Year: 2006
Type: article
Abstract: Bz-423 is a novel 1,4-benzodiazepine with both cytotoxic and cytostatic effects on activated lymphocytes. Bz-423 has been shown to suppress lupus in murine models by eliminating pathogenic lymphocytes without altering normal immune function or overt toxicities. We hypothesized that Bz-423 might enhance the apoptotic deletion of alloreactive donor T cells and therefore reduce graft-versus-host disease (GVHD). We first investigated the effect of Bz-423 on activated T cells in vitro. A 40 μM concentration of Bz-423 induced apoptotic death in >90% of both CD4+ and CD8+ T lymphocytes stimulated with allogeneic dendritic cells (DC) or ConA in the presence of syngeneic DC. Purified resting T cells were significantly less susceptible to Bz-423-induced apoptosis (data not shown). We next examined the effect of Bz-423 in vivo utilizing a well-characterized (Balb/c→B6) murine GVHD model. B6 recipient mice were conditioned with 11 Gy total body irradiation and injected with 5.0 × 106 bone marrow and 4-5.0 × 106 purified T cells from either syngeneic (B6) or allogeneic (Balb/c) donors. In order to model the administration of Bz-423 as a treatment strategy rather than a prevention strategy, animals were not treated for the first seven days after BMT. Beginning 7 days following BMT and continuing for the remainder of the experiment, Bz-423 was administered i.p. at a dose of 60 mg/kg three times weekly. As shown in the table below, treatment with Bz-423 resulted in significantly better day +60 survival (P = .001) and reduced clinical GVHD scores (P < .02) among allogeneic BMT recipients. Bz-423 also reduced GVH-associated immunodeficiency (P = .02) and decreased liver and gut histopathology of GVHD (P = .01). Delay of the onset of treatment to day 14 post-BMT also resulted in a significant survival benefit (P = .03). These data demonstrate that Bz-423 can reverse acute GVHD and induce selective apoptosis of alloreactive donor T cells in this model. Pro-apoptotic benzodiazepines may provide a strategy for the treatment of acute GVHD (Table 1).Tabled 1Syn + BzAllo + vehicleAllo + BzP Value1Calculated at the 95% confidence level, Allo + vehicle vs Allo + Bz-423; 2reported as mean clinical score ± SE; 3reported as mean value ± SD.Treatment onset: day +7 Survival (day 60)100% (n = 9)8% (n = 13)59% (n = 19).001 GVHD clinical score (day 60)21.5 ± 0.26.5 ± 0.03.1 ± 0.4<.02 Pathology (day 74)3 Liver1.3 ± 0.613.7 ± 1.58.3 ± 2.5.01 Intestine3.0 ± 2.021.3 ± 6.010.0 ± 0.8.01 Splenic reconstitution (day 74)3 T cells (×106)20.6 ± 1.81.4 ± 0.023.6 ± 0.4.02 B cells (×106)41.6 ± 12.62.5 ± 0.721.2 ± 15.6.02Treatment onset: day +14 Survival (day 60)100% (n = 3)20% (n = 5)71% (n = 6).031 Calculated at the 95% confidence level, Allo + vehicle vs Allo + Bz-423; 2reported as mean clinical score ± SE; 3reported as mean value ± SD. Open table in a new tab
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2089207135