Antibody-Mediated Rejection in a Blood Group A-Transgenic Mouse Model of ABO-Incompatible Heart Transplantation

Autor: Michael Mengel, Peter J. Cowan, S. Wang, J. Pearcey, Nella Fisicaro, A dʼApice, Annetta Kratochvil, Xiaohu Fan, Thuraya Marshall, Kesheng Tao, Lori J. West, Bruce Motyka, Katrina Labonte, Banu Sis
Rok vydání: 2016
Předmět:
Graft Rejection
0301 basic medicine
medicine.medical_specialty
Erythrocytes
medicine.drug_class
medicine.medical_treatment
Enzyme-Linked Immunosorbent Assay
Mice
Transgenic
030230 surgery
Monoclonal antibody
Organ transplantation
ABO Blood-Group System
Immunophenotyping
Mice
03 medical and health sciences
0302 clinical medicine
Antigen
Antigens
CD
ABO blood group system
Immune Tolerance
Animals
Humans
Medicine
Antigens
Promoter Regions
Genetic
Kidney transplantation
Heart transplantation
Transplantation
biology
business.industry
Graft Survival
Antibodies
Monoclonal
Glycosyltransferases
Flow Cytometry
medicine.disease
Immunohistochemistry
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Blood Group Incompatibility
Immunology
biology.protein
Heart Transplantation
Antibody
business
Cell Adhesion Molecules
Zdroj: Transplantation. 100:1228-1237
ISSN: 0041-1337
DOI: 10.1097/tp.0000000000001172
Popis: 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. 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. 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. 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.
Databáze: OpenAIRE
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