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खुला एक्सेस

अमूर्त

Influence of Metronomic Cyclophosphamide and Interleukine-2 alone or Combined on Blood Regulatory T Cells in Patients with Advanced Malignant Melanoma Treated with Dendritic Cell Vaccines

Lotte Engell-Noerregaard, Eva Ellebaek, Trine Zeeberg Iversen, Troels Holz Hansen, Marie K Brimnes, ?zcan Met, Jon Bjoern, Mads Hald Andersen, Per thor Straten and Inge Marie Svane

Background: Interleukine-2 and Cyclophosphamide are known to influence the circulating T cells and are used for immune manipulation in cancer patients. We analyzed the influence on the Treg population in three different dendritic cell (DC) vaccine trials including either concurrent interleukine-2 (IL-2), combined IL-2 and metronomic Cyclophosphamide (MCy), or only MCy.
Methods: Melanoma patients received treatment with autologous DCs. IL-2 was applied in trial I and II and MCy was applied in trial I and III. Flowcytometry analysis was performed on fresh drawn blood-samples measuring CD4, CD25 and CD127.
Results: In the trials where IL-2 was applied a marked increase in the proportion of CD4⁺CD25⁺CD127^- Tregs from baseline to the 4^th vaccine was observed. This was followed by a decrease, although not to baseline values. Additional analysis showed that the inhibitory function was predominant in the CD49d- subpopulation of Tregs which only increased slightly during treatment. The absolute lymphocyte count (ALC) and the number of CD4⁺ T cells also increased in these trials. In the trial where only MC was applied the Tregs remained stable throughout the trial whereas \\ decrease in the ALC and CD4⁺ T cells were observed.
Conclusion: We found that adjuvant treatment with low doses of IL-2 during DC vaccination therapy causes a significant increase in blood level of classically defined, CD4⁺CD25⁺CD127^-, Tregs but far less in the CD49d- subpopulation and that the use of MC was unable to reduce Treg blood level and unable to counteract IL-2 dependent increase in the CD4⁺CD25⁺CD127^- T cells.
These findings have implications for the clinical use of IL-2 as well as MCy as immune modulators.