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1.
Int J Sports Med ; 15(2): 100-4, 1994 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8157368

RESUMO

The present study was designed to test the hypothesis that the exercise-induced changes in blood mononuclear cell (BMNC) subsets, BMNC proliferative responses and lymphokine activated killer (LAK) cell activity are mediated by increased epinephrine concentrations. Healthy male volunteers 1) exercised on a bicycle ergometer (75% of VO2max, 1 h) and 2) on another day were given epinephrine as an intravenous infusion to obtain plasma epinephrine concentrations comparable with those seen during exercise. Blood samples were collected in the basal state, during the last minutes of exercise or epinephrine infusion and 2 h later. During both perturbations the %CD3+ and %CD4+ T cells declined and the %CD16+ NK cells increased. Two h afterwards the CD14+ monocytes increased, while no changes were observed in %CD8+ T cells or %CD20+ B cells. The phytohemagglutinin (PHA) response declined during both epinephrine infusion and exercise experiments. The changes in interleukin-2 (IL-2) effect on proliferation and cytotoxic activity (LAK cell activity) were more pronounced in exercise experiments than during epinephrine. Exercise and epinephrine caused increase in concentrations of lymphocytes and neutrophils, but the changes were more pronounced in exercise experiments. The results indicate that, in response to physical exercise, the rise in plasma epinephrine may contribute to the changes in cellular immunity.


Assuntos
Ciclismo/fisiologia , Epinefrina/sangue , Leucócitos Mononucleares/metabolismo , Adulto , Linfócitos B/metabolismo , Divisão Celular/fisiologia , Humanos , Interleucina-2/farmacologia , Células Matadoras Ativadas por Linfocina/metabolismo , Leucócitos Mononucleares/citologia , Masculino , Monócitos/metabolismo , Consumo de Oxigênio , Fito-Hemaglutininas/farmacologia , Linfócitos T/metabolismo
2.
J Appl Physiol (1985) ; 70(6): 2530-4, 1991 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-1885446

RESUMO

The present study was designed to test the hypothesis that the changes in natural killer (NK) cell activity in response to physical exercise were mediated by increased epinephrine concentrations. Eight healthy volunteers 1) exercised on a bicycle ergometer (60 min, 75% of maximal O2 uptake) and 2) on a later day were given epinephrine as an intravenous infusion to obtain plasma epinephrine concentrations comparable with those seen during exercise. Blood samples were collected in the basal state, during the last minutes of exercise or epinephrine infusion, and 2 h later. The NK cell activity (lysis/fixed number of mononuclear cells) increased during exercise and epinephrine infusion and dropped below basal levels 2 h afterward. The increased NK cell activity during exercise and the epinephrine infusion resulted from an increased concentration of NK (CD16+) cells in the peripheral blood. On the other hand, the decreased NK cell activity demonstrated 2 h after exercise and epinephrine infusion did not simply reflect preferential removal of NK cells from the blood, because the proportion of CD16+ cells was normalized. On the basis of the finding that indomethacin abolished the suppressed NK cell activity in vitro and the demonstration of a twofold increase in the proportion of monocytes (CD14+ cells) 2 h after exercise and epinephrine infusion, we suggest that, after stress, prostaglandins released by monocytes are responsible for downregulation of NK cell function. Our findings support the hypothesis that increased plasma epinephrine during physical stress causes a redistribution of mononuclear subpopulations that results in altered function of NK cells.


Assuntos
Epinefrina/farmacologia , Exercício Físico/fisiologia , Células Matadoras Naturais/imunologia , Adulto , Epinefrina/administração & dosagem , Epinefrina/sangue , Humanos , Indometacina/farmacologia , Infusões Intravenosas , Células Matadoras Naturais/efeitos dos fármacos , Contagem de Leucócitos , Leucócitos/efeitos dos fármacos , Masculino
3.
Int J Sports Med ; 12(2): 223-7, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1907258

RESUMO

The present study was designed to examine the effect of physical exercise on production of interleukin-1 (IL-1), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). Ten young, healthy volunteers underwent 60-min bicycle exercise at 75% of maximal oxygen uptake (VO2max). Blood samples were collected before and during the last minutes of exercise, as well as 2 h and 24 h later. Blood mononuclear cells (BMNC) were stimulated in vitro with either bacterial lipopolysaccharide or phytohaemagglutinin, and the supernatants were tested for the above-mentioned cytokines using bioassays as well as ELISA techniques. The production of IL-6 increased significantly 2 h after exercise, furthermore the production of IL-1 alpha and IL-1 beta was enhanced, although only borderline significant. TNF-alpha, IL-2 and IFN-gamma did not fluctuate in relation to exercise. The increased amounts of IL-1 and IL-6 in the supernatants generated from a fixed number of BMNC are most likely explained by the increased percentage and absolute number of blood monocytes 2 h after exercise. IL-2 and IFN-gamma are mainly produced by CD4+ and CD16+ cells. During exercise the CD4+ subset decreases, while the CD16+ subset increases. The finding of unchanged production of IL-2 and IFN-gamma was therefore expected.


