Immunomodulatory effects of Staphylococcal aureus Protein A / Immunoglobulin G complexes and their potential as a therapeutic for the treatment of osteolytic bone disease
Final Report Abstract
In health, approximately 10% of the bone is remodeled every year by the interplay of bone forming cells and bone eating cells. Multiple Myeloma (MM) is a cancer of the antibody-producing cells in the bone marrow. In MM bone remodeling is imbalanced causing destructive bone erosions associated with severe bone pain, fractures and osteoporosis. The association of bone disease with MM can be explained by different players leading to increased numbers and activity of the bone eating cells. The main culprit is the myeloma cell, which drives the excessive maturation of bone eating cells. The purpose of this study was to find out if we could interfere with this interaction between myeloma cells and bone eating cells to inhibit bone erosions. To do this we set up an ex vivo cell culture system with primary clinical tissue directly obtained from MM patients, which models the pathology of disease. The harvested cells were processed in tissue culture and analysed in various different ways to assess their phenotypic and functional features. We could show that in our hands cancerous MM cells drove the maturation of bone eating cells. To inhibit the increased numbers of bone eating cells caused by the presence of MM cells, we tested the effect of small immune-complexes of immunoglobulins in our ex vivo cell culture system. These complexes are formed by an immunoglobulin-binding bacterial protein, namely protein A from Staphylococcus aureus, and human immunoglobulin G. Previous work from our laboratory had already confirmed the inhibitory effect of this substance on bone eating cells in the context of an autoimmune disease linked to bone erosions. Importantly, in this study we demonstrated that the small immune-complexes were also able to substantially block maturation of bone eating cells driven by the MM cells. Furthermore, the biological impact of the treatment was not restricted to a block in bone eating cell maturation alone but also had a significant impact on other aspects of tumor biology, as MM cell survival is partially dependent on the presence of bone eating cells. Since the treatment with small immune-complexes decreased the number of bone eating cells, this treatment indirectly reduced survival of cancerous MM cells. Thus supporting the idea that small immune-complexes might be a potentially novel therapeutic treatment for multiple myeloma. Currently ongoing research in the host lab will focus on the effect of small immune-complexes on other bone erosion-inducing cancers and the translation of this therapy to the clinic.
Publications
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(2011) Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice. Arthritis Rheum. 63(12): 3897-907
MacLellan, LM., Montgomery, J., Sugiyama, F., Kitson, SM., Thümmler, K., Silverman, GJ., Beers, SA., Nibbs, RJ., McInnes, IB., Goodyear, CS.
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(2012) Osteoclastic inhibitory properties of small immunoglobulin complexes and their potential as a therapeutic for the treatment of osteolytic bone disease in multiple. European Hematology Association meeting, Amsterdam, Netherlands
Thümmler, K., Kitson, SM., Cody, NMD., Soutar, R., Goodyear, CS.
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(2012) Osteoclastic inhibitory properties of small immunoglobulin complexes and their potential as a therapeutic for the treatment of osteolytic bone disease. European Congress of Immunology, Glasgow, UK
Thümmler, K., Kitson, SM., Soutar, R., Goodyear, CS.
