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Title: Factors influencing the efficacy of the immune response to trypanosomiasis
Author: MacAskill, James Anderson
ISNI:       0000 0001 3614 8240
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1981
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A reliable and simple technique for the vivo labelling of trypanosomes with [75Se] methionine was developed. Between 97% and 99% of the radioactivity was protein-bound in the trypanosome and spontaneous elution in vitro was < 10% over 4 hrs. The fate of the labelled trypanosomes after i.v. injection into normal and immune CFLP mice was studied. In the latter the liver was found to be the principal site of trypanosome removal. This finding was further investigated in terms of the respective roles of antibody, macrophage activation and complement in the removal of trypanosomes from the circulation of immune mice. It was found that clearance in such animals was largely accomplished by antibody-dependent hepatic uptake; which at low antibodytitres in passively immunised animals was dependent upon C3. In contrast, at high antibody titres in passively or actively immunised mice, the hepatic uptake was independent of complement. No evidence was found to suggest that intra-vascular lysis or activated macrophages were involved in immune clearance. In studies with 75Se-labelled trypanosome, antibody mediated hepatic uptake could not be demonstrated in mice with acute fulminating T. brucei infections. This was not due to impaired macrophage function but was apparently caused by the inability of antibody production to cope with the massive parasitaemias produced by rapidly replicating infections, so that effective opsonisation of the parasites did not occur. In contrast, a strain of trypanosome which causes a more chronic infection, although initially having a similar doubling time, subsequently switched to a slower one, and thereby allowed antibody to reach levels which permitted effective opsonisation. There was no evidence to suggest that the parasite caused any significant suppression of antibody responses in these acute infections since inoculation with trypanosomes of one stock at the same time as vaccination with irradiated organisms of a second stock, did not prevent the development of antibody to the latter, as measured by the hepatic uptake of radiolabelled parasites. Genetic resistance to T. congolense infections or trypano-tolerance was investigated using a mouse model in which C57B1 mice were able to repeatedly limit the numbers of circulating parasites, while CFLP mice were unable to do so and died with a fulminating parasitaemia. It was found that infected C57B1 mice were able to remove radiolabelled parasites from their circulation, while CFLP mice could not. The immune response, as measured by vitro trypanolytic activity and immunoglobulin levels, was found to be better in C57B1 mice. No evidence was found to suggest that immunosuppression was important in the response to trypanosome antigen, as judged by the ability of chronically infected animals to respond to an irradiated trypanosome vaccine, although immunosuppression was readily demonstrable to sheep red blood cells. Furthermore, activation of the mononuclear phagocytic system or passive immunisation did not significantly alter the response of the majority of susceptible animals to infection. It was concluded that the genetic resistance of C57B1 mice to T. congolense infection was due to the efficacy of their immune response and, in particular, to the ability to maintain high levels of plasma IgM. Parasite-induced immunosuppression has been suggested to be of importance in both the susceptibility of animals to secondary infection and in the response to vaccination. The latter was investigated in T. congolense infected cattle vaccinated against Foot and Mouth Disease virus. It was found that the antibody response of infected cattle to vaccination was consistently lower than non-infected animals. This reduced antibody response was directly related to protective antibody levels by challenging cattle with live virus. The results indicated that vaccinated infected animals were more susceptible to viral challenge than vaccinated control animals. Furthermore, chemotherapy at the time of vaccination partially enhanced protection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Veterinary sciences & veterinary medicine