RESUMO
Regulatory T cells (Tregs) can be targeted in cancer immunotherapy. A previous study has shown that the chemokine CCL17 and the receptor CCR4 play a role in Treg recruitment in canine urothelial carcinoma. Here, we describe the association of tumor-infiltrating Tregs with CCL17/CCR4 expression in dogs with other carcinomas. In this study, we investigated 23 dogs with mammary carcinoma, 14 dogs with oral squamous cell carcinoma, 16 dogs with pulmonary adenocarcinoma, and 8 healthy control dogs. Immunohistochemistry showed that Foxp3+ Tregs and CCR4+ cells were increased in the tumor tissues of mammary carcinoma, squamous cell carcinoma, and pulmonary adenocarcinoma, when compared with the healthy tissues. The number of CCR4+ cells was associated with that of Foxp3+ Tregs. Double immunofluorescence labeling confirmed that most tumor-infiltrating Foxp3+ Tregs expressed CCR4. In vitro, canine carcinoma cell lines expressed CCL17 mRNA. Quantitative RT-PCR (reverse transcriptase-polymerase chain reaction) showed that CCL17 mRNA expression in canine carcinomas was increased approximately 10- to 25-fold relative to that of healthy tissues. These results suggest that the CCL17/CCR4 axis may drive Treg recruitment in a variety of canine carcinomas. CCR4 blockade may be a potential therapeutic option for tumor eradication through Treg depletion.
Assuntos
Carcinoma/veterinária , Quimiocina CCL17/metabolismo , Doenças do Cão/patologia , Receptores CCR4/metabolismo , Adenomatose Pulmonar/metabolismo , Adenomatose Pulmonar/veterinária , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Carcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/veterinária , Linhagem Celular Tumoral/metabolismo , Movimento Celular , Cães , Fatores de Transcrição Forkhead , Neoplasias Mamárias Animais/metabolismo , Receptores CCR4/efeitos dos fármacos , Linfócitos T Reguladores/metabolismoRESUMO
BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4 and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: The risk and spectrum of infections in patients receiving CD22-targeted agents (i.e. inotuzumab ozogamicin) are similar to those observed with anti-CD20 antibodies. Anti-Pneumocystis prophylaxis and monitoring for cytomegalovirus (CMV) infection is recommended for patients receiving CD30-targeted agents (brentuximab vedotin). Due to the scarcity of data, the risk posed by CD33-targeted agents (gemtuzumab ozogamicin) cannot be assessed. Patients receiving CD38-targeted agents (i.e. daratumumab) face an increased risk of varicella-zoster virus (VZV) infection. Therapy with CD40-targeted agents (lucatumumab or dacetuzumab) is associated with opportunistic infections similar to those observed in hyper-IgM syndrome, and prevention strategies (including anti-Pneumocystis prophylaxis and pre-emptive therapy for CMV infection) are warranted. SLAMF-7 (CD319)-targeted agents (elotuzumab) induce lymphopenia and increase the risk of infection (particularly due to VZV). The impact of CCR4-targeted agents (mogamulizumab) on infection susceptibility is difficult to distinguish from the effect of underlying diseases and concomitant therapies. However, anti-Pneumocystis and anti-herpesvirus prophylaxis and screening for chronic hepatitis B virus (HBV) infection are recommended. IMPLICATIONS: Specific management strategies should be put in place to reduce the risk and/or the severity of infectious complications associated to the reviewed agents.
