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

Abstract

Visual Abstract

Significance Statement 

In a mouse allograft model, the CCL8-CCR8 axis mediated early kidney inflammation through donor kidney resident macrophages. The revealed therapeutic targets could expand the transplantable donor kidney pool and promote kidney allograft longevity.

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.