Antibody-suppressor CD8+ T cells ameliorate antibody-mediated rejection following kidney transplant in mice

Abstract

Abstract Purpose CCR5 KO kidney transplant (KT) mice produce high titer alloantibody (alloAb) associated with severe antibody-mediated rejection (AMR) that reproduces AMR histology observed in human KT recipients. We previously reported the novel alloAb suppressor activity of alloprimed CXCR5+IFNγ+CD8+ T (Tab-supp) cells following hepatocellular transplant in mice. Here, we investigated the biologic impact of alloprimed CD8+ Tab-supp cells and their capacity to suppress alloAb following adoptive cell transfer (ACT) into CCR5 KO KT mice. Methods CCR5 KO (H-2b) mice were transplanted with allogeneic A/J (H-2a) kidneys, and on postoperative day (POD) 5 underwent ACT of alloprimed CD8+ Tab-supp cells (retrieved from C57BL/6 mice alloprimed with A/J alloantigen). A second cohort received concomitant bilateral native nephrectomy, and allograft survival was monitored with serial serum creatinine (>100 μmol/L defines KT graft loss). Untreated CCR5 KO KT mice served as controls. Results CCR5 KO KT mice developed high alloAb titer compared to wild-type (WT) recipients (5,800±700 vs 1,200±100; p=0.0003). ACT significantly inhibited alloAb production by 5-fold (1,200±200; p<0.0001) and POD14 AMR pathology (peritubular capillary margination and C4d deposition, arteritis) in CCR5 KO KT mice (composite histologic score 3.6±1.5 vs 8.4±0.2 in untreated controls; p=0.006). Following ACT, alloAb remained suppressed beyond POD 30, correlating with enhanced allograft survival (MST 52 vs 14 days; p=0.006). Conclusion ACT of CD8+ Tab-supp cells effectively inhibits alloAb production and AMR not only after allogeneic hepatocellular transplant, but also after vascularized solid organ transplant such as in CCR5 KO KT recipients.