Reproduction of bovine neonatal pancytopenia (BNP) by feeding pooled colostrum reveals variable alloantibody damage to different haematopoietic lineages

Bell, Charlotte; Rocchi, Mara; Dagleish, Mark P.; Melzi, Eleonora; Ballingall, Keith T.; Connelly, Maira; Kerr, Morag G.; Scholes, S. F. E.; Willoughby, Kim

doi:10.1016/j.vetimm.2012.12.002

Cited by 12 publications

(34 citation statements)

References 31 publications

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“…However, the specificity of these alloantibodies for individual MHC I alleles, or quantitative analysis of their functional activity, has not been previously demonstrated. Furthermore it has been suggested that Pregsure might also boost normal pregnancy-induced alloantibodies against paternally-derived MHC antigens [6], which have been detected previously in the sera of healthy cows [15,16].…”

Section: Introductionmentioning

confidence: 86%

“…It is characterised by profound depletion of peripheral leukocytes and thrombocytes and bone marrow trilineage hypoplasia, and is mediated by the ingestion of alloantibodies in colostrum [4][5][6]. BNP has been linked epidemiologically to vaccination of the dams of affected calves with a particular inactivated Bovine Viral Diarrhoea Virus (BVDV) vaccine (Pregsure BVD, Pfizer Animal Health) which incorporates a novel adjuvant formulation [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression

Bell

MacHugh

Connelley

et al. 2015

Vaccine

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Bovine Neonatal Pancytopenia (BNP) is a disease of calves characterised by haematopoietic depletion, mediated by ingestion of alloantibodies in colostrum. It has been linked epidemiologically to vaccination of the dams of affected calves with a particular vaccine (Pregsure) containing a novel adjuvant. Evidence suggests that BNP-alloantibodies are directed against MHC I molecules, induced by contaminant bovine cellular material from Madin-Darby Bovine Kidney (MDBK) cells used in the vaccine's production. We aimed to investigate the specificity of BNP-alloantibody for bovine MHC I alleles, particularly those expressed by MDBK cells, and whether depletion of particular cell types is due to differential MHC I expression levels. A complement-mediated cytotoxicity assay was used to assess functional serum alloantibody titres in BNP-dams, Pregsure-vaccinated dams with healthy calves, cows vaccinated with an alternative product and unvaccinated controls. Alloantibody specificity was investigated using transfected mouse lines expressing the individual MHC I alleles identified from MDBK cells and MHC I-defined bovine leukocyte lines. All BNP-dams and 50% of Pregsure-vaccinated cows were shown to have MDBK-MHC I specific alloantibodies, which cross-reacted to varying degrees with other MHC I genotypes. MHC I expression levels on different blood cell types, assessed by flow cytometry, were found to correlate with levels of alloantibody-mediated damage in vitro and in vivo. Alloantibody-killed bone marrow cells were shown to express higher levels of MHC I than undamaged cells. The results provide evidence that MHC I-specific alloantibodies play a dominant role in the pathogenesis of BNP. Haematopoietic depletion was shown to be dependent on the titre and specificity of alloantibody produced by individual cows and the density of surface MHC I expression by different cell types. Collectively, the results support the hypothesis that MHC I molecules originating from MDBK cells used in vaccine production, coupled with a powerful adjuvant, are responsible for the generation of pathogenic alloantibodies.

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Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression

Bell

MacHugh

Connelley

et al. 2015

Vaccine

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“…Using transfected cell lines, sera from BNP cows were also shown to bind specifically to the MHC I alleles present on MDBK cells and to induce complement-mediated cytotoxicity [11]. Furthermore, in vitro experiments showed that BNP alloantibodies preferentially target cells with high MHC I expression and that this correlates with the hematopoietic cell types affected in BNP [11,12,16] (Figure 2 and Section 2). Using a modified MDBK cell line with no MHC I expression (beta-2-microglobulin knockout) it was confirmed that MHC I is the dominant target of BNP alloantibodies and depending on the BNP dam accounts for 46-91% of the alloantibody specificity [12].…”

Section: Major Histocompatibility Complex Class I Molecules Are the Mmentioning

confidence: 98%

“…Experimental studies reproducing the disease demonstrated that as early as 4 h following ingestion of alloantibodies there is already a 75-95% reduction in peripheral blood lymphocytes, monocytes and neutrophils [16,17]. Detailed analysis of the time-course of hematological and bone marrow alterations indicates initial peripheral thrombocyte and leukocyte destruction followed by damage to hematopoietic precursors, with more profound damage to mononuclear lineages and relative sparing of granulocytes [16]. While there is no damage to peripheral erythrocytes, cases develop a normocytic, normochromic, nonregenerative anemia, presumably reflecting a failure to respond to hemorrhage due to loss of early erythroid precursor cells.…”

Section: Clinical Signs and Pathology Of Bnpmentioning

confidence: 99%

“…Early investigations found that colostrum obtained from cows that had previously given birth to a BNP-affected calf (BNP cows) causes BNP when fed to unrelated newborn calves [15][16][17][18]. Furthermore, serum and colostrum from BNP cows were shown to contain alloantibodies that bind to peripheral blood leukocytes, platelets and bone marrow cells [9,11,12,[18][19][20][21], and intravenous infusion of these antibodies was sufficient to induce the disease [9].…”

Section: Bnp Is An Alloimmune Disease Induced By Antibodies Absorbed mentioning

confidence: 99%

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The risks of using allogeneic cell lines for vaccine production: the example of Bovine Neonatal Pancytopenia

Benedictus

Bell

2016

Expert Review of Vaccines

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Introduction: Bovine neonatal pancytopenia (BNP) is a hemorrhagic disease that emerged in calves across Europe in 2007. Its occurrence is attributed to immunization of the calf's mother with a vaccine produced using an allogeneic cell line. Vaccine-induced alloantibodies specific for major-histocompatibility class I antigens are transferred from the mother to the calf via colostrum, leading to profound depletion of peripheral blood and bone marrow cells that is often fatal. Areas covered: Pubmed and Web of Science were used to search for literature relevant to BNP and the use of allogeneic vaccine cell lines. Following a review of the pathology and pathogenesis of this novel condition, we discuss potential risks associated with the use of allogeneic vaccine cell lines. Expert commentary: Although BNP is associated with a specific vaccine, it highlights safety concerns common to all vaccines produced using allogeneic cell lines. Measures to prevent similar vaccineinduced alloimmune-mediated adverse events in the future are discussed.

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Diseases of the Hemolymphatic and Immune Systems

2017

Veterinary Medicine

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Reproduction of bovine neonatal pancytopenia (BNP) by feeding pooled colostrum reveals variable alloantibody damage to different haematopoietic lineages

Cited by 12 publications

References 31 publications

Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression

Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression

The risks of using allogeneic cell lines for vaccine production: the example of Bovine Neonatal Pancytopenia

Diseases of the Hemolymphatic and Immune Systems

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