IMMUNE DISTURBANCES IN PATIENTS WITH EPILEPSY AND OPPORTUNITY OF IMMUNOMODULATION BY RECOMBINANT HUMAN IL-2
Abstract
Abstract: the inflammation in epilepsy pathogenesis is the subjects of scientific discussion. Extensive evidence in favor of the inflammatory theory of epileptogenesis is obtained, according to which epilepsy is a consequence of specialty inflammation in the CNS connected with both the induction of convulsions and their progression. Special attention is paid to cytokines containing in plasma mostly because they are natural pro-convulsants, the markers of inflammation, increased level of which result in higher risk of seizures. Inflammatory factors and mediators such as IL-1 p и TNF can influence on neuron transmission of mediators and promote development of hyper synchronous in neurons and hyper excitation of the brain. The specific role of cytokines IL-1 p in epilepsy is discerning due to it expression in CNS in astrocytes and microglia as a factor of chronic inflammation in CNS. The aim of our study is to evaluate the dynamics of immunological parameters in patients with epilepsy (PE) during the treatment with rIL-2-medicament (Roncoleukinum®), cytokine drug of Interleukins series containing recombinant human Interleukin-2 (rIL-2), which is a structural and functional analog of the endogenous IL-2. The results of the research of specialties of system inflammation response in epileptic patients reveal the increased level of the inflammation markers in plasma and CNS (increased concentration and violation of balance of cytokines of IL-1 p family defined by decrease of RAIL-1 concentration and RAIL-1/IL-1 coefficient). We obtained the data on decrease of content of pro-inflammatory cytokine IL-8 and increase content of BDNF in PE as a result of rIL-2-medicament treatment. Changes of these immunological parameters correlated with clinical improvement of PE: reduction of seizure frequency and positive EEG changes. These results might be used to optimize treatment of PE due to modulation of inflammatory process and increase of neurotrophic factors production required for the processes of brain neuroplasticity and neurogenesis.
About the Authors
L. V. Lipatova
St. Petersburg V.M. Bekhterev Psychoneurological Research Institute
Russian Federation
Russian Federation
N. B. Serebryanya
North-Western State Medical University named after I.I. Mechnikov, St. Petersburg
Russian Federation
Russian Federation
N. A. Sivakova
St. Petersburg V.M. Bekhterev Psychoneurological Research Institute
Russian Federation
Russian Federation
A. V. Vasilenko
St. Petersburg V.M. Bekhterev Psychoneurological Research Institute
Russian Federation
Russian Federation
T. V. Kapustina
St. Petersburg V.M. Bekhterev Psychoneurological Research Institute
Russian Federation
Russian Federation
References
1. Blinov D.V. Epilepsiya i paroksizmalnye sostoyaniya. 2014; 1: 70-84.
2. Efremov A.V., Matveevskii N.A., Trunov A.N., Safronov I.D. Akusherstvo, ginekologiya i reproduktsiya. 2011; 2: 13-15.
3. Lipatova L.V., Sivakova N.A., Skoromets T.A., Orlov I.A., Anikin S.A., Serebryanaya N.B., Simbirtsev A.S. Tsitokiny i vospalenie. 2012; 3: 61-64.
4. Molchanov O.E., Karelin M.I., Zharinov G.M. Tsitokiny i vospalenie. 2002; 1 (3): 38-47.
5. Allan S.M., Rothwell N.J. Cytokines and acute neurodegeneration. Nat. Rev. Neurosci. 2001; 2: 734-744.
6. Anderson G., Rodriguez M. Multiple sclerosis, seizures, and antiepileptics: role of IL-18, IDO, and melatonin. Eur. J. Neurol. 2011 May; 18 (5): 680-5.
7. Autry A.E., Monteggia L.M. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol. Rev. 2012 Apr; 64 (2): 238-58.
8. Beck R.D., Jr, King M.A., Ha G.K., Cushman J.D., Huang Z., Petitto J.M. IL-2 deficiency results in altered septal and hippocampal cytoarchitecture: relation to development and neurotrophins. J. Neuroimmunol. 2005; 160: 146-153.
9. Cardona A.E., Li M., Liu L., Savarin C., Ransohoff R.M. Chemokines in and out of the central nervous system: much more than chemotaxis and inflammation. J. Leukoc. Biol. 2008; 84: 587-594.
10. Connolly A.M., Chez M., Streif E.M. et al. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders,
11. Landau-Kleffner syndrome, and epilepsy. Biol. Psychiatry. 2006; 59: 354-363.
12. De Simoni M.G., Perego C., Ravizza T., Moneta D., Conti M., Marchesi F., De Luigi A., Garattini S., Vezzani A. Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus. Eur. J. Neurosci. 2000; 12: 2623-2633.
13. Dinkel K., MacPherson A., Sapolsky R.M. Novel glucocorticoid effects on acute inflammation in the CNS. J. Neurochem. 2003; 84: 705-716.
14. Ernfors P., Kucera J., Lee K.F., Loring J., Jaenisch R. Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice. Int. J. Dev. Biol. 1995; 39 (5): 799-807.
15. Hanisch U.K., Quirion R. Interleukin-2 as a neuroregulatory cytokine. Brain. Res. Brain. Res. Rev. 1995; 21: 246-284.
16. Hickey W.F., Hsu B.L., Kimura H. T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 1991; 28: 254-260.
17. Horak I., Lohler J., Ma A., Smith K.A. Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance. Immunol. Rev. 1995; 148: 35-44.
18. Huang E.J., Reichardt L.F. Neurotrophins: Roles in Neuronal Development and Function. Annu. Rev. Neurosci. 2001; 24: 677-736.
