Azzam A. Maghazachi
College of Medicine, University of Sharjah, Sharjah, UAE
Multiple Sclerosis (MS) is an autoimmune disease. Natural killer (NK) cells play crucial roles in ameliorating/exacerbating this autoimmune disease. We reported a new mechanism of action for the drug Copaxone (TEVA Inc.) upon treating multiple sclerosis (MS) patients. NK cells isolated from those patients lysed both immature (i) and mature (m) dendritic cells (DCs) isolated from the same patients. These results were based on previous findings showing that Copaxone ameliorated experimental autoimmune encephalomyelitis (EAE) in mice, corroborated with isolating NK cells that killed both iDCs and mDCs. Similarly, Vitamin D3 or FTY720 (Gilenya, Novartis) augmented IL-2-activated NK cells lysis of tumor cells, iDCs and mDCs. Recently we observed that dimethyl fumarate (Tecfidera, Biogen) and its metabolite monomethyl fumarate (MMF) also augmented NK cell lysis of both immature and mature DCs. These observations demonstrate that drugs used to treat MS patients activate NK cells to lyse antigen-presenting cells and consequently, impede autoreactive T cell activation. Intriguingly, it is safe to conclude that most, if not, all drugs used to treat MS patients have a common function, i.e., enhancing NK cell lysis of DCs. Therefore, we suggest that this method can be used as a screening tool to test any new drug before more efforts and money are put into investigating newly developed MS drugs. Consequently, we utilized this principle to examine the ability of newly generated antibodies that may have potential as drugs to treat MS/EAE disease. In collaboration with Dr. Wahib Mahana (University of Paris), several ascites were examined for their effects on NK cell lysis of DCs. We observed that one of nine ascites examined (ascites #2) augmented NK cell killing of iDCs, an activity that was comparable or even higher than the effect of GA. Such knowledge was used to investigate the plausibility of using this ascites to treat mice with EAE. Intriguingly, this ascites ameliorated EAE clinical score in these mice during the 50 days monitoring of EAE clinical score. A humanized antibody has been recently generated of this ascites and we will examine in details the potential use of this antibody to treat EAE mice and eventually MS patients.
The other part of this talk will focus on novel cell types discovered by my group, called NK17/NK1 cells. These cells are abundant in the cerebrospinal fluid (CSF) of MS patients. In addition, they secrete two detrimental cytokines for MS, namely IL-17 and IFN-. It is therefore hypothesized that they may exacerbate MS/EAE disease. We plan to generate monoclonal antibodies against these cells. These antibodies could be potential biomarker for this disease. Of note, there are currently few, if any, biomarkers for MS. Further, these antibodies could be great potential as novel therapeutic modality for MS.