Immunotherapy with dendritic cells in a humanised mouse model of rheumatoid arthritis
Lead Research Organisation:
Newcastle University
Department Name: Research, Strategy & Development
Abstract
We aim to develop a new therapy for rheumatoid arthritis (RA) using a type of immune cell called a dendritic cell (DC). RA is a painful disease that leads to stiffness and deformity of joints in hands, feet and limbs. Almost 400,000 people in the UK suffer from RA. No cure for this disease is available yet.
RA is caused by a patient’s own immune system: white blood cells mistakenly attack joints and cause destruction of cartilage and bone. We have made a special type of DC with the ability to prevent white blood cells attacking the joint (i.e. make the blood cells ‘tolerant’) and hope this can be used to treat RA. This type of DC is called tolerogenic DC (tolDC).
Our work addresses important questions that must be answered before we can test tolDC treatment in humans. For instance, we need to know how many tolDC will be required to inhibit arthritis; where they will have to be injected (e.g. in the blood, in the joint); how long they will survive in the body; and how they make white blood cells tolerant. We will address these questions using mice which develop a disease similar to RA.
If successful, our work will bring a new and hopefully beneficial treatment for RA closer to clinical use.
RA is caused by a patient’s own immune system: white blood cells mistakenly attack joints and cause destruction of cartilage and bone. We have made a special type of DC with the ability to prevent white blood cells attacking the joint (i.e. make the blood cells ‘tolerant’) and hope this can be used to treat RA. This type of DC is called tolerogenic DC (tolDC).
Our work addresses important questions that must be answered before we can test tolDC treatment in humans. For instance, we need to know how many tolDC will be required to inhibit arthritis; where they will have to be injected (e.g. in the blood, in the joint); how long they will survive in the body; and how they make white blood cells tolerant. We will address these questions using mice which develop a disease similar to RA.
If successful, our work will bring a new and hopefully beneficial treatment for RA closer to clinical use.
Technical Summary
Tolerogenic dendritic cells (tolDC) are immunoregulatory antigen presenting cells which suppress pro-inflammatory immune responses in mice and man in vivo. We have generated human and mouse tolDC with potent immunoregulatory activity by treating DC with the immunosuppressive drugs dexamethasone and vitamin D3. In a pilot study we have found that these tolDC inhibited collagen-induced arthritis in mice, and our ultimate goal is to develop tolDC vaccines as a therapeutic modality for rheumatoid arthritis (RA). Before this immunomodulatory treatment can be considered for use in the clinic, however, critical questions need to be addressed. We propose to study this experimental antigen-specific immunotherapy in a ?humanised? HLA-DR1 transgenic mouse model of arthritis. Our model is relevant to human RA, as HLA-DR1 is strongly associated with RA. In mice, it also confers susceptibility to arthritis induced by human type II collagen, a relevant candidate autoantigen of human RA. The aims of the current proposal are to determine and optimise the immunotherapeutic action of tolDC in arthritis, and to investigate the mechanism of tolerance induction in vivo. The specific objectives are to:
i) determine the effectiveness of tolDC treatment at different stages of arthritis, using both prophylactic and therapeutic regimes
ii) optimise the therapeutic action of tolDC by defining optimal dose and route of administration (intravenous, sub-cutaneous, intra-articular)
iii) study the in vivo trafficking and survival of tolDC, utilising both magnetic resonance imaging and fluorescein tagging. We hypothesise that maximal immunoregulatory effects will require a proportion of the administered cells to reach local and/or regional lymph nodes.
iv) investigate the mechanism(s) underlying induction of antigen-specific tolerance. Based on existing information, we hypothesise that disease modulation will be associated with the emergence of regulatory T-cell populations.
Our work will increase our knowledge of these cells, and of immunomodulatory therapy in general. It will provide essential pre-clinical data, bringing this novel treatment closer to clinical application.
i) determine the effectiveness of tolDC treatment at different stages of arthritis, using both prophylactic and therapeutic regimes
ii) optimise the therapeutic action of tolDC by defining optimal dose and route of administration (intravenous, sub-cutaneous, intra-articular)
iii) study the in vivo trafficking and survival of tolDC, utilising both magnetic resonance imaging and fluorescein tagging. We hypothesise that maximal immunoregulatory effects will require a proportion of the administered cells to reach local and/or regional lymph nodes.
iv) investigate the mechanism(s) underlying induction of antigen-specific tolerance. Based on existing information, we hypothesise that disease modulation will be associated with the emergence of regulatory T-cell populations.
Our work will increase our knowledge of these cells, and of immunomodulatory therapy in general. It will provide essential pre-clinical data, bringing this novel treatment closer to clinical application.