19. Huang Z., Dauer D.J., Ha G.K., Lewis M.H., Petitto J.M. Interleukin-2 deficiency-induced T cell autoimmunity in the mouse brain. Neurosci Lett. 2009; 463: 44-48.
20. Kundig T.M., Schorle H., Bachmann M.F., Hengartner H., Zinkernagel R.M., Horak I. Immune responses in interleukin-2-deficient mice. Science. 1993; 262: 1059-1061.
21. Kuramoto S., Yasuhara T., Agari T., Kondo A., Jing M., Kikuchi Y., Shinko A., Wakamori T., Kameda M., Wang F., Kin K., Edahiro S., Miyoshi Y., Date I. BDNF-secreting capsule exerts neuroprotective effects on epilepsy model of rats. Brain Res. 2011 Jan 12; 1368: 281-9.
22. LaFrance W.C. Jr., Leaver K., Stopa E.G., Papandonatos G.D., Blum A.S. Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures. Neurology. 2010 Oct 5; 75 (14): 1285-91.
23. Lapchak P.A., Araujo D.M., Quirion R., Beaudet A. Immunoautoradiographic localization of interleukin 2-like immunoreactivity and interleukin 2 receptors (Tac antigen-like immunoreactivity) in the rat brain. Neuroscience. 1991; 44: 173-184.
24. Lehtimaki K.A., Keranen T., Huhtala H., Hurme M., Ollikainen J., Honkaniemi J., Palmio J. et al.: Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration. J. Neuroimmunol. 2004; 152: 121-125.
25. Lipatova L.V., Serebryanaya N.B., Dubinina E.E., Churilova I.V., Leonova N.V., Egorova D.A., Sivakova N.A., Vasilenko A.V., Zaikova G.M. About the role of inflammation and oxidative stress in pathogenesis of drug resistant epilepsy. J. Allergy, Asthma and Immunophysiology: from basic science to clinical management. Medimond International Proceeding. London. 2013; 83-87.
26. Lipatova L.V., Serebryanaya N.B., Sivakova N.A. About the role of inflammation in drug-resistant epilepsy. Journal of Neurology. June 2013; 260 (1): 146-147.
27. Lipatova L.V., Serebryanaya N.B., Sivakova N.A. Opportunity of using recombinant human interleukin-2 in patients with epilepsy. J. Epilepsia. 2013; 54 (3): 341-342.
28. M. Guilbaud O., Chaouat G., Cayol V., Speranza M., Chambry J., Paterniti S., Moussa M., Flament M., Jeammet P. Cytokines and anorexia nervosa. Psychosom Med. 2001 May-Jun; 63 (3): 502-4.
29. Mahendran R., Mahendran R., Chan Y.H. Interleukin-2 levels in chronic schizophrenia patients. Ann. Acad. Med. Singapore. 2004 May; 33 (3): 320-3.
30. Malek T.R., Yu A., Zhu L., Matsutani T., Adeegbe D., Bayer A.L. IL-2 family of cytokines in T regulatory cell development and homeostasis. J. Clin. Immunol. 2008; 28: 635-639.
31. Paradiso B., Zucchini S., Su T., Bovolenta R., Berto E., Marconi P., Marzola A., Navarro Mora G., Fabene P.F., Simonato M. Localized overexpression of FGF-2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpine-induced status epilepticus. Epilepsia. 2011 Mar; 52 (3): 572-8.
32. Petitto J.M., Huang Z. Molecular cloning of the coding sequence of an interleukin-2 receptor alpha subunit cDNA in murine brain. J. Neuroimmunol. 1995; 59: 135-141.
33. Rubin L.A., Nelson D.L. The soluble interleukin-2 receptor: biology, function, and clinical application. Ann. Intern. Med. 1990 Oct 15; 113 (8): 619-27.
34. Samland H., Huitron-Resendiz S., Masliah E., Criado J., Henriksen S.J., Campbell I.L. rofound increase in sensitivity to glutamatergic but not cholinergic agonist induced seizures in transgenic mice with astrocyte production of IL-6. J. Neurosci. Res. 2003; 73: 176-187.
35. Schorle H., Holtschke T., Hunig T., Schimpl A., Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature. 1991; 352: 621-624.
36. Van Rijckevorsel -Harmant K., Delire M., Schmitz-Moorman W., Wieser H.G. Treatment of refractory epilepsy with intravenous immunoglobulins. Int. J. Clin. Lab. Res. 1994; 24: 162-166.
37. Vezzani A., Moneta D., Conti M., Richichi C., Ravizza T., De Luigi A., De Simoni M.G., Sperk G., Andell-Jonsson S., Lundkvist J., Iverfeldt K., Bartfai T. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc. Natl. Acad. Sci. USA. 2000; 97: 11534-11539.
38. Vezzani A., Moneta D., Richichi C., Aliprandi M., Burrows S.J., Ravizza T., Perego C., De Simoni M.G. Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia. 2002; 43: 30-35.
39. Yuhas Y., Weizman A., Ashkenazi S. Bidirectional concentration-dependent effects of tumor necrosis factor alpha in Shigella dysenteriae-related seizures. Infect Immun. 2003; 71: 2288-2291.
For citation:
Lipatova L.V., Serebryanya N.B., Sivakova N.A., Vasilenko A.V., Kapustina T.V. IMMUNE DISTURBANCES IN PATIENTS WITH EPILEPSY AND OPPORTUNITY OF IMMUNOMODULATION BY RECOMBINANT HUMAN IL-2. Epilepsy and paroxysmal conditions. 2014;6(3):6-12. (In Russ.)
Views: 14489
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Email this article 
