Several studies suggested that activation of the alternative pathway (AP) of complement participates in kidney ischemia/reperfusion (I/R) injury. In mouse models of renal artery clamping, deficiency of Complement Factor B (CFB), an essential protein of the AP, limited kidney injury and dysfunction. CFB is released in blood by hepatocytes but it is also produced by immune cells including T cells and antigen-presenting-cells.
The aim of this study was to evaluate the effect of CFB deficiency in the recipient on I/R injury and graft survival in a model of kidney transplantation (tx) in mice.
CFB-/- mice (B6, H-2Kb, n=8) or wild-type (wt) B6 mice (n=10) were transplanted with kidneys from Balb/c (H-2Kd) donors undergoing 20 min cold ischemia. Graft survival and function (by blood urea nitrogen, BUN, levels) were monitored. Anti-donor alloreactivity (by IFNΓ ELISPOT and 3H-thymidine uptake in mixed-lymphocyte-reaction, MLR) was tested in naÏve (CFB-/- and wt) mice and in long-term surviving tx mice.
CFB-/- recipients were protected from early I/R-induced graft dysfunction, as documented by lower BUN levels at 24 hr post-tx vs wt recipients (56±7 vs. 111±7 mg/dl, P<0.05). This finding associated with better graft survival in CFB-/- (median=>60 days) than in wt recipients (median=21 days; P<0.05). In CFB-/- mice with long-term graft survival (>60 days) both the frequency of donor reactive IFNΓ-producing T cells and anti-donor MLR proliferation were lower (P<0.05) than in naÏve wt mice. The latter finding was not due to an intrinsic lower CFB-/- T cell alloreactivity since T cell response in CFB-/- mice before transplant did not differ from wt.
In conclusion, absence of AP activation protected the kidney graft from I/R injury and induced better graft survival and anti-donor T cell hyporesponse. We hypothesize that in CFB-/-deficient recipients, protection from I/R prevented innate immune system activation which leads to diminished adaptive T-cell immune response.
To cite this abstract in AMA style:Cavinato R, Azzollini N, Casiraghi F, Todeschini M, Aiello S, Remuzzi G, Noris M. Role of the Alternative Pathway of Complement in Ischemia/Reperfusion and Chronic Graft Injury in a Mouse Model of Kidney Allograft [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/role-of-the-alternative-pathway-of-complement-in-ischemiareperfusion-and-chronic-graft-injury-in-a-mouse-model-of-kidney-allograft/. Accessed October 25, 2020.
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