CC BY
13
рiвнем експресп мРНК (тк-25) може стати фактором прогнозу переб^ захворювань, асоцiйованих з ВПЛ, зокрема «малих» форм уражень шийки матки, а також прогнозу ефективносп медика-
ментозно! Tepanii' nanwoMaBipycHoi шфекцп, та вибору нaйбiльш дieвих 3aco6iB iMyHOTponHoro лiкyвaння.
СПИСОК Л1ТЕРАТУРИ
1. Залесский В.Н. Противовоспалительное питание в профилактике и лечении хронических неинфекционных (в том числе опухолевых) заболеваний человека. Молекулярные защитные механизмы биоактивных компонентов пищи: монография / В.Н. Залесский, Н.В. Великая, С.Т. Омельчук - Винница: Нова книга, 2014. - 736 с.
2. Малые некодирующие рнк как перспективные биомаркеры: биогенез и терапевтические стратегии / В.В. Тигунцев, С.А. Иванова, В.Ю. Серебров,
М.Б. Бухарева // Бюлл. Сибир. медицины. - 2016. -Т. 15, № 2. - С. 112-126.
3. Ковальчук Л.В. Иммунология: практикум: учеб. пособие / Л.В. Ковальчук.- КГМА, 2010. - 176 с.
4. Caiazza C. The roles of mir-25 and its targeted genes in development of human cancer / C. Caiazza, M. Mallardo // Microna. - 2016. - Vol. 5, N 2. - P. 113-119.
5. Frixa T. Oncogenetic Micro-RNAs: key-players in malignant transformation / T. Frixa, S. Donzellis, G. Blan-dino // Cancers (Basel). - 2015. - Vol. 7, N 4. - P. 2466-85.
REFERENCES
1. Zalessky VN, Velikaya NV, Omelchuk ST. [Antiinflammatory nutrition in the prevention and treatment of chronic non-infectious (including neoplastic) diseases of man. Molecular defense mechanisms of bioactive food components: monograph]. Vinnitsa, Nova kniga, 2014;736. Russian.
2. Tiguntsev VV, Ivanova SA, Serebrov VYu, Bu-khareva MB. [Small noncoding RNAs as promising bio-markers: biogenesis and therapeutic strategies]. Bulletin of Siberian Medicine, 2016;15(2):112-26. Russian.
3. Kovalchuk LV, et al. [Immunology: a workshop]. Textbook, KGMA. 2010;176. Russian.
4. Caiazza C, Mallardo M. The roles of mir-25 and its targeted genes in development of human cancer. Mic-rona. 2016:5(2):113-9.
5. Frixa T, Donzellis S, Blandino G. Oncogenetic Micro-RNAs: key-players in malignant transformation. Cancers (Basel) 2015;7(4):2466-85.
