Blocking CCL8-CCR8-Mediated Early Allograft Inflammation Improves Kidney Transplant Function

J Am Soc Nephrol. 2022 Oct;33(10):1876-1890. doi: 10.1681/ASN.2022020139. Epub 2022 Aug 16.

Abstract

Background: In kidney transplantation, early allograft inflammation impairs long-term allograft function. However, precise mediators of early kidney allograft inflammation are unclear, making it challenging to design therapeutic interventions.

Methods: We used an allogeneic murine kidney transplant model in which CD45.2 BALB/c kidneys were transplanted to CD45.1 C57BL/6 recipients.

Results: Donor kidney resident macrophages within the allograft expanded rapidly in the first 3 days. During this period, they were also induced to express a high level of Ccl8, which, in turn, promoted recipient monocyte graft infiltration, their differentiation to resident macrophages, and subsequent expression of Ccl8. Enhanced graft infiltration of recipient CCR8+ T cells followed, including CD4, CD8, and γδ T cells. Consequently, blocking CCL8-CCR8 or depleting donor kidney resident macrophages significantly inhibits early allograft immune cell infiltration and promotes superior short-term allograft function.

Conclusions: Targeting the CCL8-CCR8 axis is a promising measure to reduce early kidney allograft inflammation.

Keywords: acute allograft rejection; allografts; inflammation; kidney transplantation; macrophages.

MeSH terms

  • Allografts
  • Animals
  • Graft Rejection
  • Graft Survival
  • Inflammation
  • Kidney Transplantation*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptors, CCR8
  • Transplantation, Homologous

Substances

  • Ccr8 protein, mouse
  • Receptors, CCR8