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

Abstract

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.

• Authors: Wing-Hong Kwan, Daigo Hashimoto, Estela Paz-Artal, Katya Ostrow, Melanie Greter, Hugo Raedler, M Edward Medof, Miriam Merad, Peter S Heeger
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 6 Pg. 2234-8 (Jun 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 22585573 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Complement
• Complement C3a
• Complement C5a

Topics

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