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УДК 616.24-002.5:616.441:612.017:577.112 https://doi.org/10.26641/2307-0404.2018.1Cpart 1).127247
S.L. Matvyeyeva, CYTOKINE PROFILE AND EFFICACY
O S Shevchenko OF CHEMOTHERAPY DEPENDING
ON THYROID STATE IN PATIENTS WITH PULMONARY TUBERCULOSIS
Kharkiv National Medical University Department of phthisiology andpulmonology Nauki av.,4, Kharkov, 61022, Ukraine Харювський нацюнальний медичний yuieepcumem кафедра фтизiатрii та пульмонологи пр. Науки, 4, XapKie, 61022, Укра'та e-mail: Kjara. clair@gmail. com
Key words: pulmonary tuberculosis, thyroid, immunity, cytokines
Ключовi слова: туберкульоз легетв, щитоподiбна залоза, iMyHimem, цитокти
Abstract. Cytokine profile and efficacy of chemotherapy depending on thyroid state in patients with pulmonary tuberculosis. Matvyeyeva S.L., Shevchenko O.S. Objective of the study is definition of cytokine balance and the outcomes of chemotherapy of tuberculosis patients depending on their thyroid state. Materials and methods: 60 tuberculosis patients with pulmonary: 30 persons with unchanged thyroid gland and 30 persons with autoimmune thyroiditis and followed subclinical hypothyroidism were compared for the structure and the function of thyroid gland, cytokine balance and outcomes of antituberculosis chemotherapy. Thyroid glands of all patients were scanned by ultrasound. The levels of free thyroxine, thyroid stimulating hormone and antibodies to thyroglobulin and thyroid peroxidase in the serum were defined. At the same time the levels of tumor necrosis factor-a, interferon- у and interleukins-2, -6, and -4 were measured. Outcomes of chemotherapy was estimated on the ground of general cri-terions: term and rate of stopping of bacilli excretion and healing of caverns in lungs. Results and discussion: In a comparative analysis of the data obtained, it was found that in tuberculosis patients with autoimmune thyroiditis and subclinical hypothyroidism compared with tuberculosis patients without thyroid pathology free thyroxine values in average decrease, the level of thyroid-stimulating hormone increases and levels of antibodies to both thyroglobulin and especially to thyroid peroxidase increase. In patients with concomitant autoimmune thyroiditis with subclinical thy-roiditis, levels of pro-inflammation cytokines TNF-a, INF-y, IL-2, IL-6 were significantly lower when compared with patients without thyroid pathology, and the level of anti-inflammation cytokine ILIL-4 was higher in a group of patients with autoimmune thyroiditis. Efficacy of chemotherapy was better in tuberculosis patients without thyroid pathology. These changes can be explained by a lower level of T4 in the systemic circulation of people with autoimmune thyroiditis and subclinical hypothyroidism. Conclusion: subclinical hypothyroidism accompanying concomitant autoimmune thyroiditis suppresses cytokine response in tuberculosis patients. That is followed worsening of treatment response during antituberculosis chemotherapy. Screening of thyroid state is recommended for TB patients for timely definition of thyroid pathology and its compensation if needed for improvement of the outcomes of antituberculosis chemotherapy.
Реферат. Цитокшовий ii|)()(|)i.n> та ефектившсть xiMioTepami залежно ввд тиреоТдного статусу хворих на туберкульоз. Матвеева С.Л., Шевченко О.С. Мета роботи: до^дження та визначення балансу цитоютв та результатiв хiмiотерапii хворих на туберкульоз залежно eid стану щитоподiбноi залози. Матерiали та методи: порiвнювали структуру та функцiю щитоподiбноi залози, баланс цитоютв та результати протитуберкульозно'1' хiмiотерапii в 60 пацieнтiв з легеневим туберкульозом: 30 оаб з незмтеною щитоподiбною залозою та 30 оаб з автоiмунним тирео'1'дитом та суб^тчним гтотиреозом. У вах пацieнтiв було проведено ультразвукове до^дження щитоподiбноi залози. Визначено рiвень вшьного тироксину, тиреотропного гормону гiпофiзу та антитш до тиреоглобулiну та тиреопероксидази в сироватцi кровi. Одночасно вимiрювали рiвень факторiв некрозу пухлини-a, ттерферону-у та iнтерлейкiнiв-2, -6 та -4. Результати хiмiотерапii оцтювалися на пiдставi загальних критерпв: термiну та частоти припинення бактерiовидiлення та загоення каверн у легенях. Результати та обговорення: у порiвняльному анал1зг отриманих даних було