α-Mannan Can Induce Acute Pulmonary Gvhd Dependent On Th17 Subsets

Fungal infection is a serious complication after allogeneic hematopoietic stem cell transplantation but its impacts on graft-versus host disease (aGVHD) remains to be elucidated. α-mannan, one of the main components of fungal cell wall, induces Th17 responses, leading to the elimination of fungi. We therefore hypothesized that fungal infection could modulate GVHD by inducing Th17 responses. Lethally irradiated B6D2F1 (H-2^b/d) mice were injected with 4 x 10⁶ BM and 4 x  10⁶ T cells from MHC-mismatched B6 (H-2^b) donors on day 0. Mice were intraperitoneally injected with 20mg of α-mannan or diluent on day 1. GVHD was severe in mannan-treated allogeneic mice, with 16.7% survival by day30, whereas 83.3% of allogeneic controls survived this period (Table). Histopathologic examination showed significantly exacerbation of GVHD pathology, especially in the lung, of mannan-treated animals than in controls (Table).

A flowcytometric analysis of the spleen and thymus after BMT showed that administration of mannan did not alter donor cell engraftment.

We then evaluated the roles of Th17 in aGVHD of mannan-treated allogeneic models using IL-17-deficient mice as donors. Infusion of IL-17-/- T cells significantly improved GVHD clinical scores (3.5+/- 0.4 vs 5.5+/-0.3 at day14, P<.05), survival (62.5% vs 12.5% at day 30, P<.05) and pulmonary GVHD pathology scores (1.0+/-0.5 vs 7.0+/-1.0 at day21, P<.05) compared with those of mannan-treated controls.

These results suggest that mannan can exacerbate acute GVHD, mainly on pulmonary lesions.Th17 contribute to the development of acute pulmonary GVHD in this model, and that targeting Th17 may therefore represent a promising therapeutic strategy for treating acute pulmonary GVHD.

 

Group	Clinical  GVHD scores on day+14	Survivals on day+30 (%)	Pathology Scores
			Lung	Liver	Intestine
TCD Diluent	1.1±0.8	100	0	0.3±0.4	0.7±0.4
TCD α-mannan	1.2±0.5	100	0	0.7±0.8	0.5±0.5
+T Diluent	3.6±0.7	83.3	1.5±0.7	2.5± 1.2	2.0± 0.8
+T α-mannan	5.7±0.5**	16.7*	7.0±1.0**	4.0± 1.8	2.5± 0.8

TCD: T cell-depleted BMT, +T: T cell-repleted BMT

Data are expressed as mean ± SD.           *P<0.01 vs control, **P<0.05 vs control