Allogeneic stem cell transplantation (allo-SCT) is potentially curative therapy for a patients suffering from leukemia, lymphoma and multiple myeloma. However, the problems associated with graft-versus-host disease (GVHD) have greatly limited the use of allo-SCT to patients with either an HLA-identical family member or unrelated donor in many transplant centers. As a consequence, the development of new therapies that could prevent or treat GVHD would be a significant advance for patients needing an allo-SCT. Currently, the most common approaches to the prevention of GVHD are either a combination of S-phase active chemotherapy drug, such as methotrexate, and a calcineurin inhibitor or in vivo methods of T cell depletion using antibodies such as Campath -1H. While these approaches can induce T cell tolerance, they do not impact on the generation of proinflammatory cytokines and chemokines that are induced by conditioning therapy and critical to the development of GVHD. As most new therapies for the treatment or prevention of GVHD have arisen from studies in solid organ transplantation, which does not involve inflammation-inducing conditioning therapy, we believe a new approach that focuses specifically on allo-SCT and the complications of conditioning treatment are needed for new agents to be developed. NF-(B is a dimmer composed of Pel proteins and is critical in the induction of T cell tolerance and the generation of over 200 proteins involved in inflammation. Our group has previously found that poorly soluable drugs that target NF-(B have a modest effect on the occurrence of GVHD in animal models, that is greatly limited by the bioavailability of the compound. In this proposal, we have initiated a collaboration with the biotechnology company, TheraLogics, to evaluate the use of two agents licensed by the company in the prevention or treatment of GVHD. NEMO-binding peptides (NBD peptides) block the activation of NF-(B by interfering with the interaction of IKK( with IKK( and IKK(. The chief scientific officer of TheraLogics, Sankar Ghosh Ph.D. has previously found that this peptide can block osteoclastogenesis in murine models mediated by the activation of NF-(B. The second compound we will evaluate will be the IKKp inhibitor, Compound A, that has been licensed by TheraLogics from Bayer. This proposal brings together two extremely experienced investigators in the biology of GVHD, in Drs Serody and Blazar, with scientists at TheraLogics who are experts on the biology of NF-(B in Drs Baldwin and Ghosh. This approach may allow the generation of a number of new compounds that are both more effective and safer for the prevention or treatment of GVHD, which could significantly increase the use of allo-SCT for those individuals who could benefit from this therapy. If these phase I studies are successful, phase II studies will pave the way for clinical trials of this therapy at the University of North Carolina at Chapel Hill. ? ?
