CpG ODN–mediated GVHD acceleration is independent of host IL-6, IL-12, and host NK cells, but is dependent on host IFNγ; a TLR7/8 agonist also increased GVHD. CpG ODNs were given intraperitoneally to cohorts of mice on d0, d7, d14, d21, and d28 (100 μg/dose). Recipients were lethally irradiated on d−1. (A) B6 IL-6^−/− mice were given BALB/c BM and splenocytes (5 × 10⁶). n = 8 per group, P < .001. (B) B6 IL-12^−/− mice were given BALB/c BM and splenocytes (15 × 10⁶). n = 8 per group, P = .003. (C) B6 IFNγ^−/− mice were given BALB/c BM and 2 × 10⁶ or 5 × 10⁶ splenocytes. n = 8 per group, P ≥ .273. (D) B6 IFNγ/IL-12^−/− mice were given BALB/c BM and splenocytes (5 × 10⁶). n = 6 per group, P = .213. (E,F) NK cell–depleted B6 mice were given BALB/c BM and splenocytes. (E) 5 × 10⁶, P = .041. (F) 2.5 × 10⁶, P = .005; n = 8 per group. (G) B6 mice were given BALB/c BM and splenocytes (5 × 10⁶), and 3M-011 or drug vehicle was given subcutaneously to cohorts of mice every other day for 4 weeks starting d0. n = 10 per group, P = .006. Data were reproduced in a second experiment.