Assuntos
Antígenos de Superfície/efeitos dos fármacos , Terapia Biológica/efeitos adversos , Doenças Transmissíveis/terapia , Terapia de Alvo Molecular/efeitos adversos , ADP-Ribosil Ciclase 1/efeitos dos fármacos , Antígenos de Superfície/imunologia , Terapia Biológica/métodos , Antígenos CD40/efeitos dos fármacos , Ensaios Clínicos como Assunto , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/virologia , Consenso , Humanos , Hospedeiro Imunocomprometido , Antígeno Ki-1/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Glicoproteínas de Membrana/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Células Mieloides/efeitos dos fármacos , Receptores CCR4/efeitos dos fármacos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/efeitos dos fármacos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/efeitos dos fármacos , Família de Moléculas de Sinalização da Ativação Linfocitária/efeitos dos fármacosRESUMO
AIM: The balance between T helper cell subsets is an important regulator of the immune system and is often examined after immune therapies. We aimed to study the immunomodulatory effect of glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) in children with Type 1 diabetes, focusing on chemokines and their receptors. METHODS: Blood samples were collected from 70 children with Type 1 diabetes included in a phase II clinical trial with GAD-alum. Expression of CC chemokine receptor 5 (CCR5) and CCR4 was analysed on CD4+ and CD8+ lymphocytes after in vitro stimulation with GAD(65) using flow cytometry, and secretion of the chemokines CCL2, CCL3 and CCL4 was detected in peripheral blood mononuclear cell supernatants with Luminex. RESULTS: Expression of Th1-associated CCR5 was down-regulated following antigen challenge, together with an increased CCR4/CCR5 ratio and CCL2 secretion in GAD-alum-treated patients, but not in the placebo group. CONCLUSION: Our results suggest that GAD-alum treatment has induced a favourable immune modulation associated with decreased Th1/Tc1 phenotypes upon antigen re-challenge, which may be of importance for regulating GAD(65) immunity.
Assuntos
Hidróxido de Alumínio/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glutamato Descarboxilase/uso terapêutico , Linfócitos T Citotóxicos/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Adolescente , Hidróxido de Alumínio/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Feminino , Citometria de Fluxo , Glutamato Descarboxilase/farmacologia , Humanos , Memória Imunológica , Ativação Linfocitária/efeitos dos fármacos , Masculino , Fenótipo , Receptores CCR4/efeitos dos fármacos , Receptores CCR5/efeitos dos fármacos , SuéciaRESUMO
Entamoeba histolytica produces Monocyte Locomotion Inhibitory Factor (MLIF), which may contribute to the delayed inflammation observed in amoebic hepatic abscesses. Leukocytes are affected through the modulation of cytokine expression and/or production. We evaluated the effects of MLIF on the activation and production of intracellular cytokines in human CD4+ T lymphocytes by flow cytometry. Cells were stimulated for 24 h with PMA, MLIF, or PMA+MLIF. Cellular activation was measured using anti-CD69. Th1/Th2 production was studied by the expression of intracellular cytokines and cytokine/chemokine receptors. MLIF increased CD69 and induced the over-expression of the IL-lss, IFN-gamma, IL-2, IL-4, and IL-10 intracellular cytokines; PMA+MLIF inhibited Th1 cytokine (IFN-gamma) and increased Th2 cytokines (IL-4 and IL-10). The co-expression of the cytokine and chemokine receptors IFN-gamma/CCR5 and IL-1ss/CCR5 was inhibited by PMA+MLIF and Th2 co-expression was increased. MLIF effects varied depending on the conditions. MLIF alone activated the Th1 and Th2 cytokines and cytokine/receptor expression; however, PMA+MLIF increased the expression of Th2 but inhibited it in Th1.
