RESUMO
Panobinostat is a pan-deacetylase inhibitor that modulates the expression of oncogenic and immune-mediating genes involved in tumour cell growth and survival. We evaluated panobinostat-induced post-transplant responses and identified correlative biomarkers in patients with multiple myeloma who had failed to achieve a complete response after autologous transplantation. Patients received panobinostat 45 mg administered three-times weekly (TIW) on alternate weeks of 28-day cycles commencing 8-12 weeks post-transplant. Twelve of 25 patients (48%) improved their depth of response after a median (range) of 4·3 (1·9-9·7) months of panobinostat. In responders, T-lymphocyte histone acetylation increased after both three cycles (P < 0·05) and six cycles (P < 0·01) of panobinostat when compared to baseline, with no differences in non-responders. The reduction in the proportion of CD127+ CD8+ T cells and CD4:CD8 ratio was significantly greater, after three and six cycles of panobinostat compared to pre-transplant, in non-responders when compared to responders. Whole marrow RNA-seq revealed widespread transcriptional changes only in responders with baseline differences in genes involved in ribosome biogenesis, oxidative phosphorylation and metabolic pathways. This study confirmed the efficacy of panobinostat as a single agent in multiple myeloma and established acetylation of lymphocyte histones, modulation of immune subsets and transcriptional changes as pharmacodynamic biomarkers of clinical benefit.
Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/terapia , Panobinostat/uso terapêutico , Transplante Autólogo/efeitos adversos , Adulto , Idoso , Antígenos CD4/efeitos dos fármacos , Antígenos CD4/imunologia , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/patologia , Feminino , Seguimentos , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Histonas/efeitos dos fármacos , Histonas/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-7/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias/métodos , Oncogenes/efeitos dos fármacos , Panobinostat/administração & dosagem , Panobinostat/efeitos adversos , Indução de Remissão , Análise de Sobrevida , Transplante Autólogo/estatística & dados numéricos , Resultado do TratamentoRESUMO
BACKGROUND: Deltamethrin (DLM) is a type 2 pyrethroid insecticide used in agriculture and home to control pests. However, emerging reports have indicated the immunotoxicity of DLM. OBJECTIVE: Thus, in the current investigation, we have checked the immune-protective role of quercetin in DLM-induced immunotoxicity by using in silico and in vitro techniques. RESULTS: In silico results have shown good interaction of quercetin towards immune cell receptors (T & B cell receptors). The findings of in vitro studies indicated the decrease in oxidative stress which is elevated by DLM in concentration & time-dependent manner. The increased caspases-3 activity was decreased by treatment of quercetin. The apoptosis induced by DLM in thymus and spleen was suppressed only at higher concentration (50µg/ml) of quercetin. Finally, the phenotypic changes due to DLM were restored by quercetin. CONCLUSION: Quercetin has strong binding affinity towards CD4, CD8 and CD28, CD45 receptors and protects the thymocytes and splenocytes against DLM-induced apoptotic signaling pathways.
Assuntos
Inseticidas/toxicidade , Linfócitos/efeitos dos fármacos , Nitrilas/toxicidade , Piretrinas/toxicidade , Quercetina/farmacologia , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Antígenos CD28/efeitos dos fármacos , Antígenos CD28/metabolismo , Antígenos CD4/efeitos dos fármacos , Antígenos CD4/metabolismo , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Inseticidas/metabolismo , Antígenos Comuns de Leucócito/efeitos dos fármacos , Antígenos Comuns de Leucócito/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Quercetina/metabolismo , Baço/imunologia , Baço/metabolismo , Baço/patologia , Timo/imunologia , Timo/metabolismo , Timo/patologia , Fatores de TempoRESUMO
OBJECTIVE: This study examines polyfunctional T-cells in psoriatic arthritis (PsA) synovial tissue and their associations with clinical disease and implications for therapy. METHODS: PsA synovial tissue was enzymatically/mechanically digested to generate synovial tissue single cell suspensions. Frequencies of polyfunctional CD4, CD8, T-helper 1 (Th1), Th17 and exTh17 cells, using CD161 as a marker of Th17 plasticity, were determined by flow cytometry in matched PsA synovial tissue and peripheral blood. Synovial T-cell polyfunctionality was assessed in relation to Disease Activity in PSoriatic Arthritis (DAPSA) and in synovial cell suspensions cultured with a current mode of treatment, phosphodiesterase 4 (PDE4) inhibitor. RESULTS: PsA synovial tissue infiltrating CD4+ T-cells expressed higher levels of interleukin (IL)-17A, interferon gamma (IFN-γ), GM-CSF and CD161, with parallel enrichment of Th1, Th17 and exTh17 T-helper subsets (all p<0.05). Interestingly, a significant proportion of synovial T-cell subsets were triple-positive for GM-CSF, tumour necrosis factor (-TNF), -IL-17 or IFN-γ compared with matched blood (all p<0.05). Importantly, frequencies of polyfunctional T-cells correlated with DAPSA: Th1-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p<0.01), Th17-GM-CSF+/TNF+/IL-17+ (r=0.6, p<0.057) and exTh17-GM-CSF+/TNF+/IFN-γ+ (r=0.7, p=0.0096), with no associations observed for single cytokine-producing T-cells. Following ex vivo culture of PsA synovial tissue cell suspensions, polyfunctional GM-CSF+TNFα+IL-17A+ or/IFN-γ+-producing T-cells (p<0.05), but not single cytokine-producing T-cells, were inhibited with a PDE4 inhibitor. CONCLUSION: These data demonstrate enrichment of polyfunctional T-cells in PsA synovial tissue which were strongly associated with DAPSA and ex vivo therapeutic response.
