Antibody-suppressor CXCR5+CD8+ T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice

• DOI: 10.1111/ajt.16988
• Publication Date: 2022-02-03T17:43:48Z
• Authors: Jason M. Zimmerer; Jing L. Han; Chelsea M. Peterson; Qiang Zeng; Bryce A. Ringwald; Clarissa Cassol; Sachi Chaudhari; Madison Hart; Jessica Hemminger; Anjali Satoskar; Mahmoud Abdel-Rasoul; Jiao-Jing Wang; Robert T. Warren; Zheng J. Zhang; Christopher K. Br...; Ginny L. Bumgardner
• Keywords: Graft Rejection; Mice, Inbred C57BL; Mice, Knockout; 0301 basic medicine; Mice; 0303 health sciences; 03 medical and health sciences; 0302 clinical medicine; Isoantibodies; Immunoglobulin G; Animals; CD8-Positive T-Lymphocytes; Kidney Transplantation

CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2b ) were transplanted with A/J kidneys (H-2a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+ CD8+ T cells and CD8-mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+ CD8+ T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5+ CD8+ T cells (but not alloprimed CXCR5- CD8+ or third-party primed CXCR5+ CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+ CD8+ T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.