встановлено, що у хворих на туберкульоз та автоiмунний тирео'1'дит з субклiнiчним гтотиреозом порiвняно з хворими на туберкульоз з ж^м-жно'' щитоподiбноi залози значення вшьного тироксину, у середньому, знижуеться, рiвень тиреотропного гормону гiпофiзу вiрогiдно пiдвищуeться, а рiвень антитш як до тиреоглобулту, так i особливо до тиреопероксидази збшьшуеться. У пацieнтiв iз супуттм автоiмунним тирео'1'дитом -з субклШчним тирео'1'дитом рiвень протизапальних цитоютв TNF-a, INF-y, IL-2, IL-6 був значно нижчим порiвняно з пащентами без патологп щитоподiбноi залози, а рiвень протизапального цитоюну IL IL-4 був вищим у групi пацieнтiв з автоiмунним тирео'1'дитом. Ефективтсть хiмiотерапii була кращою у хворих на туберкульоз без патологп щитоподiбноi залози. Ц змти можна пояснити бшьш низьким рiвнем Т4 у системнш циркуляцп хворих на автоiмунний тирео'1'дит i-з субклiнiчним гiпотиреозом. Висновки: суб^тчний гтотиреоз, що супроводжуe автоiмунний тирео'1'дит, пригнiчуe вiдповiдь цитокiнiв у хворих на туберкульоз. На^дком цього e погiршення ефективностi протитуберкульозно'1' хiмiотерапii. Скринтг стану щитоподiбноi залози рекомендуeться для хворих на туберкульоз для своeчасного визначення змтення функцп щитоподiбноi залози та, якщо це необхiдно, ii компенсацИ для полiпшення результатiв протитуберкульозног хiмiотерапii.
Acording to modern ideas, tuberculosis refers to interleukin-dependent immunodeficiency, accompanied by pronounced changes in the cytokine network of the body. Cells of the monocyte-macrophage system are activated by the thyroid gland in direct and indirect ways, which facilitates the elimination of the causative agent of tuberculosis from the body [2, 5, 7, 14].
Objective of the study is definition of cytokine balance and the outcomes of chemotherapy of tuberculosis patients depending on their thyroid state.
MATERIALS AND METHODS
60 patients with pulmonary tuberculosis (TE): 30 persons with unchanged thyroid gland (TB) (control group 1) and 30 TB patients with autoimmune thyroiditis and followed subclinical hypothyroidism (TB + AT & SH) (group of observation 2) were compared for the structure and the function of thyroid gland, cytokine balance and outcomes of antituberculosis chemotherapy. The structure of thyroid was studied in both groups of patients by ultrasound scanning with diagnostic apparatus SSF-
18/ Том XXIII/ 1 ч. 1
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240A by Toshiba Medical Systems production. The immunoassay of free thyroxine (T4 free), thyroid stimulating hormone (TSH), antibodies to thyro-globulin (at/TG) and thyroperoxidase (at/TPO) made with the reagents by the company "Ancor Bio" and spectrophotometer Tecan Sunrise [3] as well as immunoassay of some cytokines: tumor necrosis factor-a, interferon-y, interleukin-2, -6, and -4 [8] made with the reagents by the company "Vector Best" were performed before and at the end of intensive phase of chemotherapy (after 60 daily doses of standardized regimens).
Treatment response of antituberculosis chemotherapy was estimated on the ground of general criterions like rate and term of stopping of bacilli excretion and of reducing the sizes of tuberculosis caverns in lungs.
RESULTS AND DISCUSSION
Patients of control group had normal volume and echotexture of thyroid gland. Thyroid glands of TB patients with autoimmune thyroiditis (AT ) had mainly diffusely enlarged thyroid glands with heterogeneous echotexture with presence of hypo-echoic micronodules (1-2 mm) with surrounding echogenic septations. Color Droppler study in most cases showed normal or decreased flow. In 3 cases large nodules were present which may be referred as nodular Hashimoto thyroiditis [1].
When studying the hormonal profile in most TB patients of control group with normal thyroid (group
1), low normal values of free T4 (12.71±0.98) pmol/ml were revealed. In patients with TB and AT (group
2), this indicator dropped to the borderline value and amounted to (11.21±0.67) pmol/l. When compared the average values of free thyroxin in 2 months after starting the treatment (at the end of intensive phase), a significant decrease in its level in a group of patients with AT from (10.43±0.85 to 8.12±0,80) pmol/l and unsignificant decrease was found in group 2 (from 11.21±0.67 to 10.43±0.85) pmol/l (table 1).
