BACKGROUND AND PURPOSE: Immune events sustaining dendritic cell (DC)-dependent epitope spreading (ES) are of key relevance to the development of relapses during multiple sclerosis (MS). Although no drugs are currently available to target ES, its inhibition would represent a major advancement in MS therapy. Inhibitors of the enzyme PARP-1 afford protection in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). These drugs epigenetically impair antigen presentation by DCs, but whether these drugs affect ES is unknown. Here, we investigated whether short-term treatments with these compounds would impair ES, thereby preventing EAE relapses.
EXPERIMENTAL APPROACH: We used a model of relapsing EAE in SJL mice and also adopted in vivo and ex vivo models of DC-dependent T-cell polarization. The effect of PARP-1 inhibitors on ES was evaluated at the humoral and cellular level.
KEY RESULTS:Short-term treatments with PARP-1 inhibitors during the acute phase of relapsing EAE of mice induced, at later times, more tolerogenic DCs, increased numbers of Treg cells and impairment of ES at the humoral and cellular level. These effects are followed by long-lasting reduction of relapse severity and incidence, although drug treatment had been discontinued for several weeks.
CONCLUSIONS AND IMPLICATIONS: Our data emphasize the therapeutic potential of PARP-1 inhibitors in the treatment of relapsing-remitting MS and additional ES-driven autoimmune disorders.
Epitope spreading is something I have been berated for by the readership recently. It is the process by which damage causes the release of new antigenic entities that create diversity in the immune response. This could drive relapsing disease in MS.
However, whilst I fully accept that this occurs during the disease course, I have problems believing that this is always an orchestrated and predefined course. that totally explains why relapsing MS occurs, As such that the immune response to one epitope say PLP139-151 = response to amino acid sequence of residues at position 139 to 151 protoelipid protein always switches and immune response as PLP178-191 to induce the next relapse and so on. It seems that responses to some epitopes can persist, whilst others develop. How and where do these responses develop?
In the CNS, or in lymph gland tissue which is a site where specialised cells called dendritic cells accumulate and present new antigens to T cells. This could come from the blood following breakdown of myelin or dendritic cells may leave the brain carrying the the myelin. In this study they block and enzyme that affects the antigen presenting function of dendritic cells and relapses stop. So it must be epitope spread that causes relapse or is it?…Do I have to eat humble pie?……again.
Is this drug really stopping epitope spread or some other element of the immune response such as those required for the development of subsequent attacks by the same specificity? However it suggests that there is another avenue for treating RRMS… maybe?