Assuntos
Artrite Psoriásica/imunologia , Artrite Psoriásica/fisiopatologia , Linfócitos T CD4-Positivos/imunologia , Membrana Sinovial/citologia , Subpopulações de Linfócitos T/imunologia , Antígenos CD4/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Técnicas de Cultura de Células , Citometria de Fluxo , Humanos , Interferon gama/efeitos dos fármacos , Interleucina-17/imunologia , Inibidores da Fosfodiesterase 4/farmacologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologiaRESUMO
SLAMF6, a member of the SLAM (signaling lymphocyte activation molecules) family, is a homotypic-binding immune receptor expressed on NK, T, and B lymphocytes. Phosphorylation variance between T-cell subclones prompted us to explore its role in anti melanoma immunity. Using a 203-amino acid sequence of the human SLAMF6 (seSLAMF6) ectodomain, we found that seSLAMF6 reduced activation-induced cell death and had an antiapoptotic effect on tumor-infiltrating lymphocytes. CD8+ T cells costimulated with seSLAMF6 secreted more IFNγ and displayed augmented cytolytic activity. The systemic administration of seSLAMF6 to mice sustained adoptively transferred transgenic CD8+ T cells in comparable numbers to high doses of IL2. In a therapeutic model, lymphocytes activated by seSLAMF6 delayed tumor growth, and when further supported in vivo with seSLAMF6, induced complete tumor clearance. The ectodomain expedites the loss of phosphorylation on SLAMF6 that occurs in response to T-cell receptor triggering. Our findings suggest that seSLAMF6 is a costimulator that could be used in melanoma immunotherapy. Cancer Immunol Res; 6(2); 127-38. ©2018 AACR.
Assuntos
Antígenos CD8/imunologia , Imunoterapia/métodos , Melanoma/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Animais , Materiais Biomiméticos/farmacologia , Antígenos CD8/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Melanoma/genética , Melanoma/terapia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Peptídeos/genética , Peptídeos/imunologia , Peptídeos/farmacologia , Receptores de Antígenos de Linfócitos T/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/genéticaRESUMO
Activation of the renin-angiotensin-aldosterone system is common in hypertension and obesity and contributes to cardiac diastolic dysfunction, a condition for which no treatment currently exists. In light of recent reports that antihyperglycemia incretin enhancing dipeptidyl peptidase (DPP)-4 inhibitors exert cardioprotective effects, we examined the hypothesis that DPP-4 inhibition with saxagliptin (Saxa) attenuates angiotensin II (Ang II)-induced cardiac diastolic dysfunction. Male C57BL/6J mice were infused with either Ang II (500 ng/kg/min) or vehicle for 3 weeks receiving either Saxa (10 mg/kg/d) or placebo during the final 2 weeks. Echocardiography revealed Ang II-induced diastolic dysfunction, evidenced by impaired septal wall motion and prolonged isovolumic relaxation, coincident with aortic stiffening. Ang II induced cardiac hypertrophy, coronary periarterial fibrosis, TRAF3-interacting protein 2 (TRAF3IP2)-dependent proinflammatory signaling [p-p65, p-c-Jun, interleukin (IL)-17, IL-18] associated with increased cardiac macrophage, but not T cell, gene expression. Flow cytometry revealed Ang II-induced increases of cardiac CD45+F4/80+CD11b+ and CD45+F4/80+CD11c+ macrophages and CD45+CD4+ lymphocytes. Treatment with Saxa reduced plasma DPP-4 activity and abrogated Ang II-induced cardiac diastolic dysfunction independent of aortic stiffening or blood pressure. Furthermore, Saxa attenuated Ang II-induced periarterial fibrosis and cardiac inflammation, but not hypertrophy or cardiac macrophage infiltration. Analysis of Saxa-induced changes in cardiac leukocytes revealed Saxa-dependent reduction of the Ang II-mediated increase of cardiac CD11c messenger RNA and increased cardiac CD8 gene expression and memory CD45+CD8+CD44+ lymphocytes. In summary, these results demonstrate that DPP-4 inhibition with Saxa prevents Ang II-induced cardiac diastolic dysfunction, fibrosis, and inflammation associated with unique shifts in CD11c-expressing leukocytes and CD8+ lymphocytes.