The level of thyroid-stimulating hormone in the systemic blood flow in the control group 1 of patients with a normal echotexture of the thyroid gland was within the physiological normal value (1.29±0,78) mIU/ml and slightly increased (l.80±0.94) mIU/ml to the end of the intensive phase of antituberculosis chemotherapy. The level of TSH in the group-2 of TB patients with the AT significantly increased to pathological value and increased more from (4.20±1,41) to (4.80±1,52) mIU/ml to the end of intensive phase. Subclinical hypo-thyroidism was present in patients of group 2 judging on the level of T4 free which was minimal and TSH which was more than 4.2 mIU/ml. Hy-pothyroidism worsened to the end of intensive phase. Thus antituberculosis treatment leads to the suppression of thyroid function.
Table 1
Indexes of thyroid profile in TB patients depending on echotexture of thyroid gland
Groupl (TB) Group 2 (TB+ AT & SH)
Index (n= 30) (n =30)
before treatment after 60 doses before treatment after 60 doses
T4free (pmol/l) 11.21±0.67 10.43±0.85 10.43±0.85 8.12±0,80
p12>0,05 p12<0,05
TSH 1.29±0,78 1.80±0.94 4.20±1,41 4.80±1,52
(mcIU/ml) PI,2>0,05 pi,2<0,05
at/TG 5.38±1,91 6.55±1.2 18.45±1.83 38.54±1.27
(U/ml) pi,2<0,05 pi,2<0,05
at/TPO 3.24±0,39 4.41±0.94 380.54±1.27 430.22±1.63
(U/ml) PI,2<0,05 Pi,2<0,05
Levels of antibodies to thyroglobulin, as well as to thyroid peroxidase did not exceed the normal allowable values in control group 1. The content of antibodies to TG was (5.38±1.91) U/ml before starting the treatment and (6.55±1.2) U/ml to the end of intensive therapy. The content of antibodies to TPO was (3.24±0,39) U/ml before starting the treatment
and (4.41±0.94) U/ml to the end of intensive therapy. But both indicators significantly increased in the group 2 of TB patients with autoimmune thy-roiditis compared with the control group 1. TG in the group of TB patients with autoimmune thyroiditis significantly increased previously to (18.45±1.83) U/ml with further increasing to the end
of intensive therapy to (21.54±1.18) U/ml. The concentration of antibodies to TPO in these patients was (380.54±1.27) U/ml and significantly increased to (430.22±1.63) U/ml to the end of the intensive therapy. Thus, autoimmune disease in patients of the group of observation was confirmed both by getero-genous texture of thyroid and by increased level of antibodies to thyroperoxidase.
So, in a comparative analysis of the data obtained, it was found that in tuberculosis patients with autoimmune thyroiditis and subclinical hypothy-roidism compared with tuberculosis patients with unchanged thyroid gland free thyroxine values in average decreases, the level of thyroid-stimulating hormone increases and levels of antibodies to both thyroglobulin and especially to thyroid peroxidase increase. These pathological changes worsened during antituberculosis chemotherapy.
When studying the cytokine profile in a group of patients with TB + AT & SH, a significant decrease in the levels of TNF-a, INT-y compared to the control, as well as a moderate decrease in IL-2 and IL-6, and an increase in the level of IL-4 compared to the control were established (table 2). In TB patients with AT & SH, the level of TNF-a was
30.77±16.77 pg/ml, which is half the values in patients with normal thyroid status (60.84±25.01 pg/ml).
The concentration of INT-y was 2.5 times lower in patients with autoimmune thyroiditis and subclinical thyroiditis (1.22±0.81 pg/ml) when compared with patients maintaining normal thyroid status (3.74±2.45 pg/ml). Given the lower values of T4 in patients with tuberculosis with thyroid pathology, and the indication that thyroxin is a potential inducer of INF-y [4, 6], it can be assumed that the production of INF-y is related to the level of thyroxine in the systemic circulation in patients with TB and AT.
