Abstract
BackgroundThe association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts.MethodsWe prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR) and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP) by immunohistochemical staining in human renal grafts and their clinical course.ResultsqRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate.ConclusionsWe conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR.
Highlights
Results quantitative real-time PCR (qRT-PCR) results showed that the expression of complement regulatory proteins (Cregs), CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model
When anti-Crry and antiCD59 monoclonal antibodies (mAbs) were administered to the allograft, the survival period for each group was PLOS ONE | DOI:10.1371/journal.pone
We conclude that the expression of Cregs in allografts is connected with acute T cell mediated rejection (ATCMR)
Summary
It is known that the classical pathway (CP) of complement participates in antibody mediated rejection (ABMR) and C4d, a metabolite formed by CP activation, is deposited in peritubular capillaries (PTC) over a period of time. Acute T-cell mediated rejection (ATCMR) has been considered to be associated with the activation of complement to a lesser extent. Some studies reported a significant negative impact on the locally synthesized complement components in grafts in ATCMR. Serinsoz et al reported an increased C3 expression in both ATCMR and ABMR, and Pratt et al reported the locally synthesized C3 is eliminated using a C3-/- mouse, resulting in a modulated renal allograft rejection and regulated T cell responses [2, 3]. The association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts
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