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1.
Curr Opin Pharmacol ; 51: 29-33, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32480246

RESUMO

The worldwide socioeconomical burden associated with chronic respiratory diseases is substantial. Enzymes involved in the metabolism of nicotinamide adenine dinucleotide (NAD) are increasingly being implicated in chronic airway diseases. One such enzyme, CD38, utilizes NAD to produce several metabolites, including cyclic ADP ribose (cADPR), which is involved in calcium signaling in airway smooth muscle (ASM). Upregulation of CD38 in ASM caused by exposure to cytokines or allergens leads to enhanced calcium mobilization by agonists and the development of airway hyperresponsiveness (AHR) to contractile agonists. Glucocorticoids and microRNAs can suppress CD38 expression in ASM, whereas cADPR antagonists such as 8Br-cADPR can directly antagonize intracellular calcium mobilization. Bronchodilators act via CD38-independent mechanisms. CD38-dependent mechanisms could be developed for chronic airway diseases therapy.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , ADP-Ribose Cíclica/metabolismo , Pneumopatias Obstrutivas/metabolismo , Glicoproteínas de Membrana/metabolismo , Transdução de Sinais/fisiologia , ADP-Ribosil Ciclase 1/imunologia , Animais , Cálcio/imunologia , Cálcio/metabolismo , ADP-Ribose Cíclica/imunologia , Humanos , Pneumopatias Obstrutivas/imunologia , Glicoproteínas de Membrana/imunologia
2.
Hum Antibodies ; 25(3-4): 75-85, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28035914

RESUMO

This review focuses on the concept of antibodies acting as receptor agonists and antagonists, and on the potential relevance of this notion in applied medicine. Antibodies are composed of three functional units: two antigen-binding fragments (Fabs) that confer antigen specificity and one constant fragment (Fc) linking antibodies to immune effector functions. The proof-of-concept that large amounts of highly specific and homogeneous antibodies could be produced was provided in 1975 by César Milstein and Georges Köhler. These monoclonal antibody (mAb) reagents started a revolution in medical research, diagnostics, and clinical applications. Alongside diagnostic applications, mAbs were successfully used in vivo: (i) to bind (neutralize/antagonize) antigens expressed on the surface of tumor cells; (ii) to activate immune effector mechanisms; (iii) to crosslink plasma membrane receptors and hence activate therapeutic signaling pathways; and lastly, (iv) the technique was expanded to produce bispecific mAbs, which can bind two different antigens while retaining the ability to activate immune effector functions. The abilities of mAbs to bind, transduce signals, and exert immunostimulatory agonistic capacities are the central issues of this review. The starting point is that some mAbs operate as molecular agonists, substituting for the natural ligand of the receptor. Our analysis is restricted to mAbs that act as receptor agonist/antagonists by either mimicking ligand binding, or through allosteric modulation mediated by binding sites that are topographically distinct from the orthosteric binding site. Functional considerations based on the agonistic stimulation of human CD38 by specific mAbs as surrogate ligands are described as examples of the features of such molecules.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Mimetismo Molecular/imunologia , Neoplasias/tratamento farmacológico , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Regulação Alostérica , Animais , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/metabolismo , Especificidade de Anticorpos , ADP-Ribose Cíclica/imunologia , ADP-Ribose Cíclica/metabolismo , Humanos , Fragmentos Fab das Imunoglobulinas/genética , Fragmentos Fab das Imunoglobulinas/metabolismo , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/metabolismo , Fatores Imunológicos/genética , Fatores Imunológicos/metabolismo , Ligantes , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Ligação Proteica , Receptor Cross-Talk/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia
3.
Int Immunol ; 18(7): 1029-42, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16720618

RESUMO

Cross-linking of CD38 on hematopoietic cells induces activation, proliferation and differentiation of mature T and B cells and mediates apoptosis of myeloid and lymphoid progenitor cells. In addition to acting as a signaling receptor, CD38 is also an enzyme capable of producing several calcium-mobilizing metabolites, including cyclic adenosine diphosphate ribose (cADPR). It has been previously postulated that the calcium-mobilizing metabolites produced by CD38 may regulate its receptor-based activities. To test this hypothesis, we examined whether the enzyme activity of CD38 controls the apoptosis of an anti-CD38-stimulated leukemic B cell. We show that anti-CD38-induced apoptosis of Ba/F3 cells, a murine pro-B cell line, is not affected by blocking the calcium-mobilizing activity of cADPR or by inhibiting intracellular or extracellular calcium mobilization. In addition, we demonstrate that blocking CD38 enzyme activity with 2'-deoxy-2'-fluoro-nicotinamide arabinoside adenine dinucleotide has no effect on apoptosis and that Ba/F3 cells expressing catalytically inactive mutant forms of CD38 still undergo apoptosis upon CD38 cross-linking. Instead, we find that anti-CD38-induced apoptosis is dependent on tyrosine kinase and caspase activation, and that this process appears to be potentiated by the presence of membrane microdomains. Thus, the receptor-mediated functions of CD38 can be separated from its enzyme activity in a murine leukemic cell line, suggesting that CD38 plays multiple, but independent, biologic roles.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , ADP-Ribosil Ciclase/imunologia , Apoptose/imunologia , Linfócitos B/imunologia , Sinalização do Cálcio/imunologia , ADP-Ribosil Ciclase/antagonistas & inibidores , ADP-Ribosil Ciclase/metabolismo , ADP-Ribosil Ciclase 1/antagonistas & inibidores , ADP-Ribosil Ciclase 1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/enzimologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , ADP-Ribose Cíclica/imunologia , ADP-Ribose Cíclica/metabolismo , Inibidores Enzimáticos/farmacologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Capeamento Imunológico/efeitos dos fármacos , Capeamento Imunológico/imunologia , Leucemia de Células B/imunologia , Leucemia de Células B/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Microdomínios da Membrana/enzimologia , Microdomínios da Membrana/imunologia , Camundongos , NAD/análogos & derivados , NAD/farmacologia
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