Assuntos
Exercício Físico/fisiologia , Interferon gama/biossíntese , Interleucina-1/biossíntese , Interleucina-2/biossíntese , Interleucina-6/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Análise de Variância , Meios de Cultura , Ensaio de Imunoadsorção Enzimática , Humanos , Masculino
4.
APMIS ; 99(4): 340-6, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2036217

RESUMO

Multiple myeloma (MM) is characterized by an increased susceptibility to infections and to other malignancies. Selected related immune functions were studied. Spontaneous and interleukin-2-stimulated natural killer (NK) cell activities were normal in 19 patients with MM compared with 62 controls. In contrast, interferon-stimulated NK cells had a significantly lower increase in activity in MM than in controls. The normal improvement in lytic NK cell activity after addition of indomethacin to the mononuclear cell cultures (to inhibit prostaglandin-mediated suppression) was not observed in cultures from MM patients. As reported for other lymphoproliferative disorders, the levels of soluble interleukin-2 receptors in serum were significantly higher in MM (600 U/ml median value) compared with controls (317 U/ml median value), P less than 0.0001, and the concentration of interleukin-2 receptors was significantly correlated with the concentration of monoclonal immunoglobulin in serum. Blood monocyte chemotactic responsiveness was significantly lower in MM patients with both zymosan-activated serum and f-Met-Leu-Phe as cytotaxins, suggesting reduced ability to accumulate at inflammatory foci. In contrast, release of reactive oxygen radicals, believed to be associated with the killing ability of monocytes, was normal after in vitro stimulation.


Assuntos
Células Matadoras Naturais/imunologia , Mieloma Múltiplo/imunologia , Receptores de Interleucina-2/análise , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/fisiologia
5.
Int J Sports Med ; 11(2): 127-31, 1990 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2338373

RESUMO

The present study was designed to explain the mechanism of the post-exercise down-regulation of human natural killer (NK) cell activity recently described by us. Fifteen young, healthy volunteers underwent 60 min of bicycle exercise at 75% of maximal oxygen uptake (VO2max). Six of the volunteers were exercised twice with an interval of at least one month. At the second exercise test they received oral indomethacin. Blood samples were collected before and during the last minutes of exercise as well as 2 h and 24 h after work. The NK cell activity (lysis fixed number of mononuclear cells) increased during bicycle exercise, dropped to a minimum 2 h later and returned to pre-exercise levels within 24 h. During bicycle exercise the percentage of NK cells (CD16+ cells) of mononuclear cells increased significantly but returned to normal within 2 h after exercise. Two hours after exercise, however, increased monocyte cell count and neutrophils were found. The in vitro release of prostaglandin E2 from mononuclear cells was increased. Furthermore, the neutrophil chemiluminescence response was also increased in the 2 h post-exercise period; this response is associated with prostaglandin E2 production by neutrophils. Indomethacin, whether administered in vivo or in vitro, fully restored the suppressed post-exercise NK cell activity. Finally, the NK cell activity of monocyte depleted mononuclear cells did not decrease below basal levels after exercise. These findings strongly indicate that prostaglandins released from monocytes and neutrophils are involved in the post-exercise down-regulation of NK cells.


Assuntos
Regulação para Baixo/imunologia , Exercício Físico/fisiologia , Indometacina/farmacologia , Células Matadoras Naturais/imunologia , Prostaglandinas/metabolismo , Adulto , Citotoxicidade Imunológica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Células Matadoras Naturais/efeitos dos fármacos , Contagem de Leucócitos , Leucócitos Mononucleares/imunologia , Masculino , Neutrófilos/imunologia , Consumo de Oxigênio , Prostaglandinas/biossíntese
6.
Cancer Immunol Immunother ; 32(3): 201-5, 1990.
Artigo em Inglês | MEDLINE | ID: mdl-2289214

