Bortezomib attenuates acute graft-vs.-host disease through interfering with host immature dendritic cells

Abstract

To explore the conditions under which proteasome inhibitor bortezomib improves acute graft-vs.-host disease (aGVHD) and the mechanism underlying the differential effects of bortezomib on aGVHD. Murine aGVHD models (C57BL/6→BALB/c) of different severities were set up by infusing with decreasing doses of donor splenocytes (SC). Bortezomib were administered immediately or 6 days after bone marrow transplantation (BMT). Serum levels of tumor necrosis factor-α (TNF-α) and lipopolysaccharide along with the number of donor TNF-α(+) T cells in recipients before intervention were determined. Major histocompatibility complex II expression and interleukin-12 production were analyzed to evaluate the maturation state of host dendritic cells (DCs) before intervention. Phenotypic changes, apoptosis, allogeneic stimulation, and IκBα expression levels in bortezomib-treated mature DCs or immature DCs were analyzed in vitro. Neither early bortezomib (day 0 BMT) administration in a modest (SC 1 × 10(7)) or severe (SC 2 × 10(7)) aGVHD model, nor delayed administration (day +6 BMT) could protect mice form aGVHD. Marked inhibition of aGVHD was observed in a mild aGVHD model (SC 5 × 10(6)) with early intervention. This inhibition correlated with a relatively immature state of host DCs before intervention. Additional in vitro studies showed that, in comparison to mature DCs, bortezomib inhibited phenotypic and functional maturation as well as induced more potent apoptosis in immature DCs through suppression of nuclear factor-κB activity. Manipulating host immature DCs may represent a novel mechanism by which bortezomib improves aGVHD.