The content of IL-2 in the systemic blood flow of TB patients without thyroid pathology remained within the allowed physiological values (7.08±1.97 pg/ml) with a decrease of 2.5 times in TB patients with autoimmune thyroiditis (4.88±1,05 pg/ml).
The content of IL-6 in TB patients with autoimmune thyroiditis 3 times lower when compared with TB patients without thyroid pathology - relatively (16.98±1.81) and (51.87±3.54) pg/ml. The obtained data confirm the fact of an increase in serum IL-6 level in the majority of patients with active tuberculosis [10], which is a protective reaction to tuberculosis infection.
Table 2
The levels of cytokines in free bloodstream in TB patients depending of thyroid pathology
Groups
TNF-a, pg/ml
INT-y, Pg/ml
IL-2, pg/ml
IL-6, pg/ml
IL-4, pg/ml
Groupl(TB); n=30 before treatment
60.84±5.01
3.74±2.45
7.08±1.97
51.87±3.54 0.002±0,003
in 2months
68.56±4.19
4.12±1.59
8.11±2.02
60.65±3.24
0.003±0,004
Group 2
(TB+ AT & SH); n =30
before treatment
30.77±6.77
1.22±0.81
4.88±1.05
16.98±1.81
0.040±0,019
in 2months
31.23±5.94
1.59±0.83
5.09±1.11
17.07±1.67
0.071±0,009
p i,2 (before treatment) p 12 (in 2months)
<0,05 >0,05
<0,05 >0,05
<0,05 >0,05
<0,05 <0,05
<0,05 >0,05
Levels of IL-4 in TB patients with AT & SH increased compared with the control group 1. Lower values of this indicator were observed in persons with thyroid gland pathology and were (0.002±0.003) pg/ml in group 1 and (0.040±0,019) pg/ml in group 2, respectively. Obtained data are apparently due to a significant increase in the level of IL-6, which is an antagonist of IL-4, which inhibits secretion by macrophages of IL-6. Decreased secretion of IL-4 increases the resistance of the body to tuberculosis
infection and, thus, is a protective event in the formation of an immune response in patients with tuberculosis.
At the end of the intensive phase of therapy no significant changes in cytokine profile was occurred (table 2).
Thus, the results of the study demonstrate a change in the cytokine profile in patients with pulmonary tuberculosis, which is manifested by a significant increase in the levels of pro-inflammatory
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TNF-a, IL-6, as well as a moderate increase in the levels of INF-y and IL-2 and a decrease in IL-4. The established change is a manifestation of the formation of an immune response to a tuberculosis infection and is thus of a naturel protector. However, in patients with concomitant autoimmune thyroiditis with subclinical thyroiditis, levels of pro-inflammation cytokines TNF-a, INF-y, IL-2, IL-6 were significantly lower when compared with patients without thyroid pathology, and the level of antiinflammation cytokine IL IL-4 was higher in a group of patients with autoimmune thyroiditis. Efficacy of chemotherapy was better in tuberculosis patients without thyroid pathology. These changes can be explained by a lower level of T4 in the systemic circulation of people with autoimmune thyroiditis and subclinical hypothyroidism. The proinflammation cytokine of macrophage origin IL-6 is synthesized by phagocytes, fibroblasts, T-lymphocytes
of types 1 and 2 and endotheliocytes [12]. Although a number of studies have shown that IL-6 stimulates intracellular growth of mycobacteria in monocytes [11, 13], nevertheless, it has been shown that IL-6 is a key factor in the formation of tuberculosis resistance [4]. Tuberculosis of mutated mice with IL-6 deficiency led to their lethality [9]. Thus, in patients with tuberculosis, an increase in the level of IL-6 is considered as a protective reaction.