RESUMO

Multiple myeloma is characterized by an increased susceptibility to infections and to other malignancies. In a double-blind, placebo-controlled study the potential impact of immunomodulation by ranitidine was studied in 20 patients with multiple myeloma. Three patients were untreated, while 17 after previous cytotoxic therapy were in a stable phase of their disease. All were without clinical signs of infections and at that time had not been treated with other immunomodulating agents. The patients were randomized to oral ranitidine 300 mg twice a day for 21 days or placebo, and several immunological parameters related to multiple myeloma were studied. The blood monocyte chemotactic response was improved in patients treated with ranitidine, and superoxide anion production increased from 2.02 nmol/min to 3.86 nmol/min (median values), while it was unchanged in patients given placebo (2.19-2.25 nmol/min) (P less than 0.005 between groups). Among ranitidine-treated patients spontaneous NK cell activity was unchanged, while in vitro interleukin-2- and interferon-alpha-stimulated NK cell activity decreased (P less than 0.03, respectively). As production of oxygen radicals constitutes an important mechanism of monocyte killing activity against microorganisms and probably against malignant cells, it is suggested that ranitidine may be of beneficial impact in the treatment of multiple myeloma.


Assuntos
Mieloma Múltiplo/imunologia , Ranitidina/farmacologia , Adjuvantes Imunológicos/farmacologia , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Imunoglobulinas/metabolismo , Contagem de Leucócitos/efeitos dos fármacos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Mieloma Múltiplo/tratamento farmacológico , Paraproteínas/metabolismo , Ranitidina/administração & dosagem
7.
Allergy ; 44(7): 477-81, 1989 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-2817303

RESUMO

Natural killer (NK) cell activity and blood mononuclear cell subpopulations were characterized in patients with Hashimoto's thyroiditis (n = 11), Graves' disease (n = 20), non-toxic goitre (n = 10) and in normal controls (n = 22). NK cell activity against K 562 target cells and the capability of IFN-alpha, Il-2, and indomethacin to enhance NK cell activity in vitro did not differ significantly between the groups. The percentages of large granular lymphocytes, CD5+, CD4+, CD8+ and CD16+ cells were normal in patients with non-toxic goitre, Hashimoto's and Graves' diseases. There was no correlation between NK cell activities and TgAb, MAb and TSAb. Although NK cell activity is suppressed in several autoimmune diseases, NK cell function is normal in patients with autoimmune thyroid disorders.


Assuntos
Doença de Graves/imunologia , Células Matadoras Naturais/fisiologia , Tireoidite Autoimune/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Bócio/imunologia , Doença de Graves/diagnóstico , Humanos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Testes de Função Tireóidea/métodos , Tireoidite Autoimune/diagnóstico
8.
Int J Sports Med ; 10(2): 129-31, 1989 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2722326

RESUMO

Natural killer (NK) cell activity and concentration of CD16+ cells (NK cells) and CD20+ cells (monocytes) in peripheral blood were measured in highly trained racing cyclists and in age- and sex-matched untrained controls. Median NK cell activity was 38.1% (range 20.0%-57.1%) in trained vs 30.3% (range 19.7%-43.1%) in untrained (P = 0.008). Median %CD16+ cells was 17% (range 7%-33%) in trained vs 11% (3%-29%) in untrained (P = 0.007). Indomethacin in vitro enhanced the NK cell activity in both groups. There was, however, no significant difference between the NK cell activity in trained and untrained after exposure to indomethacin in vitro. Indomethacin-enhanced NK cell activity was 45.9% (range 24.4%-67.5%) in trained and 40.0% (range 23.9%-68.5%) in untrained (P = 0.138). Mean %CD14+ cells was 8.3% (range 2%-15%) in trained vs 3.8% (2%-8%) in untrained (P less than 0.0001). The increased NK cell function thus demonstrated in highly trained persons might result in better resistance against infectious disease.


Assuntos
Células Matadoras Naturais/imunologia , Educação Física e Treinamento , Adulto , Ciclismo , Citometria de Fluxo , Humanos , Indometacina/farmacologia , Masculino , Monócitos/imunologia
9.
J Cardiovasc Pharmacol ; 13(2): 320-3, 1989 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-2468964

RESUMO

Nitrates are well established in the treatment of angina pectoris and the presence of sulfhydryl groups seems to be fundamental to nitrate-induced vasodilatation. The present study was performed to elucidate if large oral doses of N-acetylcysteine (NAC, 2,400 mg X 2), a donor of sulfhydryl groups, given together with a single oral dose of the long-acting nitrate, isosorbide-5-mononitrate (5-ISMN, 60 mg), would modify the nitrate effect evaluated by exercise testing before and after additional sublingual doses of nitroglycerin (NTG). Ten patients with angina pectoris and angiographically proven significant coronary artery disease were included. All patients received a baseline therapy with beta blockers. None of the patients had developed nitrate tolerance at inclusion. NAC/5-ISMN treatment significantly prolonged the total exercise time as compared with placebo/5-ISMN (7.7 +/- 2.1 min vs. 6.8 +/- 1.7 min, p less than 0.05). This increase was of such magnitude that no further effect was obtained after additional NTG doses. This study demonstrated that increased availability of sulfhydryl groups can increase the exercise capacity in angina pectoris patients treated with 5-ISMN without nitrate tolerance.


