Mechanism of immune tolerance induction in antigen-specific human autoimmune disease.

Abstract

Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system and is considered to be a T-cell mediated autoimmune disease. The “ideal” method in treating MS would be an antigen-specific therapy that does not require generalized immunosuppression. To date there are no definitive treatments for MS but there are several licensed therapies such as -interferon. Unfortunately the effect of interferon (IFN) is reduced by the development of neutralizing antibodies (NAbs) in up to 35% of MS patients within two years of starting treatment. An immunization schedule was developed in the BALB/c mice by subcutaneous administration of recombinant human IFN, and this resulted in development of high incidence of NAbs to the protein in the BALB/c model termed “NAbs model”. The mechanism of NAbs formation in this model is believed to be similar to that observed in IFN-treated MS patients with NAbs, which is as a result of an immune response to the protein. We elected to study NAbs in the context of IFN rather than MS directly to investigate the effects of antigen-specific tolerization strategies on the outcome of NAbs and indirectly on the outcome of IFN treatment in MS disease. The depletion of the immune cells triggers a reconstitution program that leads to renewal of the immune cell repertoire. Tolerance can be induced by intravenous administration of a protein. Within this window of reconstitution following depletion, it is hoped that the immune system can be manipulated to tolerate an otherwise foreign protein (human recombinant IFN). The tolerance strategy employed in this project was immune cell depletion using antibodies and mitoxantrone, followed by intravenous re-introduction of rhIFN. Tolerance was successfully induced in the NAbs model by intravenous administration of rhIFN, and further enhanced by immune cell depletion prior to intravenous administration of rhIFN. The BALB/c “NAbs model” offers a suitable model for use in investigating induction of tolerance to rhIFN following the formation of NAbs to the protein. The antigen of interest is known and the time to NAbs formation is also known. Tolerance induction can be monitored and investigated in this model.