Browsing by Author "Dehmel, Stefan"

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    Renal allograft rejection in chemokine receptor Ccr1-/-, Ccr5-/- and Ccr1-/-/Ccr5-/- mice and impact of Ccr5 deficiency on macrophage polarization
    (2009) Dehmel, Stefan; Pfizenmaier, Klaus (Prof. Dr.)
    Previous studies showed that loss of the chemokine receptor Ccr1 or Ccr5 has a beneficial effect on survival of cardiac, carotid, corneal and islet allografts in mice. Additionally, human renal allograft recipients homozygous for a null allele of CCR5 (CCR5delta32) experience significantly prolonged allograft survival. To analyze the mechanisms underlying reduced allograft rejection in Ccr1-/- and Ccr5-/- recipient mice, a renal transplantation model was utilized, that allowed the study of the acute (7d) and the clinically more important phase of chronic (42d) allograft rejection. Ccr1-/-/Ccr5-/- mice were included to analyze whether loss of both receptors is accompanied by additional improvements. Reduced graft fibrosis, leukocyte infiltration and improved histopathology were observed in all knock-out groups, but additional improvements in Ccr1-/-/Ccr5-/- recipients were limited to certain aspects at 42d. Ccr1-/- and Ccr5-/- recipients showed significantly diminished mRNA levels of Th1-associated cytokines and chemokines at 7d. Expression of these genes was restored to wildtype levels in Ccr1-/-/Ccr5-/- recipients at 7d explaining the few additional improvements in Ccr1-/-/Ccr5-/- recipients. Ccr1-/- recipients showed Th17-shifted immune responses, while Ccr5-/- recipients exhibited dramatically increased alternative macrophage activation (AMA) at 42d which might explain the beneficial effects on long-term allograft survival observed in CCR5delta32/delta32 human transplant recipients. AMA was also observed in unchallenged spleens and elicited peritoneal macrophage of Ccr5-/- mice indicating a general role for CCR5 in macrophage polarization. Results of bone marrow-derived macrophages suggest that strain differences influence macrophage polarization and that BALB/c allografts favor the induction of AMA in Ccr5-/- macrophage. In conclusion, Ccr1 or Ccr5 deficiency in recipients has beneficial effects on renal allograft rejection though the underlying mechanisms may be different and might lead to the observed ambiguous effects in Ccr1-/-/Ccr5-/- recipients. Furthermore, no indication for redundant functions of CCR1 and CCR5 was found during renal allograft rejection.