Assuntos
Acetilcisteína/uso terapêutico , Angina Pectoris/tratamento farmacológico , Dinitrato de Isossorbida/análogos & derivados , Acetilcisteína/efeitos adversos , Administração Sublingual , Adulto , Angina Pectoris/fisiopatologia , Ensaios Clínicos como Assunto , Preparações de Ação Retardada , Método Duplo-Cego , Teste de Esforço , Humanos , Dinitrato de Isossorbida/administração & dosagem , Dinitrato de Isossorbida/efeitos adversos , Dinitrato de Isossorbida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nitroglicerina/administração & dosagem , Nitroglicerina/efeitos adversos , Nitroglicerina/uso terapêutico , Distribuição Aleatória
10.
Autoimmunity ; 2(4): 291-8, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2491612

RESUMO

The purpose of the present study was to determine whether patients with euthyroid Graves' exophthalmopathy have an impaired NK cell function compared to patients with Graves' hyperthyroidism and healthy controls. The NK cell activity measured against K562 target cells was significantly suppressed (p less than 0.01) in patients with euthyroid Graves' ophthalmopathy, whereas the NK cell activity of patients with Graves' hyperthyroidism was not. Although interferon-alpha, interleukin-2 and indomethacin significantly enhanced (p less than 0.01) the NK cell activity in all three groups, none of these agents fully restored the defective NK cell activity in euthyroid Graves' ophthalmopathy. The concentrations in the blood of large granular lymphocytes and CD16 positive cells did not differ between the three groups, furthermore an immunosuppressive serum factor was not detected. The number of effector/target cell conjugates did not differ between patients and controls, whereas the interferon-alpha induced production of a soluble natural killer cytotoxic factor (NKCF) with specificity for NK sensitive target cells was suppressed in patients with Graves' euthyroid ophthalmopathy. We conclude that one of the mechanisms underlying the defective NK cell activity in patients with euthyroid ophthalmopathy may be an impairment of the release of NKCF from the NK cells.


Assuntos
Doença de Graves/imunologia , Células Matadoras Naturais/imunologia , Proteínas , Adolescente , Adulto , Idoso , Citotoxicidade Imunológica , Feminino , Doença de Graves/fisiopatologia , Humanos , Tolerância Imunológica , Fatores Matadores de Levedura , Masculino , Pessoa de Meia-Idade , Biossíntese de Proteínas , Glândula Tireoide/fisiopatologia
11.
Scand J Immunol ; 27(6): 673-8, 1988 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3393847

RESUMO

The present study was designed to examine the effect of physical exercise on human natural killer (NK) cells. Six healthy volunteers underwent two different acute physical exercise tests with an interval of at least 1 week: (1) 60 min bicycle exercise at 80% of maximal oxygen uptake (VO2max) and (2) 60 min back-muscle training at up to 29% of VO2max; blood samples were collected before and during the last few minutes of exercise, as well as 2 h and 24 h afterwards. The NK cell activity (lysis/fixed number of mononuclear cells) increased during bicycle exercise, dropped to a minimum 2 h later and returned to pre-exercise levels within 24 h. Back-muscle exercise did not significantly influence NK cell activity. Plasma levels of adrenaline, noradrenaline, and cortisol were elevated during bicycling, but not during back-muscle exercise, indicating that exercise intensity is a determinant of NK cell activity. During bicycle exercise the NK cell subset (CD16- cells) of mononuclear cells increased significantly. Furthermore an improved interleukin 2 (IL-2) boosting of the NK cell activity was found during work as compared to IFN-alpha and indomethacin-enhanced NK cell activity. These results indicate that NK cells with a high IL-2 response capacity are recruited to the peripheral blood during exercise. The decreased NK cell activity demonstrated 2 h after work was probably not due to fluctuations in size of the NK cell pool, since the proportion of CD16+ cells was normal. The finding that indomethacin fully restored the suppressed NK cell activity in vitro and the demonstration of a twofold increase in monocyte (CD20+ cells) proportions 2 h after work, strongly indicate that prostaglandins released by monocytes during the heavy physical exercise are responsible for the down-regulation of the NK cells.


