Transplante de células-tronco mesenquimais alogênicas em cães com meningoencefalomielite de origem desconhecida
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Data
2021-02-05
Autores
Sánchez, Giovana Boff
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A meningoencefalomielite de origem desconhecida (MUO) canina é uma doença neuroinflamatória de provável origem imunomediada, altamente debilitante, que apresenta prognostico desfavorável e falha terapêutica com o uso de imunossupressores. As células-tronco mesenquimais (MSCs) são promissoras para o tratamento de doenças neuroimunes, porém, diferentes fontes podem apresentar variações no potencial imunomodulador e neuroprotetor. In vitro, avaliamos a expressão gênica de BDNF, GDNF, HGF, IDO, IL-10 e PTGES2 e o perfil secretório de IL-2, IL-6, IL-8, IL-10, GM-CSF e MCP-1 de MSCs caninas derivadas do tecido adiposo (Ad-MSCs) e placenta (PMSCs) após estimulação única com INF-γ e combinada com INF-γ com TNF-α. In vivo, avaliamos a resposta terapêutica ao transplante de Ad-MSCs alogênicas em cães com MUO que apresentaram falha terapêutica ao tratamento imunossupressor. Grupo PAC: 12 cães com MUO tratados com o protocolo imunossupressor de citarabina (ara-C) e prednisona. Grupo cMSC: Cinco cães que apresentaram falha terapêutica tratados com dois transplantes de 2,5x106 Ad-MSCs pela via intratecal (IT) (totalizando seis transplantes) ou intravenosa (IV) (totalizando três transplantes), com intervalo de 40 dias. Avaliamos a recuperação funcional, redução das lesões inflamatórias por ressonância magnética (RM) e líquido cefalorraquidiano (LCR). In vitro, observamos aumento significativo na expressão de BDNF, GDNF, HGF e IDO pelas Ad-MSCs após as estimulações, e na expressão de IDO pelas PMSCs após a estimulação combinada. Houve tendência a maior expressão de IL-10 nas células estimuladas de ambas fontes. Houve aumento significativo na secreção de IL-6 pelas Ad-MSCs e de IL-8 pelas PMSCs após estimulação. In vivo, houve tendência a melhora funcional e dos parâmetros inflamatórios no LCR em ambos grupos, indicando efeitos positivos. No grupo cMSC, a maioria dos cães teve remissão parcial e eventos adversos leves foram observados em 4/6 animais após transplantes IT, sendo ausentes pela via IV. Todos os cães do grupo PAC desenvolveram efeitos adversos. Não houve diferenças significativas nas variáveis de hemograma e bioquímica dentro e entre os grupos. O transplante de Ad-MSCs alogênicas em cães com MUO demonstrou efeitos benéficos.
Canine meningoencephalomyelitis of unknown origin (MUO) is an immune-mediated neuroinflammatory disease, highly debilitating, with poor prognosis and therapeutic failure. Mesenchymal stem cells (MSCs) are promising for the treatment of neuroimmune diseases. Different sources may present differences in the immunomodulatory/neuroprotective potential. In vitro, we evaluated the gene expression of BDNF, GDNF, HGF, IDO, IL-10 and PTGES2 and the secretory profile of IL-2, IL-6, IL-18, IL-10, GM-CSF and MCP- 1 of canine MSCs derived from adipose tissue (Ad-MSCs) and placenta (PMSCs) after priming with the pro-inflammatory cytokines INF-γ alone and combined INF-γ and TNF-α. In vivo, we evaluated the clinical response to allogeneic Ad-MSCs transplantation in dogs with MUO. PAC group: 12 dogs treated with immunosuppressant cytarabine (ara-C) and prednisone. cMSC group: 5 dogs of PAC group with therapeutic failure were treated with 2.5x106 /kg Ad-MSCs by intrathecal (IT) (n = 6) or intravenous (IV) (n = 3) delivery routes (40 days of interval). Functional recovery and the reduction of inflammatory lesions by magnetic resonance imaging (MR) and cerebrospinal fluid (CSF) were evaluated. In vitro, there was significant increase of BDNF, GDNF, HGF and IDO expression by Ad-MSCs after priming and expression of IDO after combined priming by PMSCs. Ad-MSCs had a significant increase in the secretion of IL-6 and PMSCs of IL-8 after priming. In vivo, a trend towards functional improvement was observed in both groups after treatment. In the cMSC group, most dogs had partial remission and mild adverse events were observed in 4/6 animals after IT transplantations, being absent by IV. Clinical and laboratory variables showed no statistical differences. Allogeneic Ad-MSCs transplantation demonstrated beneficial effects in dogs with MUO.
Canine meningoencephalomyelitis of unknown origin (MUO) is an immune-mediated neuroinflammatory disease, highly debilitating, with poor prognosis and therapeutic failure. Mesenchymal stem cells (MSCs) are promising for the treatment of neuroimmune diseases. Different sources may present differences in the immunomodulatory/neuroprotective potential. In vitro, we evaluated the gene expression of BDNF, GDNF, HGF, IDO, IL-10 and PTGES2 and the secretory profile of IL-2, IL-6, IL-18, IL-10, GM-CSF and MCP- 1 of canine MSCs derived from adipose tissue (Ad-MSCs) and placenta (PMSCs) after priming with the pro-inflammatory cytokines INF-γ alone and combined INF-γ and TNF-α. In vivo, we evaluated the clinical response to allogeneic Ad-MSCs transplantation in dogs with MUO. PAC group: 12 dogs treated with immunosuppressant cytarabine (ara-C) and prednisone. cMSC group: 5 dogs of PAC group with therapeutic failure were treated with 2.5x106 /kg Ad-MSCs by intrathecal (IT) (n = 6) or intravenous (IV) (n = 3) delivery routes (40 days of interval). Functional recovery and the reduction of inflammatory lesions by magnetic resonance imaging (MR) and cerebrospinal fluid (CSF) were evaluated. In vitro, there was significant increase of BDNF, GDNF, HGF and IDO expression by Ad-MSCs after priming and expression of IDO after combined priming by PMSCs. Ad-MSCs had a significant increase in the secretion of IL-6 and PMSCs of IL-8 after priming. In vivo, a trend towards functional improvement was observed in both groups after treatment. In the cMSC group, most dogs had partial remission and mild adverse events were observed in 4/6 animals after IT transplantations, being absent by IV. Clinical and laboratory variables showed no statistical differences. Allogeneic Ad-MSCs transplantation demonstrated beneficial effects in dogs with MUO.
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Palavras-chave
Doenças autoimunes desmielinizantes (SNC), Interleucinas, Meningoencefalite, Neuroimunomodulação, Terapia baseada em células e tecidos, Cell- and tissue-based therapy, Demyelinating autoimmune diseases (CNS), Interleukins