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Demasius, Wiebke (2015): Investigations on selected aspects involved in the aetiology of bovine neonatal pancytopenia (BNP). Dissertation, LMU München: Tierärztliche Fakultät



Bovine neonatal pancytopenia (BNP) is a recently emerged alloimmune disease affecting neonatal calves and is strongly associated with the vaccination of dams with a specific inactivated BVDV (Bovine Viral Diarrhoea Virus) vaccine (PregSure® BVD, Pfizer Animal Health). The vaccine comprises a unique adjuvant based on nanoparticles and has been shown to be highly contaminated with cellular proteins of the vaccine producer cell line MDBK (Madin-Darby bovine kidney). The disease is induced by ingestion of colostral alloantibodies of certain PregSure® BVD-vaccinated dams. The hypothesis that BNP-associated alloantibodies might be directed against MHC class I has been proposed. Currently, there are published observations, which contradict this hypothesis and which suggest that the aetiopathogenesis of BNP has not been fully elucidated yet. The aims of this study were to gain more insights into selected factors and underlying mechanisms involved in BNP. The hypothesis of a genetic predisposition for clinical BNP had been proposed in a previous study, but the incidence and potential genetic predisposition for subclinical cases had not been investigated thoroughly before. Therefore, a well-defined cattle resource population was monitored for the incidence, vaccination-associated epidemiological factors and a possible genetic predisposition involved in subclinical BNP. Prominent immune responses to PregSure® BVD vaccination had been reported. This study characterised the immune response to a booster immunisation with PregSure® BVD to obtain insights into the structural and quantitative regulation of the blood transcriptome after vaccination by means of deep sequencing transcriptome analysis. Furthermore, this approach should facilitate insights into the composition of the vaccine. The previously proposed hypothesis of a genetic predisposition required for giving birth to clinical BNP-calves could be confirmed in this study. Our results suggest that a genetic predisposition is potentially also involved in subclinical BNP and additionally required for a significant decrease of thrombocytes and leucocytes in healthy calves without manifestation of clinical or subclinical BNP. In the monitored cattle resource population, the frequency of subclinical BNP did not exceed the frequency of clinical BNP-cases. Further vaccination-associated epidemiological factors, e.g. frequency of vaccination or time point of vaccination relative to parturition, could be excluded. Transcriptome analysis 14 days after booster vaccination with PregSure® BVD highlighted a very coordinated immune response to double-stranded (ds) RNA, although the inactivated vaccine was directed against a single-stranded (ss) RNA BVD virus. The source of the dsRNA is unknown and could have originated from the MDBK cell line, which would underline the contamination of the vaccine with host cells from vaccine production. Alternatively, a dsRNA analogue was potentially added to improve the efficacy of the vaccine. Finally, this study identified a cytokine-like gene, which was highly upregulated across all animals after booster vaccination. This gene has not been described before in any other species. It has to be evaluated if upregulation of this gene is specific for ruminant immune response and linked to PregSure® BVD vaccination. In conclusion, this study confirmed that a genetic predisposition of PregSure® BVD-vaccinated dams is required for producing BNP-colostrum. Therefore, prospective studies will have to consider genetically determined differential immune responses between BNP- and non-BNP-dams towards exogenous proteins combined with very potent adjuvants. Regarding the MHC class I hypothesis, published observations raise the question, if MHC class I should be considered as single causal agent for BNP-associated alloantibodies. This requires further research. Potential allogeneic effects of a whole panel of contaminating proteins contained in the vaccine still have to be validated.