ADVANCED METHODS OF EXPERIMENTAL CANCER IMMUNOTHERAPY BASED ON THE DELAYED-TYPE HYPERSENSITIVITY

Introduction. Among the variety forms of inflammation, many of which contribute to the growth of tumors, classical inflammation reaction - delayed type hypersensitivity is able to eliminate. Artificially induced intratumoral it can be used successfully in immunotherapy. As the level of antitumor immunity correlates with the intensity of the reaction, we used the results of our preliminary research, which helped to increase the level of delayed type hypersensitivity several times. 0ur earlier experiments indicated a paradoxical mechanism of bi-directional control of delayed type hypersensitivity reactions at various stages by antigens class IIMHC I-A-molecules, expressed on the surface of antigen-presenting cells. This fact must be strictly taken into account when designing schemes of immunotherapy. The purpose of the research is development of effective methods for experimental immunotherapy on the basis of delayed type hypersensitivity with the use of means and methods of its regulation. Materials and methods. The above-described phenomenon was used in the development of 2 methods experimental immunotherapy of carcinoma Lewis in mice BDF1. Delayed type hypersensitivity to laboratory antigen ovalbumin induced intratumoral and stimulated point based bi-directional development of reaction or aspirin in the induction stage (indirectly increasing the expression of I-A-anti-gens), or (overpowering her) nicotinamide in the effector phase of the reaction. Results. It is shown that delayed type hypersensitivity to ovalbumin induced intratumoral and stimulated by aspirin or nicotinamide, provides inhibition of tumor growth at 81.5 % and 86.5 % compared with the control, respectively. Conclusion. It is demonstrated 2 ways of experimental immunotherapy of tumors based on delayed type hypersensitivity, with strict regard to bi-directional control reaction by I-a-antigens. According to the literature in a number of agents capable of altering the expression of I-A-molecules, in addition to aspirin and nicotinamide are a well known, widely used in the clinic drugs. The irregularity of bi-directional development of delayed type hypersensitivity during their appointment subsequently leads not only to the weak therapeutic effect, but may cause increased tumor growth. Probably this is the reason for the observed unpredictability in immunotherapy. Obviously, to develop appropriate treatment regimens need careful, targeted intervention in the specific protective immune response in accordance with its molecular mechanism of regulation. In summary, the results presented here can be the basis for the testing of these methodological approaches in the clinic.

гиперчувствительность замедленного типа, экспериментальная иммунотерапия опухоли, карцинома легкого Льюиса, delayed-type hypersensitivity, experimental immunotherapy, Lewis lung carcinoma

1. Ben-Neriah Y., Karin M. Inflamation meets cancer, with NF-kB as the mathh-maker. Nature immunol 2011;12(8):715-23. DOI: 10.1038/ni. 2060. PMID: 21772280.

2. Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature 2008;454(7203):436-44. DOI: 10.1038/nature07205. PMID: 18650914.

3. Paik K.Y., Lee I.K., Lee Y.S. et al. Clinical implications of systemic inflammatory response markers as independent prognostic factors in colorectal cancer patients. Cancer Res Treat 2014;46(1):65-73. DOI: 10.4143/crt. 2014.46.1.65. PMID: 24520225. PMCID: PMC3918529.

4. Sica A. Role of tumor-associated macrophages in cancer-related inflammation. Exp Oncol 2010;32(3):153-8. PMID: 21403610.

5. Yu H., Pardoll D., Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009;9(11):798-809. DOI: 10.1038/nrc2734. PMID: 19851315. PMCID: PMC4856025.

6. Карасева В.И. Разнонаправленный контроль I-A-молекулами, экспрессированными антигенпрезентирующими клетками, реакции гиперчувствительно сти замедленного типа к овальбумину. Иммунология 1997;6:21-3.

7. Медуницын Н.В., Алексеев Л.П. Система I-а-антигенов. М.: Медицина. 1987.

8. Hiromatsu Y., Sato M., Yamada K., Nonaka K. Inhibitory effects of nicotinamide on recombinant human interferon-gamma-induced intercellular adhesion (ICAM-1) and HLA-DR antigen expression on culture human endothelian cells. Immunol Lett 1991;31:35-40. PMID: 1347751.

9. Mochizuki M., Zigler J.S., Russell P. and Gery I. Cytostatic and cytolytic activities of macrophages. Regulation by Prostaglandins. Cell Immunol 1984;83(1):34-42. PMID: 6581870.

10. Большаков О.П., Незнанов Н.Г., Бабаханян Р.В. Дидактические и этические аспекты проведения исследований на биомоделях и на лабораторных животных. Качественная клиническая практика 2002;1:58-61.

11. Подоплелов И.И., Крылов О.Р., Медуницын Н.В. Эванс синий как адъювант для получения повышенной чувствительности замедленного типа в эксперименте. Бюллетень экспериментальной биологии и медицины 1985;6:729.

12. Трещалина Е.М., Жукова О.С., Герасимова Г.К. и др. Методические указания по изучению противоопухолевой активности фармакологических веществ: руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. Под. ред. чл.-корр. РАМН проф. Р.У. Хабриева. М.: Медицина, 2005:637-674.

13. Heagy W., Kelley V.E., Strom T.B. et al. Decreased expression of human class II antigens on monocytes from patients with acquired immune deficiency syndrome. Increased expression with interferon-gamma. J Clin Invest 1984;74(6):2089-96. DOI: 10.1172/JCI111633. PMID: 6439741. PMCID: PMC425399.

14. Stingl L.A., Sauder D.N., Iijima M. et al. Mechanism of UV-beta-induced impairment of the antigen-presenting capacity of murine epidermal cells. J Immunol 1983;130(4):1586-91. PMID: 6187815.

15. Наумов Ю.Н., Коненков В.И., Алексеев Л.П. Регуляция экспрессии генов гистосовместимости II класса. Иммунология 1993;2;6-11.