Approximately 25% of patients with monoclonal gammopathy of undetermined significance (MGUS) will eventually develop multiple myeloma (MM) or a related plasma cell dyscrasia. The molecular and cellular changes that occur in the clonal plasma cell in the progression of MGUS to myeloma are currently unknown. Interleukin-1 (IL-1) and interleukin-6 (IL-6) appear to play a dominant role in the pathogenesis of myeloma since IL-1 has prominent osteoclast activating factor activity and IL-6 is a growth factor for myeloma cells. We hypothesize that genetic differences exist between MGUS and MM which can be differentiated by molecular techniques and that aberrant expression of cytokines is responsible for the progression of MGUS to active myeloma. We have recently demonstrated the existence of a novel IL-6R mRNA in myeloma cells that encodes a soluble form of the IL-6R (sIL- 6R). Although the function of soluble receptors in vivo is unknown, they have been shown to be useful as potent immunomodulators of their respective cytokines. We further hypothesize that a mutant sIL-6R construct that can inhibit the biologic activity of IL-6 may be useful therapeutically in patients with active myeloma. To test these hypotheses we propose to: 1) determine the levels of expression of IL-1beta and IL-6 mRNA in bone marrow samples from patients with MGUS and active myeloma using flow cytometry to enrich for monoclonal plasma cells followed by reverse transcriptase/ polymerase chain reaction (RT/PCR). Cells expressing IL-1-beta will be identified morphologically using in situ hybridization techniques; 2) measure proliferation of marrow monoclonal plasma cells from patients with MGUS and active myeloma to IL-6, IL-1, oncostatin-M, leukemia inhibitory factor, IL-3, GM-CSF, and IFN-alpha by the plasma cell labeling index technique in the presence/absence of anti-IL-6 antibody; (3) measure serum levels of IL-6 and sIL-6R in normal individuals and patients with MGUS and myeloma by ELISA. We will then examine the relationship between these results and several established clinical parameters such as labeling index, beta2-microglobulin, age, and overall survival; and 4) develop mutant sIL- 6R constructs that will inhibit IL-6 activity. Because IL-6 is a central growth factor for myeloma cells, a mutant sIL-6R protein with IL-6 inhibitory activity may be helpful in the treatment of patients with multiple myeloma.
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