e. the development of lethal GVHD in a MHC-incompatible BMT model

(B6BALB/c). All BALB/c recipient mice receiving 7·5 Gy of irradiation alone died, but syngeneic BALB/c BM graft rescued all mice. Meanwhile, irradiated mice injected intravenously with B6 BM and spleen cells all died of IWR-1 in vitro lethal GVHD by day 24. In contrast, 73% of similarly treated mice survived when they were placed on oral AZM (Fig. 1a). The changes in body weight (Fig. 1b) and clinical score (Fig. 1c) following transplantation were compatible with the clinical course of lethal GVHD [7, 26]. Flow cytometric analysis found that more than 95% of BM cells at 6 months post-transplantation expressed donor-type H-2b (data selleck products not shown). Thus, AZM did not inhibit engraftment. These findings indicate that AZM attenuates lethal GVHD significantly while permitting long-term engraftment of histoincompatible donor

marrow cells. Tissue samples from GVHD target organs were taken from representative acute GVHD-positive control mice, AZM-treated mice and GVHD-negative syngeneic control mice on day 7 after BMT. Recipients of syngeneic BMT showed no signs of GVHD in their tissues (Fig. 2d,g). Skin from control mice with GVHD [32-34] showed epidermal hyperplasia, basal layer cell injury, severe inflammatory infiltrates with intraepidermal lymphocytes, acidophilic bodies and loss of hair follicles (Fig. 2b). Sirolimus ic50 Such changes were not observed in mice administered AZM (Fig. 2c). The small intestine of control mice with GVHD [7, 26, 27] showed villous atrophy with epithelial apoptosis (Fig. 2e). The liver of those control mice with GVHD showed massive infiltration of mononuclear cells,

mainly in the periportal areas (Fig. 2h). In contrast, such findings were hardly observed in the small intestine and liver of AZM-treated mice (Fig. 2f,i). The acute GVHD pathology scores [27] of the small intestine and liver of AZM-treated recipients were significantly lower than those of corresponding allogeneic control recipients (Fig. 2j,k). These results suggest that administration of AZM attenuates the development of acute GVHD-associated histopathological features in recipients of allogeneic BMT. It has not been known whether AZM affects lymphocyte functions. AZM was administered orally to C57BL/6 (B6) mice, which we used as donors in the murine BMT model, for 3 days. B6 splenic T lymphocytes were examined for their cell numbers and expression of CD69, an early activation marker of T lymphocytes. The number of splenic T lymphocytes was not affected by the AZM treatment (data not shown). After in-vitro stimulation with ConA, CD69 expression by both CD3+ and CD4+ T lymphocytes was up-regulated, but was not affected by AZM treatment (Fig. 3a). Furthermore, AZM did not affect splenic T or B lymphocyte proliferation in response to stimulation with LPS, PWM or Con A (Fig. 3b).