Therapeutic Effect of IL-21 Blockage by Gene Therapy in Experimental Autoimmune Encephalomyelitis

Altres ajuts: acords transformatius de la UABThe pathogenic role of the interleukin 21 (IL-21) in diferent autoimmune diseases, such as multiple sclerosis (MS), has been extensively studied. However, its pleiotropic nature makes it a cytokine that may exhibit diferent activity depending on the immunological stage of the disease. In this study, we developed a gene therapy strategy to block the interaction between IL-21 and its receptor (IL-21R) by using adeno-associated vectors (AAV) encoding a new soluble cytokine receptor (sIL21R) protein. We tested this strategy in a murine model of experimental autoimmune encephalomyelitis (EAE), obtaining diferent clinical efects depending on the time at which the treatment was applied. Although the administration of the treatment during the development of the immune response was counterproductive, the preventive administration of the therapeutic vectors showed a protective efect by reducing the number of animals that developed the disease, as well as an improvement at the histopathological level and a modifcation of the immunological profle of the animals treated with the AAV8. sIL21R. The beneficial efect of the treatment was also observed when inducing the expression of the therapeutic molecule once the frst neurological signs were established in a therapeutic approach with a doxycyline (Dox)-inducible expression system. All these clinical results highlight the pleiotropicity of this cytokine in the diferent clinical stages and its key role in the EAE immunopathogenesi