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 2

DAF deficiency exacerbates GvHD.

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DAF deficiency exacerbates GvHD. (A–C) GvHD in WT B6 recipients of WT BA...
(A–C) GvHD in WT B6 recipients of WT BALB/c transplants or Daf1–/– B6 recipients of Daf1–/– BALB/c transplants. (A) Survival curves for 10 × 106 or 20 × 106 doses of donor spleen cells. n = 5 per group. (B) Representative H&E-stained bowel tissue (8 days posttransplant) from a separate experiment (5 × 106 donor spleen cells). Scale bars: 50 μm. (C) IFN-γ–producing spleen cells stimulated ex vivo with αCD3/CD28 (day 8 posttransplant). (D) Survival in WT or Daf1–/– B6 recipients transplanted with WT BALB/c BM plus 1 × 106 BALB/c spleen cells. n = 5 per group, repeated with the same results. (E) Clinical GvHD scores in B6 chimeras of allogeneic BALB/c BM transplants. Shown are pooled data from 2 separate experiments (n = 10 per group). (F and G) WT BALB/c mice received B6 WT or Daf1–/– T cell–depleted BM plus 0.5 × 106 B6 WT or Daf1–/– splenocytes. (F) Survival (n = 15 per group, pooled from 3 experiments). (G) Percent skin-infiltrating T cells at 5 weeks, pooled from 2 experiments. *P < 0.05.