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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047325-11
Application #
8207833
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Johnson, David R
Project Start
2000-04-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
11
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750
Name
Temple University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Pedreno, 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
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
Delgado, Mario; Ganea, Doina (2008) Anti-inflammatory neuropeptides: A new class of endogenous immunoregulatory agents. Brain Behav Immun :
Pozo, David; Gonzalez-Rey, Elena; Chorny, Alejo et al. (2007) Tuning immune tolerance with vasoactive intestinal peptide: a new therapeutic approach for immune disorders. Peptides 28:1833-46
Ganea, Doina; Gonzalez-Rey, Elena; Delgado, Mario (2006) A novel mechanism for immunosuppression: from neuropeptides to regulatory T cells. J Neuroimmune Pharmacol 1:400-9
Sharma, Vikas; Delgado, Mario; Ganea, Doina (2006) Granzyme B, a new player in activation-induced cell death, is down-regulated by vasoactive intestinal peptide in Th2 but not Th1 effectors. J Immunol 176:97-110
Gonzalez-Rey, Elena; Varela, Nieves; Sheibanie, Amir F et al. (2006) Cortistatin, an antiinflammatory peptide with therapeutic action in inflammatory bowel disease. Proc Natl Acad Sci U S A 103:4228-33
Chorny, Alejo; Gonzalez-Rey, Elena; Ganea, Doina et al. (2006) Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo: therapeutic applications in autoimmunity and transplantation. Ann N Y Acad Sci 1070:190-5

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