Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection

PLoS One. 2016 Feb 29;11(2):e0148881. doi: 10.1371/journal.pone.0148881. eCollection 2016.

Abstract

Background: 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.

Methods: We 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.

Results: qRT-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.

Conclusions: We 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.

MeSH terms

  • Adult
  • Aged
  • Allografts
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Surface / metabolism*
  • CD59 Antigens / metabolism*
  • Complement Pathway, Alternative / genetics
  • Complement Pathway, Alternative / immunology
  • Complement System Proteins / genetics
  • Complement System Proteins / immunology
  • Complement System Proteins / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Rejection / metabolism*
  • Graft Survival / drug effects
  • Graft Survival / genetics
  • Graft Survival / immunology
  • Humans
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Rats
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Antigens, Surface
  • CD59 Antigens
  • Cr1l protein, rat
  • Receptors, Cell Surface
  • Complement System Proteins

Grant support

The authors have no support or funding to report.