Establishment of a Hyperacute Rejection Model of ABO-Incompatible Renal Transplantation in Nonhuman Primates.

Junxiang Wang,Lu Wang,Song Chen,Gang Chen,Lan Zhu,Chi Zhang,Hao Feng,Shan Zhong

doi:10.3389/fimmu.2021.807604

Abstract

The establishment of a hyperacute rejection (HAR) model of ABO-incompatible kidney transplantation (ABOi-KTx) in nonhuman primates is of great significance for the study of the relevant clinical pathophysiological processes and related interventions in ABOi-KTx. In this study, blood group B cynomolgus monkeys were presensitized with synthetic blood group A-antigen conjugated to keyhole limpet hemocyanin (A-KLH) to boost circulating anti-A antibody levels. The serum anti-A antibody levels were measured by flow cytometry using type A human reagent red blood cells (RBCs) or monkey primary renal tubular epithelial cells (RTECs) as target cells. ABOi-KTx was performed in type B monkeys using type A monkeys as donors. After 14 days of A-KLH sensitization, 12 of 16 (75%) type B monkeys had significantly elevated anti-A antibody levels. We found that in order to avoid irregular results in the detection of blood group antibodies by flow cytometry, it was more effective to use RTECs rather than RBCs as target cells. In the absence of presensitization, ABOi-KTx in three monkeys with relatively high levels of natural anti-A antibodies did not produce HAR. However, when four Type B monkeys with significantly increased anti-A antibodies after presensitization were randomly selected as recipients for ABOi-KTx, the allografts in all four monkeys developed HAR with typical pathologic characteristics. Thus, we have successfully established a monkey model of HAR in ABOi-KTx via blood group antigen presensitization, which will be helpful for the further study of rejection, accommodation, and clinical intervention in ABOi-KTx.

Highlights

ABO-incompatible kidney transplantation (ABOi-KTx) is usually contraindicated because of the risk of hyperacute rejection (HAR) mediated by naturally occurring antibodies specific to donor blood group antigens [1]
Since the sera of baboons and macaques regularly contain naturally occurring anti-A and/or anti-B antibodies [11, 13], the A and/ or B antigens expressed on vascular endothelial and epithelial cells can be targets for immune rejection by a recipient [11, 14, 15], and they may exhibit a process of ABO-incompatible rejection similar to that seen in humans
We show that by using monkey primary renal tubular epithelial cells (RTECs) expressing blood group antigen A rather than red blood cells (RBCs) as target cells, the serum levels of anti-blood group A antibodies can more accurately be evaluated by flow cytometry

Summary

Introduction

ABO-incompatible kidney transplantation (ABOi-KTx) is usually contraindicated because of the risk of hyperacute rejection (HAR) mediated by naturally occurring antibodies specific to donor blood group antigens [1]. Nonhuman primates express the ABH-specific antigens of the ABO histo-blood group system on the vascular endothelium, epithelial cells, and exocrine secretions [11]. These ABH antigens are absent from or only weakly expressed on erythrocytes of both Old and New World monkeys [11, 12]. Since the sera of baboons and macaques regularly contain naturally occurring anti-A and/or anti-B antibodies [11, 13], the A and/ or B antigens expressed on vascular endothelial and epithelial cells can be targets for immune rejection by a recipient [11, 14, 15], and they may exhibit a process of ABO-incompatible rejection similar to that seen in humans

Methods

Results

Conclusion