An albumin interleukin 33 fusion protein with enhanced lymph node retention suppresses murine models of multiple sclerosis

Abstract

Abstract Interleukin-33 (IL-33) is an immunoregulatory cytokine that suppresses pathogenic Th17 T cells. Recombinant IL-33 has been shown to prevent disease onset in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. However, the systemic administration of IL-33 has not been clinically translated, in part because the cytokine’s short half-life makes it difficult to achieve therapeutically effective concentrations in the secondary lymphoid organs. To overcome this challenge, we have recombinantly fused mouse serum albumin (SA) to IL-33. ST2(IL-33R)-expressing mouse group 2 innate lymphoid cells treated with serum albumin fused IL-33 (SA IL-33) increased CD25 expression and IL-13 production in a dose-dependent manner. SA fusion prolonged IL-33 half-life and increased its concentration in the lymph nodes of naïve C57BL/6 mice. Prophylactic administration of SA IL-33 prevented the onset MOG-induced EAE, demonstrating equal efficacy to the clinically approved MS drug fingolimod. In mice with already-established EAE, administration of SA IL-33 reduced disease score and improved weight gain. At the cellular level, SA-IL-33 treatment reduced the frequency of CD45+ cells, including disease causing Rorgt+ CD4+ T cells, in the spinal cord. EAE mice treated with SA-IL-33 displayed an increase in ST2+ FoxP3+ CD25+ Tregs and Th2 T cells in both the spleen and spinal cord draining lymph nodes, suggesting that SA-IL-33 treatment suppresses EAE by expanding the protective type 2 response.