When measuring total triiodothyronine and thyroxine levels and markers of immune status in healthy people at the age of concentration, thyroid hormones were associated with inflammation markers, IL-6 expression by activated monocytes and CD + T-lymphocyte receptors [7]. These data, as well as our results obtained by examining patients with tuberculosis, prove the fact of regulation cytokine production by thyroid hormones.
Table 3
Estimation of treatment response of TB patients at the end of intensive therapy depending on thyroid state
Stopping of bacilli excretion Reducing of the cavitation
Groups n Term n Term
absolute % (months) absolute % (months)
Groupl(TB) n=30 24 79.77 1,71±0,08 23 76,66 2,58±0,08
Group 2 (TB+ AT&SH) n =30 20 66.66* 2,20±0,14* 18 60,00* 3,11±0,15*
Note: * the intergroup value is significantly different, p <0.05.
At the end of intensive therapy treatment response in TB patients with normal thyroid state (control group 1) was better compared with TB patients with AT & SH judging on the ground of rates and terms of stopping of bacilli excretion and reducing of the cavitation in size (table 3). CONCLUSIONS
Subclinical hypothyroidism accompanying concomitant autoimmune thyroiditis suppresses cyto-
kine response in tuberculosis patients. That is followed worsening of treatment response during antituberculosis chemotherapy. Screening of thyroid state is recommended for TB patients for timely definition of thyroid pathology, especially of the suppression of its function and its compensation if needed for improvement of the outcomes of antituberculosis chemotherapy.
REFERENCES
1. Andersen L, Middleton WD, Teefley SA, et al. Hashimoto thyroiditis: part 1, sonographic analysis of the nodular form of Hashimoto thyroiditis. 2010;195:208-15.
2. Frick LR, Rapanelli M, Bussman UA, Kleche AJ, et al. Involvement of thyroid hormones in the alterations
of T-cell immunity and tumour progression. Biol. Psychiatry. 2009;65:935-42.
3. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, et al. Laboratory medicine practice guidelines. Laboratory support for the
diagnosis and monitoring of thyroid disease. Thyroid. 2003;13:3-126.
4. Ladel CH, Blum C, Dreher A, et al Lethal tuberculosis in interleukin-6 deficient mutant mice. Infect Immunol. 1997;65:4843-49.
5. Perrotta C, Buldorini M, Assi E, et al The thyroid hormone triiodothyronine controls macrophage maturation and functions. Immunol. And Inf. Dis. 2014;184:230-47.
6. Lin HY, Thacore H, Davies FB, Mortino IJ, et al Potentiation by thyroxine of interferon-gamma-induced HLA-DR expression is protein kinase A- and C-de-pendent. J. Interferon Cytokine Res. 1996;16(1):17-24.
7. Hodkinson CF, Simpson EEA, Beattie JH, et al. Preliminary evidence of immune function modulation by thyroid hormones in healthy men and women aged 5577 years. J. Endocrinol. 2009;202:55-63.
8. Franchimont P, Reuter A, Vrindts-Gevaert Y, Bastings M, Malaise M, Sondag C, Frere MC, Gysen P. Production of tumor necrosis factor-alpha, interferon-gamma and interleukin-2 by peripheral blood mono-
nuclear cells of subjects suffering from rheumatoid arthritis. Scand J Rheumatol. 1988;17(3):203-12.
9. Reinfenberg K, Kopf M, Kaufmann SH. Lethal tuberculosis in interleukin-6-deficient mice. Infect Immunol. 1997;65:4843-49.
10. Verbon A, Suffermans N, Van Deventer SJH, Van Der Poll T. Serum concentration of cytokines in patients with active tuberculosis (TB) and after treatment. Clin Exp Immunol. 1999;115:110-13.
11. Shiratsuchi H, Johnson JL, Ellner JJ Bidirections effects of cytokines on the growth of M. avium within human monocytes. J.Immunol. 1999;146:3165-70.
