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

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. Breuer, Ginny L. Bumgardner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 CXCR5CD8+ 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.

Original languageEnglish (US)
Pages (from-to)1550-1563
Number of pages14
JournalAmerican Journal of Transplantation
Volume22
Issue number6
DOIs
StatePublished - Jun 2022

Keywords

  • T cell biology
  • alloantibody
  • antibody-mediated (ABMR)
  • chemokine receptors
  • chemokines
  • immune regulation
  • immunobiology
  • kidney transplantation
  • nephrology
  • rejection
  • science
  • translational research

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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