Antibody responses to xenogenic antigens—a study in the mouse‐to‐rat system

Abstract

Antibodies play a crucial role in the rejection of an organ that has been transplanted between different animal species, i.e. xenotransplantation. In previous work, we have induced a state of humoral tolerance where mouse-to-rat heart grafts continued to beat under ciclosporine A monotherapy. Initially, a combined treatment with ciclosporine A and 15-deoxyspergualin was given. This state of tolerance could not be reproduced when the vascularised heart graft was replaced with a free tissue graft or xenogeneic blood transfusions. To gain further insight into the humoral response against mouse antigens, we studied the antibody production in naive rats and rats challenged with heart transplants, heart cells, mononuclear cells (MNC) and erythrocytes from mice. Rats not challenged with any mouse cells or organs had a moderate amount of antibodies targeted against mouse MNC as well as rosette-forming cells in the spleen targeted against mouse erythrocytes. A challenge with either mouse MNC or erythrocytes lead to immunisation with antibodies of both IgM and IgG subtype directed against both MNC and erythrocytes. Antibody titres against mouse erythrocytes in animals challenged with MNC were not detectable until day 7, whereas antibody titres against mouse MNC in animals challenged with erythrocytes were detected on day 1. Immunisation with mouse erythrocytes raised the titre of rosette-forming cells in the spleen compared with naive rats (P < 0.05). Our data indicate that different xenogeneic antigens in the mouse-to-rat system are shared between heart cells, MNC and erythrocytes; however, the immunisation patterns differ regarding the time when antibodies are first detected.

Recombinant IL-33 prolongs leflunomide-mediated graft survival by reducing IFN-γ and expanding CD4+Foxp3+ T cells in concordant heart transplantation

“…Although IL-33-treated mice have been shown previously to produce more IgG1 and IgM isotype alloantibodies, 12 no statistically differences in IgG1 and IgM levels were seen in our study, which may be related to the function of Lef. 9,28,29 In summary, we have provided in this study the first evidence that IL-33 and Lef combination therapy following mouse-to-rat heart transplantation resulted in significant prolonging of graft survival, which was associated with markedly decreased Th1 cells and IFN-γ, and with increased IL-10 and CD4 + Foxp3 + Tregs. These findings reveal previously undefined functions of IL-33 in xenotransplantation.…”

The free radical scavenger S‐PBN significantly prolongs DSG‐mediated graft survival in experimental xenotransplantation

“…The impact of S‐PBN on the survival of vascularized xenografts was documented. Median graft survival increased from 7 to 14 days when S‐PBN was added to the treatment with DSG, an inhibitor of antibody production that has been extensively used in this small animal model as monotherapy to inhibit AHXR [1,3,4,22].…”