Assuntos
Adamantano/análogos & derivados , Aorta/efeitos dos fármacos , Diástole/efeitos dos fármacos , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Coração/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Adamantano/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Angiotensina II/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/metabolismo , Cardiomegalia/induzido quimicamente , Dipeptidil Peptidase 4/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Ecocardiografia , Fibrose/induzido quimicamente , Expressão Gênica/efeitos dos fármacos , Coração/fisiopatologia , Inflamação , Interleucina-17/metabolismo , Interleucina-18/metabolismo , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-jun/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Vasoconstritores/toxicidadeRESUMO
BACKGROUND: A close association between periodontitis and diabetes has been demonstrated in human cross-sectional studies, but an exact relationship between periodontitis and prediabetes has not been established. Previous studies using animal model systems consistently have shown that hyperinsulinemia occurs in animals with periodontitis compared to animals with healthy periodontium (while maintaining normoglycemia). Because bacterial lipopolysaccharide (LPS) plays an important role in the pathogenesis of periodontitis, we hypothesized that LPS may stimulate insulin secretion through a direct effect on ß cell function. To test this hypothesis, pancreatic ß cell line MIN6 cells were used to determine the effect of Porphyromonas gingivalis (Pg) LPS on insulin secretion. Furthermore, expression of genes altered by Pg LPS in innate immunity and insulin-signaling pathways was determined. METHODS: MIN6 cells were grown in medium with glucose concentration of normoglycemia (5.5 mM). Pg LPS was added to each well at final concentrations of 50, 200, and 500 ng/mL. Insulin secretion was measured using enzyme-linked immunosorbent assay. Gene expression levels altered by Pg LPS were determined by polymerase chain reaction (PCR) array for mouse innate and adaptive immunity response and mouse insulin-signaling pathways, and results were confirmed for specific genes of interest by quantitative PCR. RESULTS: Pg LPS stimulated insulin secretion in the normoglycemic condition by ≈1.5- to 3.0-fold depending on the concentration of LPS. Pg LPS treatment altered the expression of several genes involved in innate and adaptive immune response and insulin-signaling pathway. Pg LPS upregulated the expression of the immune response-related genes cluster of differentiation 8a (Cd8a), Cd14, and intercellular adhesion molecule-1 (Icam1) by about two-fold. LPS also increased the expression of two insulin signaling-related genes, glucose-6-phosphatase catalytic subunit (G6pc) and insulin-like 3 (Insl3), by three- to four-fold. CONCLUSIONS: We have demonstrated for the first time that Pg LPS stimulates insulin secretion by pancreatic ß cell line MIN cells. Pg LPS may have significant implications on the development of ß cell compensation and insulin resistance in prediabetes in individuals with periodontitis.
Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Lipopolissacarídeos/farmacologia , Porphyromonas gingivalis/fisiologia , Imunidade Adaptativa/efeitos dos fármacos , Imunidade Adaptativa/genética , Animais , Antígenos CD8/efeitos dos fármacos , Técnicas de Cultura de Células , Linhagem Celular , Genes MHC da Classe II/efeitos dos fármacos , Glucose/farmacologia , Glucose-6-Fosfatase/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Receptores de Lipopolissacarídeos/efeitos dos fármacos , Lipopolissacarídeos/imunologia , Camundongos , Porphyromonas gingivalis/imunologia , Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para CimaRESUMO
BACKGROUND: Interleukin (IL)-2 therapy impacts T-cell homeostasis. Whether IL-2 expanded CD4(+) T cells may persist following viral rebound has not been fully investigated. METHODS: Patients with CD4(+) T cells 500/µl or more and HIV RNA less than 50 copies/ml were randomized to continue antiretroviral therapy (ART) either alone (n = 67) or combined with three IL-2 cycles (n = 81; 6 million units) twice daily for 5 days at weeks 0, 8, and 16 before stopping ART (week 24). Patients were followed up to 168 weeks. RESULTS: At week 24, median CD4(+) T-cell counts were 1198 and 703 cells/µl in the IL-2 and control groups, respectively (Pâ<â0.001). At week 72, 27% (IL-2 group) and 45% (control group; P = 0.03) of patients were in failure (defined as no interruption of ART at week 24, CD4 drop below 350 cells/µl or ART resumption). After week 24, a biphasic decline (before and after week 32) of CD4 was noted -106 and -7 cells/µl per month in controls and -234 and -17 in IL-2 group (all Pâ≤â0.0001). At week 96, IL-2-expanded CD4(+)CD25(+) T cells remained higher than in the control group (26 vs. 16%, P = 0.006). CONCLUSION: In IL-2-treated patients, CD4(+)CD25(+) T cells persisting despite viral replication allow a longer period of ART interruption.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/tratamento farmacológico , Interleucina-2/administração & dosagem , ADP-Ribosil Ciclase 1/efeitos dos fármacos , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/metabolismo , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/imunologia , Humanos , Subunidade alfa de Receptor de Interleucina-2/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Viral , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
Lupus is a chronic inflammatory autoimmune disease influenced by multiple genetic loci including Fas Ligand (FasL) and P2X7 receptor (P2X7R). The Fas/Fas Ligand apoptotic pathway is critical for immune homeostasis and peripheral tolerance. Normal effector T lymphocytes up-regulate the transmembrane tyrosine phosphatase B220 before undergoing apoptosis. Fas-deficient MRL/lpr mice (lpr mutation) exhibit lupus and lymphoproliferative syndromes due to the massive accumulation of B220(+) CD4(-)CD8(-) (DN) T lymphocytes. The precise ontogeny of B220(+) DN T cells is unknown. B220(+) DN T lymphocytes could be derived from effector CD4(+) and CD8(+) T lymphocytes, which have not undergone activation-induced cell death due to inactivation of Fas, or from a special cell lineage. P2X7R is an extracellular ATP-gated cell membrane receptor involved in the release of proinflammatory cytokines and TNFR1/Fas-independent cell death. P2X7R also regulate early signaling events involved in T-cell activation. We show herein that MRL/lpr mice carry a P2X7R allele, which confers a high sensitivity to ATP. However, during aging, the MRL/lpr T-cell population exhibits a drastically reduced sensitivity to ATP- or NAD-mediated stimulation of P2X7R, which parallels the increase in B220(+) DN T-cell numbers in lymphoid organs. Importantly, we found that this B220(+) DN T-cell subpopulation has a defect in P2X7R-mediated responses. The few B220(+) T cells observed in normal MRL(+/+) and C57BL/6 mice are also resistant to ATP or NAD treatment. Unexpectedly, while P2X7R mRNA and proteins are present inside of B220(+) T cells, P2X7R are undetectable on the plasma membrane of these T cells. Our results prompt the conclusion that cell surface expression of B220 strongly correlates with the negative regulation of the P2X7R pathway in T cells.
Assuntos
Membrana Celular/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Western Blotting , Antígenos CD4/efeitos dos fármacos , Antígenos CD4/metabolismo , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/metabolismo , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Mutantes , NAD/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Receptores Purinérgicos P2X7/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate the efficacy of two topically applied immunomodulative agents through the detection of lymphocyte subsets using monoclonal antibodies against CD4, CD8 and MHC II. METHODS: Fifty patients from the Departments of Medical Biochemistry, Dermatology and Pathology at Cairo University with different degrees of alopecia areata (AA) were included in this study. They were classified into two groups each of 25 patients. Each patient was treated with the immunomodulative agent on one side of the scalp and the other side was left as a control. Biopsies were taken from all patients at the beginning of treatment and at the end of the study. Tissue specimens were prepared for histologic and immunophenotypic analysis. The main outcome measures were the uses of diphencyprone (DPCP) and topical tacrolimus as two topical immunotherapeutic modalities in the treatment of AA. RESULTS: A clinical response of 68% was achieved in group A (treated with DPCP) while group B (treated with 0.1% tacrolimus) showed an insignificant clinical response. Decreased expression of CD4 and increased expression of CD8 and MHC II was detected in the post-treated areas compared with pretreated areas in cases treated with DCPC. In tacrolimus-treated cases, there was a decrease in CD4 and MHC II, with no change in CD8 between the pre- and post-treated areas. CONCLUSION: DCPC is one of the most accepted therapeutic modalities in the treatment of AA, with a favourable prognosis among patchy hair loss. MHC II expression was the one correlating with clinical response. Tacrolimus, though beneficial in other dermatoses, could not be considered effective in the treatment of AA.
