Autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) are thought to result from breaks in tolerance. In the early stages, self-reactive T cells play a major role. Late stage progression is due primarily to the chronic inflammatory environment created by innate immune cells, i.e. macrophages and synoviocytes in RA and macrophages/microglia in MS. Effective therapies should address both early and late stages, avoid generalized immunosuppression, and have local rather than systemic effects. We showed previously that dendritic cells (DC) differentiated in the presence of the neuropeptide vasoactive intestinal peptide (VIP) become tolerogenic, and induce regulatory T cells (Treg). The VIP-induced DC (DCVIP) prevent collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE), stop disease progression in early stages, but do not affect innate immune cells responsible for later stages. Systemic VIP administration affects both T cells and suppresses the inflammatory activity of macrophages, synoviocytes, and microglia. However, the requirement for repeated, high VIP doses leads to side effects due to its pleiotropic functions. Therefore we propose to evaluate the therapeutic potential of genetically altered VIP expressing DC, which in addition to being tolerogenic, will deliver VIP locally, inhibiting the release of proinflammatory agents. The VIP-expressing DC (LentiVIP-DC) will be tested in EAE and CIA models.
In Specific Aim 1, we propose to establish the best conditions for DC transduction. LentiVIP-DC will be analyzed in terms of phenotype, migration, cytokine profile and effects on T cells and macrophages.
In Specific Aim 2 and 3 we propose to use LentiVIP-DC in EAE and CIA models. We will assess LentiVIP-DC migration to spleen, CNS, and affected joints, and investigate the effects on clinical disease, on splenic and local cytokine/chemokine expression and on T cell differentiation. The combined therapeutic approach using tolerogenic DC transduced with VIP-expressing lentiviral vectors should allow for the generation of antigen- specific Treg, as well as the local release of immunosuppressive VIP. This double-directional system represents a novel approach in the treatment of autoimmune diseases.
Autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) affect more than 2 million Americans and represent a serious health problem and a major cause of disability in the US and other Western countries. In addition to the often devastating consequences for the quality of life of individuals suffering from MS or RA, the economic impact at both personal and national level is substantial. In spite of intensive and sustained research efforts, existing treatment options do not substantially prevent tissue damage and clinical disability. The ultimate goal of the present proposal is the development of a combined therapy based on genetically modified tolerogenic dendritic cells, which represents a novel therapeutic approach for the treatment of autoimmune diseases.
|Kong, Weimin; Hooper, Kirsten M; Ganea, Doina (2016) The natural dual cyclooxygenase and 5-lipoxygenase inhibitor flavocoxid is protective in EAE through effects on Th1/Th17 differentiation and macrophage/microglia activation. Brain Behav Immun 53:59-71|
|Yen, Jui-Hung; Kong, Weimin; Hooper, Kirsten M et al. (2015) Differential effects of IFN-Î² on IL-12, IL-23, and IL-10 expression in TLR-stimulated dendritic cells. J Leukoc Biol 98:689-702|
|Ganea, D; Hooper, K M; Kong, W (2015) The neuropeptide vasoactive intestinal peptide: direct effects on immune cells and involvement in inflammatory and autoimmune diseases. Acta Physiol (Oxf) 213:442-52|
|PedreÃ±o, Marta; Morell, Maria; Robledo, Gema et al. (2014) Adrenomedullin protects from experimental autoimmune encephalomyelitis at multiple levels. Brain Behav Immun 37:152-63|
|Delgado, Mario; Ganea, Doina (2013) Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids 45:25-39|
|Nishimori, Jessalyn H; Newman, Tiffanny N; Oppong, Gertrude O et al. (2012) Microbial amyloids induce interleukin 17A (IL-17A) and IL-22 responses via Toll-like receptor 2 activation in the intestinal mucosa. Infect Immun 80:4398-408|
|Toscano, Miguel G; Ganea, Doina; Gamero, Ana M (2011) Cecal ligation puncture procedure. J Vis Exp :|
|Toscano, Miguel G; Delgado, Mario; Kong, Weimin et al. (2010) Dendritic cells transduced with lentiviral vectors expressing VIP differentiate into VIP-secreting tolerogenic-like DCs. Mol Ther 18:1035-45|
|Gonzalez-Rey, Elena; Ganea, Doina; Delgado, Mario (2010) Neuropeptides: keeping the balance between pathogen immunity and immune tolerance. Curr Opin Pharmacol 10:473-81|
|Ganea, Doina (2008) Neuropeptides: active participants in regulation of immune responses in the CNS and periphery. Brain Behav Immun 22:33-4|
Showing the most recent 10 out of 32 publications