Selective elimination of alloreactivity in vitro and in vivo while sparing other T-cell-mediated immune responses.

Selective elimination of alloreactive cells was carried out in the set-up of T-cell-mediated immunotherapy in an effort to gain the benefits of hematopoietic allogeneic transplantation while reducing the risk of GVHD. Low MW chemical compounds were screened for their effect on T-cell-mediated immune responses of murine- and human-derived lymphocytes. Selected compounds were further tested in secondary MLR assays in which sensitization to alloantigens was carried out in vitro, in the presence or absence of a given compound, followed by exposure to related and unrelated alloantigens or T-cell mitogenic stimulation. At a low concentration of <1 µM, a quinazoline derivative named AO#349 [2-(3,4,5-trimethoxyphenyl)-N-p-tolylquinazolin-4-amine], was able to induce 78-90% inhibition of a selective allogeneic response while retaining >92% immune reactivity to unrelated alloantigens and mitogenic stimuli in vitro. Following allogeneic sensitization in the presence of AO#349, elimination of alloreactivity to the priming alloantigens was also proved in a murine model of GVHD: 10 out of 15 sub-lethally irradiated mice inoculated with these sensitized cells were GVHD-free for >200 days. AO#349 was efficient in induction of a selective elimination of alloreactivity and should be considered for clinical application in allogeneic cell-mediated immunotherapy.

Effect of cadmium on bone repair in young rats.

The effect of cadmium (Cd) in drinking water on repair of bone at a site of hole injury to the tibia of young rats was followed using quantitative methods. The rats (3-4 wk old) were given 20 ppm and 200 ppm Cd for 5 wk and compared to a control group. A slight reduction (about 10%) in body weight and water and food consumption was observed in cadmium-exposed rats as compared to control rats. Clinical chemistry tests in the blood and histology of kidney, liver, and bone did not indicate changes related to Cd toxicity. A significant reduction (43%) in alkaline phosphatase (ALP) and tartarate-resistant acid phosphatase (TRAP) (46%) enzymatic activity was observed at 4 and 7 d postinjury respectively, in the site of injury in the rats receiving 200 ppm Cd in drinking water as compared to control rats. Calcium accumulation in the newly formed repair tissue at the site of injury was also significantly reduced (53%) at 13 d postinjury in the Cd-treated (200 ppm) rats as compared to control rats. It is concluded that Cd probably exhibits an effect on the bone repair process as reflected by reduction in ALP activity (osteoblastic cells) and mineralization at the site of injury in the tibia of young rats.