REDUCTION IN IL-33 PLASMA LEVELS MIGHT BE INVOLVED IN T-CELL DYSREGULATION IN CHRONIC LYMPHOCYTIC LEUKEMIA

Background: It is now clear that chronic lymphocytic leukemia (CLL) is a proliferative disorder that requires the help of its microenvironment to be maintained and to progress. In CLL neoplastic B cells inhibit normal T lymphocytes, and the alteration of several cytokines may also contribute to this T-cell dysregulation. In this context particular relevance may have some recently discovered cytokines, such as interleukin (IL)-33 and IL-31. IL-33 can activate dendritic cells directly driving polarization of naïve T cells towards a Th2 phenotype. IL-31 coordinates the interaction of different immune cells, including T-cells, mast cells, and eosinophils, with epithelial cells. Aims: We analyzed the plasma levels of IL- 33, and IL-31, in patients with B-CLL. In the same subjects we also evaluated the lymphocyte immunophenotypical pattern, and we performed IgVH gene analysis, CD38 positivity and ZAP-70 expression to evaluate a possible correlation between interleukin concentrations and biological risk. Methods: The study population included 77 patients with B-CLL (38 F -39 M) with a median age of 72.38 ± 11.1 years. In a small group of patients the dosage of the cytokines was performed before and after different treatment protocols. Plasma from 63 normal subjects were also included as controls. IL-31 and IL-33 protein levels were measured using the commercially available ELISA kits. Data were presented as interquartile range IQR and range except age presented as mean ± Standard deviation. Results: The IL-31 was detectable in 40/77 (40.05%) CLL patients and in 36/63 (57.14%) controls, and there was not statistical difference between patients and controls (c2 = 1.15, P = 0.28). The IL-33 was detectable in 50/77 (64.94%) CLL patients and in 35/63 (55.56%) controls. There was no statistical difference in detectability between them (c2 = 1.28, P = 0.26) therefore the two groups were statistically comparable. There was a significant difference (p < 0.0001) between the levels of IL-33 in patients affected by CLL (411.5 and 617.2 pg/ml) and those measured in controls (1,375.3 and 2,035.4 pg/ml). There was not a significant difference between the levels of IL-31 in patients affected by CLL (1,783.5 and 10,692.8 pg/ml) and those measured in controls (3,278.4 and 10,067.1 pg/ml). There was a significant difference, although not in a statistically way (P = 0.072), between the IL-33 levels in CLL patients before and after therapy (83.67 and 1,421 vs. 837.22 and 1,790.38 pg/ml). There was a positive correlation in CLL patients between IL-31 plasma levels and IL-33 (rho = 0.962, P < 0.0001), while we found a negative correlation in patients between IL-31 levels and IL-33 and CD20 expression (respectively rho = -0.6, P = 0.014 and rho = - 0.43, P = 0.031). There was a positive correlation in patients between levels of IL-33 and CD3 expression (rho = 0.81, P = 0.027). Summary / Conclusion: : In leukemia patients, T-cell function has been suppressed with the disease progress. Cytokines play a critical role in the control of the immune responses. To the best of our knowledge, ours is the first study that demonstrated decreased concentrations of IL-33 in patients with CLL, and this reduction might justify the reduction of the Th2 response observed in these patients. In conclusion, our study might contribute to better understand the cellular immune features in CLL patients, confirms the value of multicytokine analyses for the evaluation of CLL patients, and could open a new scenario in understanding the pathophysiology of CLL.