Assuntos
Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/imunologia , Ciclopropanos/uso terapêutico , Imunossupressores/uso terapêutico , Tacrolimo/uso terapêutico , Administração Tópica , Adolescente , Adulto , Alopecia em Áreas/metabolismo , Anticorpos Monoclonais , Biomarcadores , Antígenos CD4/efeitos dos fármacos , Antígenos CD4/metabolismo , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/metabolismo , Criança , Ciclopropanos/imunologia , Egito , Feminino , Antígenos de Histocompatibilidade Classe II/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Dermatoses do Couro Cabeludo/tratamento farmacológico , Dermatoses do Couro Cabeludo/imunologia , Dermatoses do Couro Cabeludo/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismo , Tacrolimo/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Our investigation was carried out on an assumption that end results among patients radically-treated for colorectal cancer might be improved by use of enteroabsorption. The study group included 17, controls--13 patients with diagnostically verified stage I-III tumors. Mixed sorbent (microcellulose + polysorb) (6g) was administered, once a week, on the average of 20 days after operation. Immunological vigor was assayed 3 weeks after surgery: immunoglobulin levels--by turbodimetric method, cellular profile of lymphocytes--monoclonal antibodies to cell markers CD3, CD4, CD8, CD16 and CD22. As a result of adjuvant treatment CD22 (B-lymphocytes) concentration increased significantly--from 17.70 to 21.66 (22%), while CD16 (innate killers) both in absolute numbers (19%) and by percentage points (9%). Circulating immunocomplex levels in the sorbent-treatment group were significantly lower (37.44 ths units) than in control (48 ths units) (average 28%). No relapse or metastases were reported in either group.
Assuntos
Celulose/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Enteroadsorção , Polímeros/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Complexo CD3/efeitos dos fármacos , Antígenos CD4/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/cirurgia , Complemento C3/efeitos dos fármacos , Complemento C4/efeitos dos fármacos , Feminino , Humanos , Imunoglobulinas/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia Adjuvante , Receptores de IgG/efeitos dos fármacos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/efeitos dos fármacosRESUMO
OBJECTIVE: The pathogenesis of symptoms of uncomplicated diverticular disease (UDD) is unclear, but changes in gut microflora and physiologic inflammation may be implicated. The objective of the study was to investigate the distribution of gut homing lymphocytes in peripheral blood and intestinal mucosa of UDD patients, and the effects of luminal antibiotic treatment. MATERIAL AND METHODS: Ten UDD patients and 10 age- and gender-matched healthy subjects underwent peripheral blood sampling, and colonoscopy with biopsies taken from the transverse and sigmoid colon. Treatment consisted of a 2-month course of rifaximin 1.2 g/day for 15 days/month. Blood sample and mucosal biopsies were repeated in UDD patients at the end of treatment. Flow cytometry was performed using monoclonal antibodies (CD3, CD4, CD8, CD25, CD19, CD45, CD62L, CD103). RESULTS: In peripheral blood, both CD4+ and CD8+/CD103+ were significantly higher in patients at baseline than in controls (0.95% versus 0.36%, and 0.5% versus 0.09%, respectively). After treatment, peripheral CD4+/CD103+ decreased (0.27%), while CD8+/CD103+ did not change (0.35%); on the contrary, peripheral CD25+ increased, the CD4+ subpopulation showing significantly higher levels than those in controls. No difference was found between lymphocytes in the diverticular sigmoid mucosa of patients at baseline and those in controls, but there was a significant decrease in CD8+/CD62L+ after treatment. In the normal transverse colon, CD4+/CD62L+ of patient at baseline were significantly lower than in controls. After treatment, CD4+/CD103+ levels significantly increased, while CD8+/CD62L+ levels significantly decreased. CONCLUSIONS: Both central and mucosal immunity may be modified in UDD patients, with an increased recruitment of CD103+ lymphocytes. A 2-month course of rifaximin appears to reduce CD103+ levels, suggesting a decrease in mobilization of mucosal homing.
