Demonstration of early functional compromise of bone marrow derived hematopoietic progenitor cells during bovine neonatal pancytopenia through in vitro culture of bone marrow biopsies

Abstract

BackgroundBovine neonatal pancytopenia (BNP) is a syndrome characterised by thrombocytopenia associated with marked bone marrow destruction in calves, widely reported since 2007 in several European countries and since 2011 in New Zealand. The disease is epidemiologically associated with the use of an inactivated bovine virus diarrhoea (BVD) vaccine and is currently considered to be caused by absorption of colostral antibody produced by some vaccinated cows (“BNP dams”). Alloantibodies capable of binding to the leukocyte surface have been detected in BNP dams and antibodies recognising bovine MHC class I and β-2-microglobulin have been detected in vaccinated cattle. In this study, calves were challenged with pooled colostrum collected from BNP dams or from non-BNP dams and their bone marrow hematopoietic progenitor cells (HPC) cultured in vitro from sternal biopsies taken at 24 hours and 6 days post-challenge.ResultsClonogenic assay demonstrated that CFU-GEMM (colony forming unit-granulocyte/erythroid/macrophage/megakaryocyte; pluripotential progenitor cell) colony development was compromised from HPCs harvested as early as 24 hour post-challenge. By 6 days post challenge, HPCs harvested from challenged calves failed to develop CFU-E (erythroid) colonies and the development of both CFU-GEMM and CFU-GM (granulocyte/macrophage) was markedly reduced.ConclusionThis study suggests that the bone marrow pathology and clinical signs associated with BNP are related to an insult which compromises the pluripotential progenitor cell within the first 24 hours of life but that this does not initially include all cell types.

Pathogenicity of Bovine Neonatal Pancytopenia-associated vaccine-induced alloantibodies correlates with Major Histocompatibility Complex class I expression

“… 1 reproduced BNP in calves by feeding colostrum from BNP dams and found there was only a transient drop in neutrophil levels in blood, with levels restoring to normal within 12 hours after colostrum ingestion. Furthermore, they showed that in bone marrow, mature cells of the neutrophil, eosinophil and erythroid lineages were less affected, which was confirmed by other studies 9 20 . BNP Ab binding matched the pathology of BNP, with high Ab binding of cells that are affected in BNP such as PBMC and a subset of bone marrow cells, whereas endothelial cells and granulocytes showed very low BNP Ab binding ( Figs 5 and 7 ).…”

Bovine neonatal pancytopenia - Comparative proteomic characterization of two BVD vaccines and the producer cell surface proteome (MDBK)

“…The rapid decrease in the number of platelets and leukocytes in the circulating blood within the first few hours after colostrum intake is most likely directly antibody-mediated and probably not due to bone marrow depletion. Whereas the haematopoietic progenitor cells are compromised in their ability to form colonies as early as 24 hours after uptake of colostral antibodies, the decrease of haematopoietic progenitor cells develops over a longer period of time [6]. Thus, we suspect the antigen or antigens to be located on PBL, platelets and, in regard to the bone marrow depletion, also on haematopoietic progenitor cells of the myeloid and lymphoid lineages.…”

“…Defects in coagulation of platelets, the decline of platelets and thus the low platelet count are the main cause for the multiple haemorrhages leading to the death of affected calves. However, the antigen(s) appear(s) to be also expressed on mature PBL as Assad et al demonstrated binding of colostrum-derived antibodies to several PBL subsets and platelets [3], and further on hematopoietic progenitor cells of the myeloid and lymphoid lineages in the bone marrow, as these are, according to Laming et al, comprised already 24 hours after colostrum intake and show a drastic decline within the first 6 days after colostrum intake [6]. …”

A Functionally Different Immune Phenotype in Cattle Is Associated With Higher Mastitis Incidence

“…These alloantibodies were transmitted to calves, regardless of kin, via the colostrum of these dams (8, 10) and caused bovine neonatal pancytopenia (BNP) (7, 11–13), even years after the vaccine has been taken off the market (14). BNP calves suffered from hemorrhagic diathesis, thrombo and leukocytopenia and bone marrow depletion, which resulted in a deadly bleeding disorder (10, 15, 16). Several authors hypothesized alloimmune reactions against the major histocompatibility complex class I (MHC I) as causal for BNP (17–20).…”