Postnatal xenogeneic B-cell tolerance in swine following in utero intraportal antigen exposure.

PMID 26314946


The objective of this study was to investigate the humoral immune response to xenogeneic antigens administered during the fetal state utilizing a baboon-to-pig model. Nine fetuses from an alpha-1,3-galactosyltransferase gene knockout (GalT-KO) MGH-miniature swine sow underwent transuterine ultrasound-guided intraportal injection of T-cell depleted baboon bone marrow (B-BM) at mid-gestation. Two juvenile GalT-KO swine undergoing direct B-BM intraportal injection were used as controls. Postnatal humoral tolerance was induced in the long-term surviving piglets as demonstrated by the absence of any antibody response to baboon donor cells. In addition, a second intraportal B-BM administration at 2.5 months post-birth led to no antibody formation despite re-exposure to xenogeneic antigens. This B-cell unresponsiveness was abrogated only when the animal was exposed subcutaneously to third-party xenogeneic and allogeneic antigens, suggesting that the previously achieved humoral non-responsiveness was donor specific. In comparison, the two juvenile GalT-KO control swine demonstrated increasing anti-baboon IgM and IgG levels following intraportal injection. In summary, xenogeneic B-cell tolerance was induced through in utero intraportal exposure to donor cells and this tolerance persisted following postnatal rechallenge with donor B-BM, but was lost on exposure to third-party antigen, possibly as a result of cross-reactive antibody formation.