Assuntos
Antígenos CD/imunologia , Antígenos CD4/imunologia , Antígenos CD8/imunologia , Doença Diverticular do Colo/tratamento farmacológico , Doença Diverticular do Colo/imunologia , Fármacos Gastrointestinais/uso terapêutico , Cadeias alfa de Integrinas/imunologia , Rifamicinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais , Antígenos CD/efeitos dos fármacos , Biomarcadores/metabolismo , Antígenos CD4/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Estudos de Casos e Controles , Colo Sigmoide/imunologia , Colo Transverso/imunologia , Colonoscopia , Doença Diverticular do Colo/patologia , Feminino , Citometria de Fluxo , Humanos , Cadeias alfa de Integrinas/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rifaximina , Resultado do TratamentoRESUMO
Cellular immune responses directed against protozoan parasites are key for controlling pathogen replication and disease resolution. However, an uncontrolled, or improperly controlled, response can be deleterious to the host in terms of both allowing for the establishment of pathology, as well as less effective establishment of memory responses. Human cutaneous leishmaniasis is a disease caused by the infection with Leishmania spp. following a bite from the sandfly, the natural vector of this disease. Tens of millions worldwide are currently infected with Leishmania and no effective vaccines have been developed to date. In the face of the complexity presented by the interaction between a host (humans) with the parasite, Leishmania, and the fact that this parasite is inoculated by another complex, biologically active, vector, the sandfly, it is clearly important to study the immunoregulatory mechanisms that are induced in humans naturally infected by this parasite if we hope to develop effective vaccines and immunotherapeutic treatments in the future. Our laboratory has focused over the years on the study of the local and systemic T cell response during the first episode of cutaneous leishmaniasis suffered by individuals before they undergo antimony treatment. The goal of this review is to briefly outline our findings with hopes of putting our most recent studies concerning the dichotomy between alpha/beta TCR and gamma/delta TCR expressing, CD4-CD8- (double negative-DN) T cells in the context of a balanced immune response against Leishmania and to discuss the implications of these findings toward our understanding of human leishmaniasis.
Assuntos
Antígenos CD4/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Leishmania , Leishmaniose Cutânea/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Arginase/imunologia , Previsões , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologiaRESUMO
OBJECTIVE: Somatostatin regulates immune inflammatory response via apoptosis and adhesion of leukocytes in many diseases. This article reported a study that aimed to observe the mechanism and effect of somatostatin on the immune inflammatory response through apoptosis and adhesion of leukocytes in severe acute pancreatitis. METHODS: Thirty-eight patients with severe acute pancreatitis, that fulfilled the guidelines for the treatment of severe acute pancreatitis of China and Balthazar computed tomography severity index (>or=5) were enrolled consecutively. Nineteen of these patients received our routine treatment and 19 received additional somatostatin. In all patients the expressions of CD4, CD8, CD95/CD95 ligand and CD18/CD62 ligand on leukocytes were determined by flow cytometry, both upon admission and on the fourth day. Thirty healthy volunteers constituted the normal healthy group. RESULTS: In the treatment group, CD4, CD4:CD8 ratio and CD62 ligand on leukocytes increased from 11.4+/-8.2, 0.47+/-0.10 and 25.5+/-9.2 to 22.1+/-9.7, 0.68+/-0.11 and 36.2+/-11.7 (P<0.05) respectively, while CD95 ligand on both lymphocyte and polymorphonuclear cells increased from 0.65+/-0.21 and 0.76+/-0.29 to 1.18+/-0.32 and 1.58+/-0.43 after treatment with somatostatin (P<0.05). Furthermore, lactate dehydrogenase, aspartate aminotransferase, amylase, C reactive protein and acute physiology and chronic healthy evaluation (APACHE II) score in the treatment group reduced faster than those in the control group (P<0.05), though there was no difference in mortality (15.7% vs 5.3%) between the two patient groups (P>0.05). CONCLUSION: Somatostatin can modulate the immune inflammatory response and the severity of severe acute pancreatitis through apoptosis and adhesion of leukocytes, but this modulatory effect by itself is not strong enough to improve the final.
Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Somatostatina/farmacologia , Regulação para Cima/efeitos dos fármacos , APACHE , Doença Aguda , Adulto , Idoso , Apoptose/efeitos dos fármacos , Antígenos CD18/efeitos dos fármacos , Antígenos CD18/metabolismo , Antígenos CD4/efeitos dos fármacos , Antígenos CD4/metabolismo , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/metabolismo , Adesão Celular/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Selectina L/efeitos dos fármacos , Selectina L/metabolismo , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Pancreatite/imunologia , Estudos Prospectivos , Receptor fas/efeitos dos fármacos , Receptor fas/metabolismoRESUMO
Fifteen piglets were used to determine the effect of vitamin E supplementation on the number of CD4-immunoreactive (CD4+) T-lymphocytes, CD8-immunoreactive (CD8+) T-lymphocytes and IgA-immunoreactive (IgA+) B-lymphocytes per follicle in the Peyer's patch of distal ileum and the mesenteric lymph nodes of weaned piglets. Piglets, following a 3-day adaptation period after weaning, were assigned to one of three experimental groups: control (no vitamin E supplementation), vitamin E supplementation of 100 mg/kg of diet and vitamin E supplementation of 300 mg/kg of diet. Supplementation of vitamin E lasted for a period of 36 days. The basal diet contained 80 mg alpha-tocopherol/kg of diet. All piglets were killed at day 39 after weaning and samples of the distal ileum and adjacent mesenteric lymph nodes were collected. The number of cells for each lymphocyte subset was counted in the Peyer's patch and the mesenteric lymph nodes follicles, in cryostat sections processed for immunohistochemistry. Results showed that vitamin E supplementation (300 mg/kg diet) of piglets caused an increase (P < 0.05) in the number of IgA+ B-lymphocytes in the Peyer's patch, but not in the mesenteric lymph nodes, compared with the corresponding values in control animals. Vitamin E supplementation had no effect (P > 0.05) on the number of CD4+ and CD8+ T-lymphocytes in the follicles of the Peyer's patch and the adjacent mesenteric lymph nodes. Thus, vitamin E had relatively minor effects on distribution of the major immunocompetent cells in the gut. The numbers of CD4+ and CD8+ T-lymphocytes as well as IgA+ B-lymphocytes per follicle were higher by 26-77% (P < 0.05) in the mesenteric lymph nodes than the corresponding values in the Peyer's patch.
Assuntos
Antioxidantes/administração & dosagem , Linfócitos/efeitos dos fármacos , Nódulos Linfáticos Agregados/imunologia , Vitamina E/administração & dosagem , Animais , Antígenos CD4/efeitos dos fármacos , Antígenos CD4/imunologia , Contagem de Linfócito CD4/veterinária , Relação CD4-CD8/veterinária , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/imunologia , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Imunoglobulina A/efeitos dos fármacos , Imunoglobulina A/imunologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Mesentério , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/efeitos dos fármacos , Distribuição Aleatória , Suínos , DesmameRESUMO
We have demonstrated that GA therapy induces a differential upregulation of GA-specific, cytotoxic/suppressor CD8+ T-cell responses in MS patients. We utilized a novel combination of flow sorting and anchored PCR to analyze the evolving clonal composition of GA-specific CD4+ and CD8+ T-cells. TCRbeta chain analysis revealed the development of an oligoclonal GA-specific CD8+ repertoire with persistence of dominant clones over long periods. Interestingly, some sequences resembled published oligoclonal CD8+ TCR sequences from MS lesions. In contrast, GA-specific CD4+ responses were polyclonal and showed continual evolution of their repertoire. This clonotypic and functional analysis provides mechanistic insights into GA therapy.
Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Peptídeos/farmacologia , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/genética , Antígenos CD8/imunologia , Células Clonais/efeitos dos fármacos , Células Clonais/imunologia , Feminino , Citometria de Fluxo/métodos , Acetato de Glatiramer , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Esclerose Múltipla/fisiopatologia , Peptídeos/uso terapêutico , Reação em Cadeia da Polimerase/métodos , Receptores de Antígenos de Linfócitos T alfa-beta/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologiaRESUMO
The study included 37 patients with chronic tonsillitis. Before and after tonsillectomy all the patients' humoral and cellular immunities were studied. Local thermometry and physiological test "pharynx" were made. For optimization of early postoperative period, all the tonsillectomized patients were given a domestic immunomodulator with local anti-inflammatory activity gepon. The results of gepon therapy allowed conclusion that local use of immunomodulator gepon early after bilateral tonsillectomy is justified and can be recommended for wide clinical practice.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Fatores Imunológicos/uso terapêutico , Oligopeptídeos/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Tonsilectomia/métodos , Tonsilite/cirurgia , Adolescente , Adulto , Antígenos CD8/efeitos dos fármacos , Doença Crônica , Feminino , Humanos , Fatores Imunológicos/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Masculino , Neutrófilos/efeitos dos fármacosRESUMO
Juzen-taiho-to (TJ-48), a mixture of extracts from 10 medicinal herbs, has been used traditionally to treat patients with anemia, anorexia or fatigue. It is well known that the treatment of TJ-48 result in the decrease of patient's complaints, as well as the increase of NK cytolytic activity (NK activity) although its augmentation is not clear in the other kampo formula from the clinical viewpoint. To investigate its biological activities, such as the augmentation of NK activity, we analyzed the effects of TJ-48 on the expression of killer-cell immunoglobulin-like receptors (KIRs) in vitro experiment. The peripheral lymphocytes were incubated in medium alone, or medium containing TJ-48 or interleukin-2 (IL-2) plus TJ-48 at several concentrations for 48 h. After each incubation, cells were collected and their KIRs were detected by flow cytometry using monoclonal antibodies CD158a and CD158b. TJ-48 increased the populations of CD16+CD158a+ and CD16+CD158b+ cells in a dose-dependent manner. In contrast, CD16-CD158a/b+ cells did not increase. Additionally, the extract of TJ-48 enhanced the increase of KIRs expression induced by IL-2. These actions contribute to the augmentation of NK cytolytic activity by TJ-48, and might explain, in part, its antitumor effects which has been observed in vivo.
