No abstract

The ␤-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophagetropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (M r 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca 2؉ signaling at nanomolar concentrations. The inhibition of ␤-chemokine receptors by TAK-779 appeared to be specific to CCR5 because the compound antagonized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Consequently, TAK-779 displayed highly potent and selective inhibition of R5 HIV-1 replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of R5 HIV-1 clinical isolates as well as a laboratory strain at a concentration of 1.6-3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.

We have established a novel immunotherapeutic approach involving dendritic cells (DCs) with potent immunoregulatory property (designated as regulatory DCs [rDCs]) for acute graft-versus-host disease (GVHD) and leukemia relapse in allogeneic bone marrow (BM) transplantation (BMT) in mice bearing leukemia. rDCs displayed high levels of MHC molecules and extremely low levels of costimulatory molecules. A single injection of rDCs following allogeneic BMT controlled the ability of the transplanted T cells to induce acute GVHD and graft-versus-leukemia (GVL) effect in the recipients bearing leukemia, and that resulted in protection from the lethality caused by acute GVHD and tumor burden. Thus, the use of rDCs may be therapeutically useful for the treatment of acute GVHD and leukemia relapse in allogeneic BMT.