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Publication
Effects of the oral antidiabetic sitagliptin on thymic T-cell subsets of an animal model of multiple sclerosis
Abstract(s)
Introdução: A Esclerose Múltipla (EM) é uma das principais causas de incapacidade neurológica em adultos jovens. A par com o contexto autoimune, os doentes com EM apresentam uma involução tímica precoce e alteração da homeostase das células T CD4 que parecem aumentar a suscetibilidade do doente à auto-reatividade. Os tratamentos disponíveis são apenas sintomáticos e não mitigam os processos centrais da doença: desmielinização e remielinização. Contudo, estudos recentes associam a inibição farmacológica do alvo CD26/DPP-IV com uma diminuição da incidência, início dos sintomas e gravidade geral da doença.
Objetivo: Dado o envolvimento do CD26/DPP-IV na maturação das células T no timo, no processo auto-reativo das células T e na inflamação autoimune, este trabalho visou avaliar o efeito de um inibidor da DPP-IV o antidiabético oral sitagliptina na modulação da involução tímica e respetivo benefício farmacológico num ensaio pré-clínico de EM.
Methods: Murganhos C57BL/6 adultos foram submetidos ao modelo de EM induzido por cuprizona. A sitagliptina foi administrada oralmente numa dose de 50mg/Kg de peso corporal. A caracterização da morte de células do timo (7-AAD) e subpopulações de células T (coloração extracelular CD4, CD8, CD3) foi realizada por citometria de fluxo. A expressão de genes que codificam proteínas associadas à mielina (MBB, PLP; cerebelo) foi analisada por RT-PCR. As experiências com animais receberam aprovação (# 12/2018) pelo organismo local (iCBR-FMUC) de Bem-Estar Animal (ORBEA).
Resultados: A sitagliptina promoveu a involução tímica durante a fase de desmielinização da doença, caracterizada por i) uma reversão do aumento global do ratio CD3high/low (sugerindo um bloqueio da maturação das células T) e ii) um fenótipo dominante de células T CD8+/CD3high. Surpreendentemente, a sitagliptina bloqueou a remielinização cerebelar espontânea induzida por suspensão da cuprizona.
Conclusões: Estes resultados permitem-nos concluir que a regeneração tímica e a remielinização central são processos que, embora simultâneos, são independentes. É improvável que uma intervenção com sitagliptina se traduza em ganhos terapêuticos neste modelo animal de EM. Estudos futuros serão necessários para avaliar o potencial dos inibidores da DPP-IV nas doenças autoimunes, permitindo revelar efeitos secundários
plausíveis, que ainda carecem de esclarecimento.
Introduction: MS is one of the leading causes of neurological disability in young adults. Besides autoimmune inflammation, MS patients display early thymic involution and perturbed naïve CD4 T-cell homeostasis that seem to increase patient’s susceptibility to autoreactivity. Available treatments are only symptomatic and do not tackle the core of the disease: demyelination along with spontaneous remyelination. Notably, thepharmacological inhibition of CD26/DPP-IV was correlated with a decreased incidence, onset of symptoms and overall disease severity. Aim: Given the involvement of CD26/DPP-IV on thymic T cell maturation, autoreactive T cells activation and autoimmune inflammation, the current work aimed to assess whether a currently approved DPP-IV inhibitor sitagliptin (an antidiabetic drug) - would modulate thymic involution and provide pharmacological benefits in MS. Methods: Adult C57BL/6 mice were assigned to the cuprizone-induced model of MS. Sitagliptin was orally given at a dose of 50mg/Kg BW. Flow cytometry allowed the characterization of thymocyte cell death (7-AAD) and T-cell subpopulations (CD4, CD8, CD3 extracellular staining). RT-PCR was employed to characterize the cerebellar myelinrelated MBP/PLP gene expression. Animal experiments received approval (# 12/2018) by the local (iCBR-FMUC) Animal Welfare Body (ORBEA). Results: Sitagliptin remodeled thymic involution during the demyelination phase of the disease, featured by i) an arrest in the overall increase in CD3 high/low ratio (suggestive of T cells maturation blockade) and ii) a dominant thymic CD8+/CD3high T phenotype. Unexpectedly, sitagliptin blocked cuprizone-induced cerebellar remyelination. Conclusion: From our observations it is possible to conclude that thymic regeneration and central remyelination are simultaneous, albeit independent processes. It is unlikely that sitagliptin affords protection in the cuprizone-animal model of MS. Future studies are encouraged to assess the potential of DPP-IV inhibitors repurposing in autoimmune diseases, allowing us to disclose plausible side-effects that are still lacking elucidation.
Introduction: MS is one of the leading causes of neurological disability in young adults. Besides autoimmune inflammation, MS patients display early thymic involution and perturbed naïve CD4 T-cell homeostasis that seem to increase patient’s susceptibility to autoreactivity. Available treatments are only symptomatic and do not tackle the core of the disease: demyelination along with spontaneous remyelination. Notably, thepharmacological inhibition of CD26/DPP-IV was correlated with a decreased incidence, onset of symptoms and overall disease severity. Aim: Given the involvement of CD26/DPP-IV on thymic T cell maturation, autoreactive T cells activation and autoimmune inflammation, the current work aimed to assess whether a currently approved DPP-IV inhibitor sitagliptin (an antidiabetic drug) - would modulate thymic involution and provide pharmacological benefits in MS. Methods: Adult C57BL/6 mice were assigned to the cuprizone-induced model of MS. Sitagliptin was orally given at a dose of 50mg/Kg BW. Flow cytometry allowed the characterization of thymocyte cell death (7-AAD) and T-cell subpopulations (CD4, CD8, CD3 extracellular staining). RT-PCR was employed to characterize the cerebellar myelinrelated MBP/PLP gene expression. Animal experiments received approval (# 12/2018) by the local (iCBR-FMUC) Animal Welfare Body (ORBEA). Results: Sitagliptin remodeled thymic involution during the demyelination phase of the disease, featured by i) an arrest in the overall increase in CD3 high/low ratio (suggestive of T cells maturation blockade) and ii) a dominant thymic CD8+/CD3high T phenotype. Unexpectedly, sitagliptin blocked cuprizone-induced cerebellar remyelination. Conclusion: From our observations it is possible to conclude that thymic regeneration and central remyelination are simultaneous, albeit independent processes. It is unlikely that sitagliptin affords protection in the cuprizone-animal model of MS. Future studies are encouraged to assess the potential of DPP-IV inhibitors repurposing in autoimmune diseases, allowing us to disclose plausible side-effects that are still lacking elucidation.
Description
Keywords
Esclerose múltipla Intoxicação por cuprizona Involução tímica Inibidores CD26/DPP-IV Sitagliptina Remielinização espontânea Multiple Sclerosis Cuprizone intoxication Thymic involution Inhibitors Sitagliptin Spontaneous remyelination