[Mechanisms of development of side effects and drug resistance to asparaginase and ways to overcome them]. / Mekhanizmy razvitiia pobochnykh éffektov i lekarstvennoi ustoichivosti k asparaginazam i puti ikh preodoleniia.

Asparaginase is one of the most important chemotherapeutic agents against acute lymphoblastic leukemia, the most common form of blood cancer. To date, both asparaginases from E. coli and Dickeya dadantii (formerly known as Erwinia chrysanthemi), used in hematology, induce chemoresistance in cancer cells and side effects in the form of hypersensitivity of immune reactions. Leukemic cells may be resistant to asparaginase due to the increased activity of asparagine synthetase and other mechanisms associated with resistance to asparaginase. Therefore, the search for new sources of L-asparaginases with improved pharmacological properties remains a promising and prospective study. This article discusses the mechanisms of development of resistance and drug resistance to L-asparaginase, as well as possible ways to overcome them.

[Increased suppressor activity of transformed ex vivo regulatory T-cells in comparison with unstimulated cells of the same donor]. / Povyshennaia supressornaia aktivnost' transformirovannykh ex vivo reguliatornykh T-kletok v sravnenii s nestimulirovannymi kletkami togo zhe donora.

Regulatory T-cells CD4⁺CD25⁺FoxP3⁺CD127low (Tregs) play a key role in the maintenance of tolerance to auto antigens, inhibit function of effector T and B lymphocytes, and provide a balance between effector and regulatory arms of immunity. Patients with autoimmune diseases have decreased Treg numbers and impaired suppressive activity. Transformed ex vivo autologous Tregs could restore destroyed balance of the immune system. We developed a method for Treg precursor cell cultivation. Following the method, we were able to grown up 300-400 million of Tregs cells from 50 ml of peripheral blood during a week. Transformed ex vivo Tregs are 90-95% CD4⁺CD25⁺FoxP3⁺CD127low and have increased expression of transcription genes FoxP3 and Helios. Transformed ex vivo Tregs have increased demethylation of FoxP3 promoter and activated genes of proliferation markers Cycline B1, Ki67 and LGALS 1. Transformed ex vivo Tregs have increased suppressive activity and up to 80-90% these cells secrete cytokines TNFα и IFNγ. Our data suggest transformed ex vivo autologous Tregs have genetic, immunophenotypic and functional characteristics for regulatory T-cells and further can be used for adoptive immunotherapy autoimmune diseases and inhibition of transplantation immunity.