DESCRIPTION (provided by applicant): The capacity of the pregnancy state to suppress multiple sclerosis (MS) disease attacks is robust; in fact, it is more powerful than any of the currently available treatments for this disease. Preliminary results suggest that pregnancy specific glycoproteins (PSGs), the most abundant placentally derived proteins in the maternal serum, could play an important role in protecting the fetus from immune rejection and at the same time may be critically involved in the suppression of MS disease attacks during pregnancy. PSGs are members of the carcinoembryonic antigen (CEA) family, which in turn belong to the immunoglobulin superfamily of proteins. Recently several PSG family members were cloned and the proteins they encode expressed. Both recombinant human and mouse PSGs were found to induce IL-10 and TGF-beta production by macrophages. The tetraspanin CD9 was recently shown to be the receptor for murine PSG-17 and -19, and is likely the receptor for other PSG family members. In addition to macrophages, dendritic cells and T lymphocytes (both CD4 and CD8) express high levels of CD9 on their surface. We hypothesize that PSGs are involved regulating the maternal immune system during pregnancy by triggering antigen presenting cell production of lL-10 and TGF-beta, which shifts the immune response to Th2 via inhibition of IL-12 synthesis, and inhibition of IFN-gamma production by T cells. The shift in immune responses towards Th2 would likely result in the reduced capacity of myelin specific T cells to induce inflammatory autoimmune disorders such as MS and its animal model experimental autoimmune encephalomyelitis (EAE). During the two years of this exploratory project, we will test this hypothesis by: (1) determining whether recombinant mouse PSG-17 induces a The bias in naive and memory/effector mouse T-cells, and (2) determining whether PSG-17 treated mouse T cells have a reduced capacity to induce passive EAE. This R21 grant proposal represents an entirely novel direction in the effort to unravel the mechanisms governing MS suppression during pregnancy. This study constitutes a first step towards understanding the mechanisms by which maternal immunity is altered by PSGs during pregnancy and may lead to new approaches for the treatment of MS. New directions in basic and clinical research are likely to be discovered and we anticipate the future submission of an RO 1 or program project grant to explore these new frontiers.
|Effective start/end date||8/2/04 → 6/30/07|
- National Institutes of Health: $174,594.00