Heme-oxygenase-1 in host tissues prevents visceral GVHD by regulating donor T cell expansion. (169.24)

Abstract Heme oxygenase-1 (HO-1), a ubiquitously expressed enzyme that degrades heme, has anti-inflammatory, anti-apoptotic and anti-proliferative actions yet its role in alloreactivity is unclear. Previously we demonstrated that HO-1 mRNA levels were elevated in recipient tissues of IFNγR-/- animals resistant to acute GVHD of the GI tract. Here we demonstrate that HO-1 expression in host tissues is critical for the suppression of acute GVHD as B6.HO-1-/- recipients of allogeneic BALB/c.WT grafts developed severe acute GVHD with rapid mortality (0% survival at d10) while WT mice survived longer term (median survival 42d). This was T cell mediated since mice transplanted with T cell depleted grafts showed no evidence of acute GVHD. Histological analysis revealed B6.HO-1-/- recipients developed severe acute GVHD of the GI tract and liver. TNF and IFNγ were elevated in the sera of B6.HO-1-/- recipients and systemic IFNγ but not TNF neutralization prevented hyperacute gut GVHD. The transplantation of grafts containing luciferase+ donor T cells demonstrated increased bioluminence signals in the mesenteric lymph node, spleen and GI tract of HO-1-/- recipients. Furthermore, the absolute number of donor CD4+ and CD8+ T cells co-producing the pro-inflammatory cytokines TNF and IFNγ were increased early after BMT in the lymph nodes of B6.HO-1-/- recipients, demonstrating that HO-1 within recipient tissue controls the acquisition and expansion of donor T cell effector function after BMT.