The role of IKK2 in autoreactive lymphocytes: Implications for the understanding of neurologic autoimmune diseases and therapeutic interventions

Experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myasthenia gravis (EAMG) are animal models for the human neurologic autoimmune diseases multiple sclerosis and myasthenia gravis, respectively. The pathophysiology of EAE is characterized by a T-cell-mediated cellular immune response, while T-cell-dependent B-cell-responses are predominant in EAMG. Intracellular signalling through nuclear-factor kB (NF-kB) is an important pathway in autoimmune responses, as shown in human diseases as well as in animal models for autoimmunity. One of the key regulatory elements in activation of NF-kB is the IKK complex which contains the protein kinase IKK2. We will study the in vitro and in vivo effects of IKK2deficiency in T-cells on the immune responses during EAE and EAMG using conditional gene targeted mice. Furthermore, we will assess the therapeutic value of IKK inhibition by testing the effect of an IKK specific inhibitory compound, PS-1145, on the disease course of EAE and EAMG. These studies will contribute to the understanding of disease processes as well as to the evaluation of new potential targets in the treatment of multiple sclerosis and myasthenia gravis.