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Antibody-Mediated Rejection in a Blood Group A-Transgenic Mouse Model of ABO-Incompatible Heart Transplantation.
- Source :
-
Transplantation [Transplantation] 2016 Jun; Vol. 100 (6), pp. 1228-37. - Publication Year :
- 2016
-
Abstract
- Background: ABO-incompatible (ABOi) organ transplantation is performed owing to unremitting donor shortages. Defining mechanisms of antibody-mediated rejection, accommodation, and tolerance of ABOi grafts is limited by lack of a suitable animal model. We report generation and characterization of a murine model to enable study of immunobiology in the setting of ABOi transplantation.<br />Methods: Transgenesis of a construct containing human A1- and H-transferases under control of the ICAM-2 promoter was performed in C57BL/6 (B6) mice. A-transgenic (A-Tg) mice were assessed for A-antigen expression by histology and flow cytometry. B6 wild-type (WT) mice were sensitized with blood group A-human erythrocytes; others received passive anti-A monoclonal antibody and complement after heart transplant. Serum anti-A antibodies were assessed by hemagglutination. "A-into-O" transplantation (major histocompatibility complex syngeneic) was modeled by transplanting hearts from A-Tg mice into sensitized or nonsensitized WT mice. Antibody-mediated rejection was assessed by morphology/immunohistochemistry.<br />Results: A-Tg mice expressed A-antigen on vascular endothelium and other cells including erythrocytes. Antibody-mediated rejection was evident in 15/17 A-Tg grafts in sensitized WT recipients (median titer, 1:512), with 2 showing hyperacute rejection and rapid cessation of graft pulsation. Hyperacute rejection was observed in 8/8 A-Tg grafts after passive transfer of anti-A antibody and complement into nonsensitized recipients. Antibody-mediated rejection was not observed in A-Tg grafts transplanted into nonsensitized mice.<br />Conclusions: A-Tg heart grafts transplanted into WT mice with abundant anti-A antibody manifests characteristic features of antibody-mediated rejection. These findings demonstrate an effective murine model to facilitate study of immunologic features of ABOi transplantation and to improve potential diagnostic and therapeutic strategies.
- Subjects :
- Animals
Antibodies, Monoclonal immunology
Antigens immunology
Antigens, CD genetics
Cell Adhesion Molecules genetics
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Erythrocytes cytology
Erythrocytes immunology
Flow Cytometry
Glycosyltransferases genetics
Graft Survival
Humans
Immune Tolerance
Immunohistochemistry
Immunophenotyping
Mice
Mice, Inbred C57BL
Mice, Transgenic
Promoter Regions, Genetic
ABO Blood-Group System immunology
Blood Group Incompatibility immunology
Graft Rejection
Heart Transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 1534-6080
- Volume :
- 100
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 27120451
- Full Text :
- https://doi.org/10.1097/TP.0000000000001172