NF-{kappa}B as a target for the prevention of graft versus host disease: comparative efficacy of bortezomib and PS-1145.
Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR.
Blood. 2005 Sep 20; [Epub ahead of print]
Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI, USA; Departments of Medicine and Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.
NF-kappaB is a transcription factor that controls expression of a number of genes that are important for mediating immune and inflammatory responses. In this study, we examined whether bortezomib and PS-1145, which both inhibit NF-kappaB, could protect mice from lethal graft versus host disease (GVHD) which is characterized by immune activation and proinflammatory cytokine production. When administered within the first two days post-transplantation, both bortezomib and PS-1145 protected mice from fatal GVHD, did not compromise donor engraftment, and effected a marked reduction in the levels of serum cytokines that are normally increased during GVHD. Extending the course of bortezomib administration or delaying the initiation of this agent for as little as three days post-BMT, however, significantly exacerbated GVHD-dependent mortality due to severe pathological damage in the colon. In contrast, prolonged administration of PS-1145, which in contrast to bortezomib is a selective inhibitor of NF-kappaB, caused no early toxicity and resulted in more complete protection than observed with an abbreviated PS-1145 treatment schedule. These results confirm a critical role for NF-kappaB in the pathophysiology of GVHD and indicate that targeted inhibition of NF-kappaB may have a superior therapeutic index and constitute a viable therapeutic approach to reduce GVHD severity. |