Assuntos
Adjuvantes Imunológicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Plantas Medicinais , Receptores Imunológicos/metabolismo , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/metabolismo , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Citometria de Fluxo , Humanos , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêuticoRESUMO
Interleukin-12 (IL-12) plays a critical role in producing an immune response, as indicated in many ways, e.g., induction of interferon-gamma (IFN-gamma), and augmentation of the cytotoxic activity of resting activated T cells and natural killer (NK) cells. In this study, we examined whether intratumoral injection of a recombinant retrovirus vector expressing IL-12s induce antitumor and antiangiogenic effects in a murine model using a murine head and neck squamous cell carcinoma (NR-S1). In vitro the levels of vascular endothelial growth factor (VEGF) mRNA and protein expression were decreased in IL-12 gene transfected NR-S1 cell. in vivo direct IL-12 gene therapy resulted in significantly remarkable inhibition of tumor growth compared to the control group. The tumor regression by direct IL-12 gene therapy was also associated with decreased vessel density, and apoptosis and increased infiltration of CD8(+) T cells and CD56(+) NK cells in the tumor increased. Also, the number of IFN-gamma expressed cells of spleen cells was increased in the treatment group compared with the control group. These results suggested that direct IL-12 gene therapy appears to be effective in reducing tumor growth by triggering both antiangiogenic effects and an immunological enhancing mechanism through induction of IFN-gamma.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma de Células Escamosas/terapia , Terapia Genética/métodos , Neoplasias de Cabeça e Pescoço/terapia , Interleucina-12/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Antígeno CD56/efeitos dos fármacos , Antígeno CD56/imunologia , Antígenos CD8/efeitos dos fármacos , Antígenos CD8/imunologia , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/imunologia , Contagem de Células , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/imunologia , Imuno-Histoquímica , Técnicas In Vitro , Injeções , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/administração & dosagem , Interleucina-12/farmacologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/química , Camundongos , RNA Mensageiro/efeitos dos fármacos , Transfecção/métodos , Fator A de Crescimento do Endotélio Vascular/metabolismoAssuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adulto , Alemtuzumab , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Antígenos CD4/efeitos dos fármacos , Antígenos CD8/efeitos dos fármacos , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , MasculinoRESUMO
Androgens influence some immunological processes, including alternation of the number and function of the circulating lymphocytes and monocytes. In the present study, the effects of three different doses of testosterone on the numbers and percentages of the peripheral blood cells were investigated; the lymphocyte subsets were determined and the proliferation of lymphocyte was detected. Groups of Sprague-Dawley rats were treated with 0.5, 2.5, 12.5 mg/kg or only vehicle, respectively. Compared with controls, the results of complete blood counts showed that the absolute and relative numbers of monocytes decreased. The lymphocyte subpopulations determined by flow cytometry indicated an increase in CD8+ T cells, whereas the CD3+, CD4+ and CD4+CD8+ T cells remained unchanged. Thus, the immunoregulatory index (CD4+/CD8+ ratio) decreased. The proliferative activities determined by MTT assay were down-regulated. In conclusion, the immunosuppressive effects of testosterone may be attributed to a decline in number of monocytes, CD4+/CD8+ ratio and proliferative activities together with an increase of CD8+ T cells in Sprague-Dawley rats.