Antigen-presenting cell-derived complement modulates graft-versus-host disease

J Clin Invest. 2012 Jun;122(6):2234-8. doi: 10.1172/JCI61019. Epub 2012 May 15.


Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation (allo-HCT) that results from donor allogeneic T cell attack on host tissues. Based on previous work implicating immune cell-derived C3a and C5a as regulators of T cell immunity, we examined the effects of locally produced C3a and C5a on murine T cell-mediated GvHD. We found that total body irradiation, a conditioning regimen required to permit engraftment of allo-HCT, caused upregulation and activation of alternative pathway complement components by recipient APCs. Allo-HCT with decay accelerating factor-null (Daf1(-/-)) host BM and Daf1(-/-) donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organ-infiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell-mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / pathology
  • Complement C3a / genetics
  • Complement C3a / immunology*
  • Complement C5a / genetics
  • Complement C5a / immunology*
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / pathology
  • Graft vs Host Disease / therapy
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Mice
  • Mice, Knockout
  • Receptors, Complement / genetics
  • Receptors, Complement / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Transplantation Conditioning*
  • Transplantation, Homologous
  • Whole-Body Irradiation


  • Receptors, Complement
  • Complement C3a
  • Complement C5a