12. Van Snick J Interleukin 6; an overview. Ann Rev Immunol. 1990;8:253-78.
13. Vallis RS, Ellner JJ. Cytokines and tuberculosis. J. Leuk Biol. 1994;55:676-81.
14. De Vito P, Incerpi S, Pedersen JZ, et al Thyroid hormones as modulators of immune activators at cellular level. Thyroid. 2011;21:879-90.
СПИСОК Л1ТЕРАТУРИ
1. Hashimoto thyroiditis: part 1, sonographic analysis of the nodular form of Hashimoto thyroiditis / L. Andersen, W. D. Middleton, S. A. Teefley [et al.] // A.J.R. Am. J. Roentgenology. - 2010. - Vol. 195. -P. 208-215.
2. Involvement of thyroid hormones in the alterations of T-cell immunity and tumour progression / L.R. Frick, M. Rapanelli, U.A. Bussman, A.J. Kleche [et al.] // Biological Psychiatry. - 2009. - Vol. 65. - P. 935-942.
3. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease / Z. Baloch, P. Carayon, B. Conte-Devolx [et al.] // Thyroid. - 2003. - Vol. 13. - P. 3-126.
4. Ladel C.H. Lethal tuberculosis in interleukin-6 deficient mutant mice / C.H. Ladel, C. Blum, A. Dreher [et al.] // Infect. Immunol. - 1997. - Vol. 65. - P. 4843-4849.
5. Perrotta C. The thyroid hormone triiodothyronine controls macrophage maturation and functions / C. Per-rotta, M. Buldorini, E. Assi // Immunol. Infect. Diseases. - 2014 - Vol. 184. - P. 230-247.
6. Potentiation by thyroxine of interferon-gamma-induced HLA-DR expression is protein kinase A- and C-de-pendent / H.Y. Lin, H. Thacore, F.B. Davies [et al.] // J. Interferon Cytokine Researches.- 1996.- Vol. 16, N 1.- P.17-24.
7. Preliminary evidence of immune function modulation by thyroid hormones in healthy men and women aged 55-77 years / C.F. Hodkinson, E.E.A. Simpson, J.H. Beattie [et al.] // J. Endocrinol. - 2009. - Vol. 202. - P. 55-63.
8. Production of tumor necrosis factor-alpha, in-terferon-gamma and interleukin-2 by peripheral blood mononuclear cells of subjects suffering from rheumatoid arthritis / P. Franchimont, A. Reuter, Y. Vrindts-Gevaert [et al.] // Scand. J. Rheumatology. - 1988. - Vol. 17, N 3. - P. 203-212.
9. Reinfenberg K. Lethal tuberculosis in interleukin-6-deficient mice / K. Reinfenberg, M. Kopf, S. H. Kaufmann // Infect. Immunol. -1997. - Vol. 65. - P. 4843-4849.
10. Serum concentration of cytokines in patients with active tuberculosis (TB) and after treatment / A. Verbon, N. Suffermans, S. J. H. Van Deventer, T. Van Der Poll // Clin. Experimental. Immunology. -1999. - Vol. 115. -P. 110-113.
11. Shiratsuchi H. Bidirections effects of cytokines on the growth of M. avium within human monocytes / H. Shiratsuchi, J.L. Johnson, J.J. Ellner // J. Immunol. -1999. -Vol. 146. - P. 3165-3170.
12. Van Snick J. Interleukin 6; an overview / J. Van Snick // Ann. Review Immunol. - 1990. - Vol. 8. -P. 253-278.
13. Vallis R.S. Cytokines and tuberculosis / R.S. Val-lis, J. Ellner // J. Leukocyte Biology. - 1994. - Vol. 55. -P. 676-681.
14. De Vito P. Thyroid hormones as modulators of immune activators at cellular level / P. De Vito, S. Incerpi, J.Z. Pedersen [et al.] // Thyroid. - 2011. - Vol. 21. -P. 879-890.
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