Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired immune- mediated disorder of the peripheral nerves often requiring ongoing immunosuppressive therapy and leaving patients with varying degrees of disabilities. The need for chronic immunosuppressive treatment is a major treatment challenge in clinical practice. This proposal provides a novel approach to long-term treatment. Proof of principle will be established in the spontaneous autoimmune peripheral polyneuropathy (SAPP) model of CIDP with the intention of potentially moving this project toward a clinical trial. The SAPP model in B7-2 KO NOD mice mimics a progressive and unremitting course of CIDP with onset of neuropathy symptoms at 20 weeks of age. Tolerogenic, bone marrow derived dendritic cells (tDCs) have been shown to home to inflamed tissues and lymphoid tissues to suppress autoimmune responses by priming T cells to become regulatory T cells (Tregs). Vasoactive intestinal peptide (VIP) was shown to play an active role in generation of tDCs. DCs induced with VIP display therapeutic potential in an EAE (experimental autoimmune encephalomyelitis) model resulting from an antigen-specific Treg induction. VIP expressing DCs, transduced with lentiviral vectors, (LV-VIP-DCs) exerted a sustained clinical effect on mouse model of EAE reducing the progression of the disease. In this study, we intend to deliver LV-VIP-DCs intravenously to SAPP mice to suppress immune reactions against myelin proteins in the peripheral nerves and prevent disease (Aim1) or reverse or attenuate the disease process (Aim 2a, b). We have preliminary data showing that we successfully generated lentivirus carrying human VIP gene, isolated and characterized dendritic cells from bone marrow and showed efficacy in a group of SAPP mice. In this proposed study, SAPP mice will receive 3x106 LV-VIP-DCs via intravenous injection before the disease onset of neuropathy (at age 16 weeks;
Aim 1) and at the disease onset with a higher dose (5x106 LV-VIP-DCs at 21 weeks of age;
Aim 2 a) and the third cohort will receive multiple treatments during the course of the disease with two weeks intervals (5x106 LV-VIP-DCs at age 21, 23 and 25 weeks;
Aim2 b). Mice will be sacrificed 12 weeks after the onset of treatment. Outcome measures for all experiments in Aim 1 and 2 will include clinical observations, functional studies, electrophysiological and histologicl studies of the peripheral nerves comparing treated and age matched control cohorts. Our approach translates to the treatment of CIDP given that autologous DCs (patient's own cells) or DCs derived from HLA (human leukocyte antigen) matched donors provide a feasible source of DCs that can be transduced with the VIP gene and used in the treatment of CIDP especially in cases refractory to other forms of therapy.

Public Health Relevance

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nerves with clinical features of weakness, sensory loss, imbalance and impaired ambulation that may lead to substantial disability. The need for chronic immunosuppressive treatment is a major treatment challenge in clinical practice. This proposal describes a novel translational approach combining intestinal vasoactive peptide (VIP), lentivirus vector and bone marrow derived dendritic cells in the development of a therapeutic tool to treat CIDP. Proof of principle will be established in the spontaneous autoimmune peripheral polyneuropathy (SAPP) model of CIDP.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS085278-01A1
Application #
8770759
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43205