在HLA - A2转基因致敏小鼠模型中，抗CD20抗体可抑制抗HLA抗体的形成。

Anti-CD20 antibody suppresses anti-HLA antibody formation in a HLA-A2 transgenic mouse model of sensitization.

作者信息

Wu Gordon D, He Yao, Chai Ning-ning, Toyoda Mieko, Dunn Robert, Kehry Marilyn R, Klein Andrew S, Jordan Stanley C

机构信息

Comprehensive Transplant Center at Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.

出版信息

Transpl Immunol. 2008 Jul;19(3-4):178-86. doi: 10.1016/j.trim.2008.05.004. Epub 2008 Jun 10.

DOI:10.1016/j.trim.2008.05.004

PMID:18595710

Abstract

BACKGROUND

B cell depletion by anti-CD20 antibody is used in desensitization protocols and for treatment of antibody-mediated rejection (AMR). However, little is known about the efficacy and the mechanism(s) of action.

METHODS

A mouse model of HLA sensitization was used to study the effectiveness of anti-CD20 treatment on B cell depletion and anti-HLA antibody suppression.

RESULTS

Immunization of C57BL/6 mice with skin grafts from a transgenic C57BL.Tg/HLA-A2.1 mouse resulted in robust production of anti-HLA IgM and IgG antibodies, and accelerated rejection of a secondary skin allograft (within 3 days) featured by intragraft IgG and C4d deposition. Both IgM and IgG alloantibodies are specific to HLA-A2 as well as to a panel of class I HLA, including A1, A3, A25, A26, A29, and A30. These alloantibodies were complement-dependently cytotoxic (CDC) against HLA-A2 expressing target cells. Administration of 2 doses of a mouse-anti-mouse CD20 monoclonal antibody significantly reduced the levels of anti-HLA IgG2a antibodies, suppressed serum CDC, and prolonged survival of the secondary skin allografts. Suppression of anti-HLA IgG antibodies was associated with significant depletion of B220(+)/CD5(-) B cells from the blood, the spleen and the bone marrow of the treated animals.

CONCLUSION

Anti-CD20 treatment effectively depletes B220(+)/CD5(-) B cells, resulting in potent suppression of anti-HLA IgG and prolongation of skin graft survival. The data are in support for the use of anti-CD20 antibodies in highly-HLA sensitized patients undergoing desensitization and for the treatment of AMR.

摘要

背景

抗CD20抗体介导的B细胞清除已用于脱敏方案及抗体介导性排斥反应（AMR）的治疗。然而，其疗效及作用机制仍知之甚少。

方法

采用HLA致敏小鼠模型研究抗CD20治疗对B细胞清除及抗HLA抗体抑制的有效性。

结果

用转基因C57BL.Tg/HLA-A2.1小鼠的皮肤移植物免疫C57BL/6小鼠，可导致抗HLA IgM和IgG抗体的大量产生，并加速二次皮肤同种异体移植物的排斥反应（3天内），其特征为移植物内IgG和C4d沉积。IgM和IgG同种异体抗体对HLA-A2以及一组I类HLA具有特异性，包括A1、A3、A25、A26、A29和A30。这些同种异体抗体对表达HLA-A2的靶细胞具有补体依赖性细胞毒性（CDC）。给予两剂小鼠抗小鼠CD20单克隆抗体可显著降低抗HLA IgG2a抗体水平，抑制血清CDC，并延长二次皮肤同种异体移植物的存活时间。抗HLA IgG抗体的抑制与治疗动物血液、脾脏和骨髓中B220(+)/CD5(-) B细胞的显著减少有关。