Group 1
Elliot Akama-Garren
Grade 12
Henry M Gunn High School, Palo Alto CA
From Cancer to Autoimmune Disease: Selective Tyrosine Kinase Inhibition for the Treatment of Multiple Sclerosis
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that afflicts approximately one million individuals worldwide. Tyrosine kinases such as ErbB-1 and ErbB-2 are critical in inflammatory regulation and are promising targets for the treatment of cancers and autoimmune diseases, as shown in animal models of rheumatoid arthritis. Upon investigating the potential for tyrosine kinase inhibition to treat experimental autoimmune encephalomyelitis (EAE), a murine model of MS, we found that lapatinib (ErbB-1 and ErbB-2 inhibitor) decreases the severity of EAE. To investigate the differential effects of ErbB-1 versus ErbB-2 inhibition, we examined the potential of AG825 (ErbB-2 inhibitor) and AG1478 (ErbB-1 inhibitor) to treat EAE. In vivo, our data suggest that ErbB-2 inhibition decreases EAE severity, whereas ErbB-1 inhibition has no effect. In vitro, we show that ErbB-2 is differentially transcribed in mouse brain endothelial cells, as compared to macrophages and splenoctyes. We also show that lapatinib did not affect splenocyte proliferation or cytokine production, confirming that ErbB-2 inhibition does not indiscriminately suppress the immune system. In conclusion, in contrast to existing globally immunomodulatory treatments, ErbB-2 inhibition is a novel and potentially promising treatment for MS because of the specific nature of tyrosine kinase expression and the selectivity of pharmacological inhibitors such as AG825 and lapatinib.
