Antigen-presenting cell–derived complement modulates graft-versus-host disease
Wing-Hong Kwan, … , Miriam Merad, Peter S. Heeger
Wing-Hong Kwan, … , Miriam Merad, Peter S. Heeger
Published May 15, 2012
Citation Information: J Clin Invest. 2012;122(6):2234-2238. https://doi.org/10.1172/JCI61019.
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Brief Report Immunology

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

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Figure 1

TBI causes DC complement upregulation and complement-dependent augmentation of T cell reactivity.

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TBI causes DC complement upregulation and complement-dependent augmentat...
(A) Quantitative PCR for complement components performed on splenic DC mRNA purified from B6 mice before (time 0) or 24 hours after TBI. fB, factor B; fD, factor D. (B) Kinetics of gene expression in splenic DCs or macrophages obtained from untreated or TBI-treated mice. Experiments were performed in triplicate. (C) Representative immunoblot for C3 (and β-actin control) performed on lysates of splenic DCs isolated before or 24 hours after TBI. Quantitative densitometry (n = 3) normalized to β-actin is also shown. (D) Quantitative PCR for DAF and expression of DAF assessed by flow cytometry (inset) on splenic DCs isolated from untreated (solid line) or TBI-treated (24 hours; filled) B6 mice. Each experiment in A–D was repeated twice with similar results. (E) C5a ELISA, performed on supernatants of unstimulated splenic DCs obtained from untreated or TBI-treated (24 hours) B6 mice, pooled from 4 experiments. (F) Representative CSFE dilution plots of B6 T cells mixed with allogeneic H-2d WT or C3/C5-deficient splenic DCs obtained from untreated or TBI-treated mice. (G) Quantification of proliferation (>4 divisions), calculated as the ratio of response to DCs from irradiated mice to that from nonirradiated mice, and expressed as a percentage. Data are representative of 2 different experiments. *P < 0.05.