Intravenous injection (i.v.) of soluble proteins can induce antigen-specific tolerance in experimental autoimmune encephalomyelitis (EAE). I.V. tolerance effectively prevents or suppresses the disease. Dendritic cells (DCs) play a crucial role in initiation and regulation of adaptive immune responses. There are two distinct subsets of DCs in murine spleens: CD8+CD11c+CD11b- and CD8-CD11c+CD11b+. We have shown that induction of i.v. tolerance expands subtype of CD11c+CD11b+ DCs in the spleen and CNS of mice immunized for EAE. Adoptive transfer of these cells into mice with ongoing EAE rapidly ameliorates the disease and induces strong Treg and Th2 responses. These results demonstrate that CD11c+CD11b+ cells are a potent tolerogenic DC subset, and warrant further research on their mechanisms of action. The central hypothesis of this proposal is that CD11c+CD11b+ DCs play a major role in i.v. tolerance in EAE. To test this hypothesis, the following specific aims are proposed:
Aim 1. To determine the role of apoptotic T cells in the induction of tolerogenic CD11c+CD11b+ DCs in EAE. We have shown that i.v. injection of myelin antigen into mice with EAE induced by the same antigen results in: a) apoptosis of a significant number of activated myelin-specific T cells;and b) generation of CD11c+CD11b+ DCs. We hypothesize that DCs which phagocytize apoptotic T cells acquire tolerogenic CD11c+CD11b+ phenotype.
Aim 2. To study the role of CD11c+CD11b+ DCs in antigen specificity of i.v. tolerance. I.V. tolerance is antigen specific. T cells play an important role in this process;however, we have shown that adoptively transferred CD11c+CD11b+ DCs from tolerized mice suppress EAE. We hypothesize that tolerogenic DCs convert Th1 and Th17 cells to Th2 and Treg phenotype in an antigen-specific manner.
Aim 3. To study the role of soluble mediators in tolerogenic action of CD11c+CD11b+ DCs. It is not clear whether it is cell-cell contact between tolerogenic CD11c+CD11b+ DCs and antigen-specific T cells or soluble mediators produced by DCs that mediate tolerance. We hypothesize that tolerogenic DCs act both by cell-cell contact and by secretion of soluble factors to induce tolerance. These studies should result in a better understanding of the role of dendritic cells in i.v. tolerance, and provide an insight into their potential use as a therapy for human autoimmune diseases.

Public Health Relevance

Intravenous injection (i.v.) of soluble proteins can induce antigen-specific tolerance, a phenomenon termed "i.v. tolerance." In experimental autoimmune encephalomyelitis (EAE), which is an animal model of human multiple sclerosis, i.v. tolerance effectively prevents disease. The exact mechanisms underlying i.v. tolerance suppression of disease are not well understood. Dendritic cells (DCs) are immune cells that play a crucial role in regulation of immune responses. We showed that induction of i.v. tolerance induces a particular type of DC and that transfer of these DCs into mice with ongoing EAE rapidly suppresses disease. Our results suggest that these DCs play a crucial role in i.v. tolerance. We propose to investigate mechanisms underlying generation of DCs in i.v. tolerance, and in which way(s) they suppress disease. These studies should result in a better understanding of the role of dendritic cells in i.v. tolerance, and provide an insight into their potential use as a therapy for human autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048435-10
Application #
8535215
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Utz, Ursula
Project Start
2004-07-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$319,617
Indirect Cost
$112,745
Name
Thomas Jefferson University
Department
Neurology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Zhou, F; Ciric, B; Zhang, G-X et al. (2014) Immunotherapy using lipopolysaccharide-stimulated bone marrow-derived dendritic cells to treat experimental autoimmune encephalomyelitis. Clin Exp Immunol 178:447-58
Li, Hongmei; Gonnella, Patricia; Safavi, Farinaz et al. (2013) Low dose zymosan ameliorates both chronic and relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 254:28-38
Kalantari, Tahereh; Kamali-Sarvestani, Eskandar; Zhang, Guang-Xian et al. (2013) Generation of large numbers of highly purified dendritic cells from bone marrow progenitor cells after co-culture with syngeneic murine splenocytes. Exp Mol Pathol 94:336-42
Zhou, Fang; Lauretti, Elisabetta; di Meco, Antonio et al. (2013) Intravenous transfer of apoptotic cell-treated dendritic cells leads to immune tolerance by blocking Th17 cell activity. Immunobiology 218:1069-76
Zhou, Fang; Ciric, Bogoljub; Zhang, Guang-Xian et al. (2013) Immune tolerance induced by intravenous transfer of immature dendritic cells via up-regulating numbers of suppressive IL-10(+) IFN-ýý(+)-producing CD4(+) T cells. Immunol Res 56:1-8
Fitzgerald, Denise C; Zhang, Guang-Xian; Yu, Shuo et al. (2012) Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and experimental autoimmune encephalomyelitis severity in the absence of IL-12 receptor signaling. J Neuroimmunol 247:32-7
Li, Hongmei; Nourbakhsh, Bardia; Cullimore, Melissa et al. (2011) IL-9 is important for T-cell activation and differentiation in autoimmune inflammation of the central nervous system. Eur J Immunol 41:2197-206
Li, Hongmei; Nourbakhsh, Bardia; Safavi, Farinaz et al. (2011) Kit (W-sh) mice develop earlier and more severe experimental autoimmune encephalomyelitis due to absence of immune suppression. J Immunol 187:274-82
Gran, B; Yu, S; Zhang, G X et al. (2010) Accelerated thymocyte maturation in IL-12R?2-deficient mice contributes to increased susceptibility to autoimmune inflammatory demyelination. Exp Mol Pathol 89:126-34
Das Sarma, Jayasri; Ciric, Bogoljub; Marek, Ryan et al. (2009) Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J Neuroinflammation 6:14

Showing the most recent 10 out of 14 publications