Inhibition of terminal complement components in presensitized transplant recipients prevents antibody-mediated rejection leading to long-term graft survival and accommodation

J Immunol. 2007 Oct 1;179(7):4451-63. doi: 10.4049/jimmunol.179.7.4451.

Abstract

Ab-mediated rejection (AMR) remains the primary obstacle in presensitized patients following organ transplantation, as it is refractory to anti-T cell therapy and can lead to early graft loss. Complement plays an important role in the process of AMR. In the present study, a murine model was designed to mimic AMR in presensitized patients. This model was used to evaluate the effect of blocking the fifth complement component (C5) with an anti-C5 mAb on prevention of graft rejection. BALB/c recipients were presensitized with C3H donor skin grafts 7 days before heart transplantation from the same donor strain. Heart grafts, transplanted when circulating anti-donor IgG Abs were at peak levels, were rejected in 3 days. Graft rejection was characterized by microvascular thrombosis and extensive deposition of Ab and complement in the grafts, consistent with AMR. Anti-C5 administration completely blocked terminal complement activity and local C5 deposition, and in combination with cyclosporine and short-term cyclophosphamide treatment, it effectively prevented heart graft rejection. These recipients achieved permanent graft survival for >100 days with normal histology despite the presence of systemic and intragraft anti-donor Abs and complement, suggesting ongoing accommodation. Furthermore, double-transplant experiments demonstrated that immunological alterations in both the graft and the recipient were required for successful graft accommodation to occur. These data suggest that terminal complement blockade with a functionally blocking Ab represents a promising therapeutic approach to prevent AMR in presensitized recipients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology*
  • Complement System Proteins / metabolism*
  • Cyclophosphamide / pharmacology
  • Cyclosporine / pharmacology
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Graft Rejection / prevention & control
  • Graft Survival / immunology*
  • Heart Transplantation / immunology
  • Heart Transplantation / pathology
  • Male
  • Mice
  • Necrosis / immunology
  • Necrosis / pathology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Skin Transplantation / immunology
  • Skin Transplantation / pathology
  • Survival Rate
  • Time Factors
  • Transplantation, Homologous / immunology

Substances

  • Antibodies
  • Proto-Oncogene Proteins c-bcl-2
  • Cyclosporine
  • Cyclophosphamide
  • Complement System Proteins