Development ofNovel Compounds to Treat Autoimmune and Inflammatory Diseases and Graft Versus Host Reactions

Recently, several new classes of agents were developed to treat patients with malignant diseases. This progress has been based on the advances made in our understanding of critical pathways involved in tumor development and growth. Dysregulated processes leading to uncontrolled regulation of proliferation, cell cycle progression, angiogenesis and apoptosis have provided rational targets for novel therapies. Compounds inhibiting protein phosphorylation and signal transduction like tyrosine kinase inhibitors and inhibitors of proteasomal degradation have demonstrated promising results and were approved for the treatment of patients with malignant diseases. However, based on in vitro and in vivo studies, there is now an emerging evidence that these agents can affect the function and differentiation of normal, non-malignant cells like dendritic cells or T lymphocytes, resulting in immunosuppression. In our review we present recent data on the immune regulatory effects of tyrosine kinase inhibitors like imatinib that is approved to treat chronic myeloid leukemias, or inhibitors of FLT3, currently used to treat acute leukemias, as well as proteasome inhibitors and peroxisome proliferator- activated receptor agonists and discuss their possible role and application in the treatment of autoimmune and graft versus host disease.