Assuntos
Citocinas/biossíntese , Oligopeptídeos/farmacologia , Receptores CCR4/efeitos dos fármacos , Receptores CCR5/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Células Cultivadas , Entamoeba histolytica/imunologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Oligopeptídeos/biossíntese , Receptores CCR4/imunologia , Receptores CCR5/imunologia , Acetato de Tetradecanoilforbol/farmacologia , Células Th1/imunologia , Células Th2/imunologiaRESUMO
OBJECTIVE: To examine local inhibition of Th2 cell infiltration as the basis for demonstrating the superior clinical effect of trichloroacetic acid (TCA) treatment for allergic rhinitis. METHODS: Mirror-image sections of the inferior turbinate mucosae of both sides were obtained from 26 patients who underwent TCA treatment on one side because of the nasal anatomy status and who eventually underwent bilateral inferior turbinectomy because of failure of the TCA treatment. Th2 cell counts, defined as counts of cells positive for anti-CD4 antibody and anti-CKR4 antibody (double-positive cells) were obtained for comparison. The differences between the TCA-treated and non-TCA-treated mucosae were analyzed by Mann-Whitney's U test. RESULTS: Th2 cell infiltration was characteristically found just beneath the epithelium and in the periglandular areas. The mean count+/-standard deviation of Th2 cells was 4.96+/-2.72 cells/mm(2) in the TCA-treated mucosae and 12.03+/-7.19 cells/mm(2) in the non-treated mucosae, the difference being significant (p<0.01). CONCLUSION: TCA treatment induces inhibition of Th2 cell infiltration. This corroborates the suggestion that TCA treatment can inhibit local type I allergic reactions.
Assuntos
Cáusticos/farmacologia , Cáusticos/uso terapêutico , Rinite Alérgica Perene/terapia , Células Th2/efeitos dos fármacos , Ácido Tricloroacético/farmacologia , Ácido Tricloroacético/uso terapêutico , Adulto , Anticorpos Anti-Idiotípicos/imunologia , Antígenos CD4/imunologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/patologia , Receptores CCR4/efeitos dos fármacos , Rinite Alérgica Perene/imunologiaRESUMO
The present studies were conducted to better define the mechanism of action of polyethylene hexamethylene biguanide (PEHMB) (designated herein as NB325), which was shown in previous studies to inhibit infection by the human immunodeficiency virus type 1 (HIV-1). Fluorescence-activated flow cytometric analyses of activated human CD4(+) T lymphocytes exposed to NB325 demonstrated concentration-dependent reductions in CXCR4 epitope recognition in the absence of altered recognition of selected CD4 or CD3 epitopes. NB325 also inhibited chemotaxis of CD4(+) T lymphocytes induced by the CXCR4 ligand CXCL12. However, NB325 did not cause CXCR4 internalization (unlike CXCL12) and did not interfere with CXCL12 binding. Additional flow cytometric analyses using antibodies with distinct specificities for extracellular domains of CXCR4 demonstrated that NB325 specifically interfered with antibody binding to extracellular loop 2 (ECL2). This interaction was confirmed using competitive binding analyses, in which a peptide derived from CXCR4 ECL2 competitively inhibited NB325-mediated reductions in CXCR4 epitope recognition. Collectively, these results demonstrate that the biguanide-based compound NB325 inhibits HIV-1 infection by specifically interacting with the HIV-1 coreceptor CXCR4.
Assuntos
Fármacos Anti-HIV/farmacologia , Biguanidas/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Receptores CCR4/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Quimiotaxia/efeitos dos fármacos , Citometria de Fluxo , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Peptídeos/químicaRESUMO
Psoriasis, atopic dermatitis and allergic contact dermatitis are T-cell-mediated inflammatory skin diseases; chemokine receptors (CCR) 4 and 10 play an important role in the ligand-mediated recruitment of T cells into the skin in mice and humans, specifically with regards to tethering, firm adhesion and subsequent extravasation to the sight of injury. We utilized established murine models of dinitrofluorobenzene-, trimellitic acid anhydride- or oxazalone-induced contact hypersensitivity, to reflect the various Th-polarizations of different skin diseases, and investigated the functional effect of antibody blocking of single CCR ligands or combination therapy to block all CCR4 and CCR10 ligands. Our results indicate a greater reduction in inflammatory response--measured by oedema formation, myeloid cell and neutrophil infiltration and activity and CD3+ cell infiltration at the site of injury--with combination antibody therapy to CCR4 and CCR10 ligands versus controls, in nearly every tested condition. We conclude that blocking CCR4 and CCR10 simultaneously, or their ligands, should be beneficial in the treatment of T-cell-mediated skin diseases.