Immunoglobulin therapy ameliorates the phenotype and increases lifespan in the severely affected dystrophin-utrophin double knockout mice

Autor(es)

Nunes, Bruno Ghirotto ^[1] ; Loures, Flavio Vieira ^[2] ; Siqueira Bueno, Heloisa Maria ^[1] ; Cangussu, Erica Baroni ^[1] ; Goulart, Ernesto ^[1] ; Coatti, Giuliana Castello ^[1] ; Caldini, Elia Garcia ^[3] ; Condino-Neto, Antonio ^[2] ; Zatz, Mayana ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Human Genome & Stem Cell Res Ctr, Inst Biosci, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Sch Med, Dept Pathol, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Human Genetics; v. 25, n. 12, p. 1388-1396, DEC 2017.
• Citações Web of Science: 0

Resumo

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by mutations in the dystrophin gene, affecting 1:3500-5000 boys worldwide. The lack of dystrophin induces degeneration of muscle cells and elicits an immune response characterized by an intensive secretion of pro-inflammatory cytokines. Immunoglobulins modulate the inflammatory response through several mechanisms and have been widely used as an adjuvant therapy for autoimmune diseases. Here we evaluated the effect of immunoglobulin G (IG) injected intraperitoneally in a severely affected double knockout (dko) mouse model for Duchenne muscular dystrophy. The IG dko treated mice were compared regarding activity rates, survival and histopathology with a control untreated group. Additionally, dendritic cells and naive lymphocytes from these two groups and WT mice were obtained to study in vitro the role of the immune system associated to DMD pathophysiology. We show that IG therapy significantly enhances activity rate and lifespan of dko mice. It diminishes muscle tissue inflammation by decreasing the expression of costimulatory molecules MHC, CD86 and CD40 and reducing Th1-related cytokines IFN-gamma, IL-1 beta and TNF-alpha release. IG therapy dampens the effector immune responses supporting the hypothesis according to which the immune response accelerates DMD progression. As IG therapy is already approved by FDA for treating autoimmune disorders, with less side-effects than currently used glucocorticoids, our results may open a new therapeutic option aiming to improve life quality and lifespan of DMD patients. (AU)

• Processo FAPESP: 15/19435-2 - Avaliação terapêutica de Imunoglobulina G humana em modelo murino para Distrofia Muscular de Duchenne
• Beneficiário: Bruno Ghirotto Nunes
• Linha de fomento: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 14/04783-2 - Estudo da função das células dendríticas plasmocitóides e mielóides frente à infecção pelo fungo Paracoccidioides brasiliensis
• Beneficiário: Flávio Vieira Loures
• Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores