Ctla-4 polymorphism in multiple myeloma and monoclonal gammopathy of undetermined significanc E

Multiple myeloma (MM) is a B lineage malignancy with unknown etiology. 'he cytotoxic T lymphocyte antigen4 (CTLA-4) plays an important role in the regulatior of T-cell activation and differentiation of T helper (Th) subsets. Th cells, especially the ' Ti2 cells or its cytokines such as IL-6 and IL-10, have been implicated in MM cell growth md survival. A polymorphic microsatellite locus within the CTLA-4 gene has previoi sly been considered to influence CTLA-4 mRNA and protein expression, consequently affeci ing T-cell activation mechanisms. In order to reveal whether such CTLA-4 polymorphisr i is associated with benign or malignant monoclonal gammopathies, we analysed the genot /pe and allele distributions of the CTLA-4 microsatellite polymorphism in 73 Caucasian patients with MM, 27 with MOUS and 100 ethnically matched healthy individual; as controls. The results showed that frequencies of the genotype 86/86 were significai illy decreased in MGUS and MM (p < 0.003, odds ratio (OR) = 0.14, 95% confidence inteival (CI) = 0.03 to 0.61; p < 0.05, OR = 0.48, 95% CI = 0.24 to 0.95 by Fishers exact test, respectively) as compared with controls. The decreased frequencies of the genotype 86/ 86 and allele 86 were most pronounced in MM patients with M-components of X as compared to K-light chain isotype (p < 0.05, OR = 0.13, 95% CI = 0.02 to 1.06; p < 0 02, OR = 0.33, 95% CI = 0.14 to 0.78; by Fishers exact test). We are currently developg a flow cytometry method for comparisons of intracellular CTLA-4 protein expression in activated T-cells isolated from patients and controls. Preliminary data indicate th.it a differential CTLA-4 allele carriage may influence the protein expression level. Taten together, the results show that the CTLA-4 microsatellite polymorphism might represent a susceptibility locus for MM and MGUS. Hypothetically, polymorphic CTLA-4 expression could via differential T-cell activation and tumor promoting cytokine product on, be implicated in monoclonal gammopathies.