The role of IKK2 in autoreactive lymphocytes: Implications for the understanding of neurologic autoimmune diseases and therapeutic interventions
Zusammenfassung der Projektergebnisse
The goal of this project was to examine the role of the protein kinase IκB-kinase 2 (IKK2) during autoimmune T and B cell responses. IKK2 is a crucial part of the intracellular signaling pathway leading to the activation of NF-κB during inflammatory processes. For these studies we employed conditional IKK2- deficient mice which lack IKK2 specifically in T cells, as well as IKK2-inhibitory compounds. We were able to demonstrate that absence of IKK2 in T cells prevents induction of experimental autoimmune encephalomyelitis (EAE), an animal model of Multiple sclerosis (MS). IKK2-deficiency led to impaired proliferation and cytokine production in encephalitogenic T cells. Interestingly, we could overcome the resistance to EAE by introducing a transgenic pathogenic T cell receptor, pointing towards a role for IKK2 in priming and expansion of autoreactive T cells. Administration of IKK2-inhibitory compounds led to diminished EAE, but could not completely suppress disease. Furthermore, no significant effect of these inhibitors could be detected when they were administered during ongoing disease. However, together with the recently published observation by van Loo et al. (Nat. Immunology 2006), showing that IKK2 deficiency in resident cells of the central nervous system ameliorates EAE, IKK2 remains a promising target for therapeutic intervention in patiens with MS. Furthermore, we started to investigate the relevance of IKK2 in T cells for the development of B-cell dependent autoimmunity. Although T cell-dependent B cell responses seem to be reduced in mice lacking IKK2 in T cells, the question whether IKK2 inhibitiory compounds have an impact on B cell-dependent autoimmune diseases requires further investigation.
