Protection and treatment of experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein and expansion of dendritic cells using Flt-3L

We have shown that the oral administration of the neuroantigen myelin basic protein (MBP) to mice can both prevent and treat the autoimmune disease experimental autoimmune encephalomyelitis (EAE). The antigen presenting cells (APC) involved in the presentation of orally introduced antigens are unknown, but we hypothesize that dendritic cells (DC) play this role during oral tolerance induction, since DC are implicated in both tolerance and immunity in vivo. Expansion of DC using the growth factor Flt-3 ligand (FL) expands both lymphoid-derived and myeloid-derived CD11c+/MHC Class II+ DC in the gut-associated lymphoid tissue (GALT) and periphery of B10.PL mice. Further, DC expansion enhances oral tolerance to MBP in FL-treated mice fed either a low or high dose of MBP prior to the induction of EAE. Moreover, oral MBP in conjunction with DC expansion begun after resolution of the acute phase of EAE profoundly decreases the severity of chronic disease when compared to controls. In protected mice, ELISPOT analyses show that both Th1 and Th2 cytokine secreting cells are dramatically decreased, suggesting an anergy/deletion mechanism for the inactivation of autoreactive T cells in vivo.; Mechanistic studies indicate that MBP specific T cells undergo rapid activation in vivo followed by multiple cell divisions after oral antigen administration in FL treated and control mice. T cell activation is more extensive in FL-treated mice compared to control mice indicating that activation and proliferation of MBP specific T cells may represent part of the tolerization process. MBP specific T cells from MBP-fed, FL-treated mice are hyporesponsive in vitro reinforcing the idea that antigen specific T cells are rendered anergic after feeding. DC isolated from the peripheral and mesenteric lymph nodes of FL-treated MBP-fed mice are capable of stimulating MBP specific T cells ex vivo, indicating that DC became loaded with oral antigens in vivo.; These studies suggest that DC play a key role in presentation of MBP to self-reactive T cells, participate in the induction of oral tolerance, and that combining FL mediated DC expansion with oral antigen administration enhances oral tolerance in the face of an ongoing autoimmune disease process.