Assuntos
Células Matadoras Naturais/imunologia , Esforço Físico , Adulto , Antígenos de Diferenciação/análise , Análise Química do Sangue , Humanos , Imunidade Inata , Contagem de Leucócitos , Linfócitos/classificação , Masculino
12.
Clin Exp Immunol ; 70(1): 209-16, 1987 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3500813

RESUMO

Natural killer (NK) cell activity against K562 target cells was measured in patients within 24 h of acute myocardial infarction (AMI) and regularly thereafter for 6 weeks. NK cell activity was suppressed on days 1, 3, and 7 (P less than 0.01), day 14 (P less than 0.05) and at 6 weeks (P = 0.05) when compared to controls. Interferon, interleukin 2 and indomethacin enhanced NK cell activity on all days measured, but did not completely restore the defective NK cell activity. Serum from the patients did not suppress the NK cell activity of healthy mononuclear cells. The number of NK cells, identified as large granular lymphocytes (LGL), measured on days 1, 3, and 14 and at 6 weeks was not reduced in comparison to that of controls. Thus, the defective NK cell activity can be characterized as functional.


Assuntos
Citotoxicidade Imunológica , Células Matadoras Naturais/imunologia , Infarto do Miocárdio/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Humanos , Indometacina/farmacologia , Interferon Tipo I/farmacologia , Interleucina-2/farmacologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade
13.
Allergy ; 41(7): 532-6, 1986 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-3789334

RESUMO

The in vivo and in vitro effects of indomethacin on the natural killer (NK) cell activity against K 562 target cells were studied. In vivo administration of indomethacin, 3 X 50 mg for 7 days to normal donors did not influence baseline NK cell activity, which means that treatment with prostaglandin (PG) inhibitors can be allowed in studies on NK cell activity of persons with normal PG production. The NK cell activity of fresh mononuclear cells was boosted with pharmacological concentrations of indomethacin in vitro, while frozen cells were not. Our results indicate that indomethacin enhances the NK cell activity in vitro by blocking the prostaglandin production of monocytes, since monocyte depleted effector cells were not boosted by indomethacin.


Assuntos
Imunidade Inata/efeitos dos fármacos , Indometacina/farmacologia , Células Matadoras Naturais/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imunidade Celular/efeitos dos fármacos , Técnicas In Vitro , Masculino
14.
Acta Pathol Microbiol Immunol Scand C ; 93(2): 79-84, 1985 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2409740

RESUMO

Natural killer (NK) cell activity against the leukemia cell line K-562 was tested in 45 patients with rheumatoid arthritis (RA) who either had not received any remission-inducing drugs for more than 6 months or had received penicillamine for at least 6 months. Baseline NK cell activity and interferon (IF)-enhanced NK cell activity did not differ from that observed in 45 controls matched for age and sex, and neither NSAID (non steroidal anti-inflammatory drugs) nor penicillamine influenced NK cell activity. There was no correlation between NK cell activity and acute-phase reactants.


Assuntos
Artrite Reumatoide/imunologia , Interferons/imunologia , Células Matadoras Naturais/imunologia , Adulto , Idoso , Linhagem Celular , Citotoxicidade Imunológica , Eritrócitos/imunologia , Feminino , Humanos , Leucemia Mieloide , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/imunologia
15.
Acta Pathol Microbiol Immunol Scand C ; 92(5): 319-23, 1984 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-6516854

RESUMO

Natural killer (NK) cell activity was studied in 8 patients with classic or definite rheumatoid arthritis (RA) by investigating the killing of K 562 cells by peripheral blood lymphocytes before, during, and after intravenous methylprednisolone pulse therapy (MPPT). MPPT produced a considerable fall in NK activity and after 3 months NK activity was less than half that before MPPT.


Assuntos
Artrite Reumatoide/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Metilprednisolona/uso terapêutico , Adulto , Idoso , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
16.
Acta Pathol Microbiol Immunol Scand C ; 92(4): 221-5, 1984 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-6507107

RESUMO

Natural killer (NK) activity against K 562 target cells was studied in 60 patients with definite or classic rheumatoid arthritis (RA), grouped by medication into 1) Controls not in remission-inducing therapy, 2) Patients treated with penicillamine, and 3) Patients treated with azathioprine. NK activity was found to be completely suppressed in the azathioprine group as compared with the controls (3.2 +/- 4.2% versus 35.9 +/- 14.8% specific lysis; p less than 0.01) except for one patient who received incomplete azathioprine treatment. The NK activity was not suppressed in the penicillamine group.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Azatioprina/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Artrite Reumatoide/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Penicilamina/farmacologia
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