Trägt leukozytäres Acetylcholin zur chronischen Abstoßung von Nierentransplantaten bei?

Abstract

Acute rejection episodes are important risk factors for chronic rejection of renal allografts [1]. We recently demonstrated that monocytes, which accumulate in graft blood vessels during fatal acute rejection, produce acetylcholine (ACH) [2]. In this study, we test the hypothesis that leukocytic ACh contributes to the pathogenesis of chronic renal allograft vasculopathy. Kidneys were transplanted in the allogeneic Fischer 344 to Lewis rat strain combination. Intravascular graft leukocytes were investigated during an acute rejection episode on day 9 post-transplantation and during the process of vascular remodeling on day 42. The expression of the high-affinity choline transporter (CHT1) and of choline acetyltransferase (ChAT) was analyzed by quantitative RT-PCR, by Western blotting, and by immunohistochemistry. Furthermore, renal allograft recipients were treated with Rivastigmine, an ACh-esterase inhibitor, or placebo (n = 5, each). Nine days after isogeneic transplantation, numerous leukocytes accumulated in the blood vessels of the graft (allograft: ~ 140 × 106; isograft: ~ 10 × 106). Leukocyte numbers decreased until day 42 after allogeneic transplantation (~ 40 × 106). However, in comparison to day 42 isografts, their number was still 4-fold higher. The mRNA and protein expression of CHT1 and ChAT was higher in leukocytes from day 9 and day 42 allografts compared to isografts (p ≤ 0.05, je n = 4). Both proteins were predominantly expressed by monocytes. ACh itself was present at about the same level in leukocytes from isografts and allografts but could not be detected in leukocytes from the blood vessels of normal untreated kidneys. Rivastigmine treatment enhanced the development of allograft vasculopathy, which was evaluated by histomorphometry. In summary, our results are in line with our hypothesis that ACh contributes to chronic allograft vasculopathy. Hence, treatment of allograft recipients with antagonists of ACh-receptors may prevent chronic allograft rejection.