to be unraveled (Woolhouse et al. 2002). Both experimental (Lively & Dybdahl 2000) and theoretical analyses (e.g. Nowak & May 1994) point to the inherent difficulties of prediction of the course of these interactions. Prediction and detection of the ecopathological consequences of the use of immunocontraception of wild animals will also be made difficult by the spread of emerging infectious diseases as a result of human activity (Daszak et al. 2000).

The effect of immunocontraception upon genetic diversity could be significant. There is the possibility that restriction of breeding to a small group of animals which are closely related will result in localized inbreeding. This will be especially likely if their capacity to resist the immunocontraceptive is the result of shared uncommon genotype. Acevedo-Whitehouse et al.(2003) have shown that in California sea lions, inbreeding is associated with a wide range of diseases. They suggest that inbred individuals could act disproportionally as reservoirs of infectious agents.

Selection based upon immune responses could be on one of two parts of the genome: the MHC (major histocompatability complex) region which governs responses to specific immunogens, or other genes, e.g. NRAMP which govern the functioning of the immune system in general (Bellamy 1999). The tightly linked MHC genes and the resultant linkage disequilibrium mean that selection on one gene will result in changes in gene frequencies at other loci. This could either raise or lower susceptibility to other pathogens. Understanding of the non-MHC genetic component of variability of the immune response is much less advanced than for the MHC component. This understanding is needed to attempt any predictions concerning immunocontraception-based selection.

Experimental approaches to this question have until now been very difficult. The existence of genetic maps of some wild animals (e.g. Tammar wallaby (Zenger et al. 2002)) may now allow a genomic approach, in which whole genome DNA typing may allow the identification of changes in gene frequency which accompany the application of immunocontraception or a pathogen, through comparing treated and control populations. A concomitant survey of pathogens in the two groups may identify susceptibility regions, whose existence could be further tested in lab-based investigation. The genome would thus be assayed for these genes, and test the extent to which the same genes are involved in responses to different pathogens and to immunocontraception.

A good model system to address these questions is wildlife tuberculosis which is of economic significance in several countries, e.g. Britain (Delahay et al. 2002), New Zealand (Buddle et al. 2002), and the United States (Palmer et al. 2002). Considerable information on the genetic control of response to mycobacterial antigens is available (North & Medina 1998, Kramnik et al. 2000, Bellamy 2003). The possibility of obtaining results relevant to human mycobacterial susceptibility may also encourage use of this system.

We conclude that attempting to use the immunological system to modulate reproduction could be incompatible with the basic biological function of resisting pathogens. We have not discussed some of the practical issues. For example, all fertility control methods have the problem of delivery of the control agent. Highly valued animals must be treated without harming them. When this is the case, fertility control methods with fewer concomitant problems, such as surgical sterilization or the use of steroids or gonadotropin-based hormones, would be competitive with immunocontraception (Cooper & Herbert 2001).

	Acknowledgements

Top Abstract Introduction Target species Immune responses to self... Variation in response and... Immunogenetic issues Acknowledgements References

 
We acknowledge helpful comments from John Aitken, Tony Basten, Kathy Belov, David Briscoe, Bryce Buddle, Margaret Carrington, Charles Daugherty, Dick Frankham, Cathy Herbert, John McKenzie, Bill Sherwin, Jim Shields, Roger Short, and Kyall Zenger. Our research on population control in koalas and kangaroos is supported by the Australian Research Council grant LPO560344. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

	Footnotes

 
Received 21 May 2006
First decision 22 June 2006
Revised manuscript received 30 July 2006
Accepted 10 October 2006

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