Dendritic Cell Targeting

Autoimmune diseases continue to challenge our understanding of the immune system and pathogenic activity. Frost & Sullivan believes that while further study of dendritic cell targeting in specific disease pathways is necessary, the therapy could provide the necessary relief for millions of patients.

Dendritic cells are professional antigen-presenting cells in the skin, mucosa and lymphoid tissues. Their main function is to process antigens and present them to T cells to promote immunity to foreign antigens and tolerance to self-antigens. This dual role suggests that dendritic cells are likely to contribute to autoimmune diseases such as psoriasis, myasthenia gravis and lupus. Developments in technology have allowed new therapeutic treatments to specifically target dendritic cells in pathways responsible for disease expression.

Role of Psoriatic Inflammation in Regulating Airway Inflammation

Psoriasis is an autoimmune inflammatory skin disease characterized by activated IL-23/STAT3/Th17 signaling. Psoriatic inflammation has been shown to be associated with airway inflammation in patients with asthma.

A study by scientists at King Saud University in Saudi Arabia investigated the effect of imiquimod-induced psoriatic inflammation on airway inflammation caused by intranasal administration of cockroach extract in mice. Psoriatic inflammation in allergic mice was associated with increased airway inflammation. Analysis of the liver showed increased cytokine and transcription factors in T-helper (Th)17 and Th2. Splenic CD4+ T and CD11c+ dendritic cells in psoriatic mice had increased STAT3/RORC and interleukin (IL)-23 mRNA expression, respectively. The study suggests that systemic IL-23/STAT3 axis is responsible for enhanced airway inflammation during psoriasis, and that anti-asthma therapy alone may not sufficiently alleviate it in asthmatics with psoriasis. IL-23/STAT3 expression in dendritic cells may emerge as an important target for the management of airway inflammation and asthma in psoriatic patients.

Enhancing Immune Tolerance in Myasthenia Gravis

Myasthenia gravis is an autoimmune disorder that results in muscle fatigue and weakness when autoantibodies attack the acetylcholine receptor (AChR)—the disease-associated antigen—at the neuromuscular junction. No tolerogenic treatment is currently available.

Scientists from the Carlo Besta Neurological Institute in Italy and the University of Gothenburg in Sweden have developed a novel fusion protein, mCTA1–T146, which carries a dominant epitope from the AChR for treatment of experimental autoimmune myasthenia gravis in mice. Treated mice developed significantly fewer symptoms and exhibited less tissue destruction and lower serum anti-AChR antibody titers. Lymph node cells in treated mice demonstrated upregulated gene expression concomitant with suppressed Th1 and Th17 CD4+ T cell development. The study could pave the way for novel immune tolerance induction therapies for the clinical management of autoimmune disorders; however, the high amount of fusion peptide required to produce results raises safety and efficacy concerns that could hinder clinical trials on humans.

Role of Plasmacytoid Dendritic Cells in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance resulting in the generation of pathogenic autoantibodies and immune complexes. Available biologic agents have targeted the B cell, but other promising therapeutic targets, such as the plasmacytoid dendritic cell (pDC)-type I interferon (IFN) pathway, have recently been discovered.

Scientists at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and the Lerner Research Institute genetically modified Siglec H-positive pDCs and selectively ablated pDCs to prevent binding to toll-like-receptor (TLR) 7 in mouse lupus models. The results indicated that pDCs were indispensable for the production of systemic inflammation and effector T-cell responses triggered by TLR7 ligand. 

Although pDCs have been proposed as a key source of aberrant IFN-I production in SLE, the exact mechanism of action is poorly understood. Still, dendritic cell depletion soon could be a novel therapeutic strategy in the management of autoimmune disorders.

The Road Ahead

Autoimmune diseases continue to challenge our understanding of the immune system and pathogenic activity. Current biologics and treatment options have varying effects on disease progression and may produce adverse effects. Frost & Sullivan believes that while further study of dendritic cell targeting in specific disease pathways is necessary, the therapy could provide the necessary relief for millions of patients.

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