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April 11, 2008

Dampening dangerous inflammation

Immune therapy using unique immune cells significantly reduces inflammation in mouse models of human disease

Figure 1: Treatment with dendritic cells clears the airways. A section of an inflamed mouse lung shows numerous immune cells stained in purple that lead to airway constriction (left). Treatment with regulatory dendritic cells significantly reduces the inflammation, leading to open airways (right).

© J. Allergy Clin. Immunol./American Academy of Allergy, Asthma & Immunology /121/99 (2008)

A team of Japanese researchers is working to find better treatments for chronic inflammation. New work by the team demonstrates that conditions such as lethal disease associated with tissue and organ transplantation1, and asthma2, can be successfully treated with specialized immune cells to reduce inflammation.

Led by Katsuaki Sato at the RIKEN Research Center for Allergy and Immunology in Yokohama, the team studied dendritic cells of the immune system, so called because of the many ‘dendrites’, or branched projections, on their surface. Dendritic cells initiate immune responses by directly communicating with other immune cells. One outcome of such communication is the production of ‘guardian’ lymphocytes that keep the immune system in balance; referred to as ‘regulatory T cells’, these lymphocytes are increasingly seen as critical players in a myriad of diseases.

Sato’s team has demonstrated that therapeutic treatment of mice with specially conditioned dendritic cells significantly reduces inflammation. Referring to such dendritic cells as ‘regulatory dendritic cells’ (or simply ‘DCregs’), the team—in a series of articles in the past few years—has described the protective effect of immunotherapy with DCregs in mouse models of human disease.

As Sato explains, “to exploit a novel immunotherapeutic strategy using dendritic cells for immuno-pathogenic diseases, we have tried to establish use of DCregs with a potent immuno-regulatory property even under inflammatory conditions.” By focusing on ameliorating inflammation when it is chronically present and especially difficult to treat, the team’s work is different from other attempts to maximize the efficacy of immune therapy.

Using mouse models of human disease, Sato’s team studied bone-marrow transplantation rejection for graft-versus-host disease (GVHD) and lung-airway inflammation for asthma. DCregs produced in the laboratory and then injected into mice with these diseases demonstrated significantly reduced inflammation (Fig. 1). Looking closely at the recipient mice, the team noted that the treatment was associated with increased numbers of regulatory T cells—key suppressors of inflammation.

According to Sato, the next key step is to clarify the molecular mechanisms responsible for the production of regulatory T cells by DCregs. Longer term, Sato is clearly set on the goal of treating human diseases with DCregs: “we have recently established the methods to prepare a large number of human DCregs for clinical application.”

Although not yet ready for the clinic, immunotherapy with DCregs has clear potential thanks to the work reported by Sato and his team that demonstrates the unique power of regulatory dendritic cells to reign in lethal inflammation.

References

  1. Fujita, S., Sato, Y., Sato, K., Eizumi, K., Fukaya, T., Kubo, M., Yamashita, N. & Sato, K. Regulatory dendritic cells protect against cutaneous chronic graft-versus-host disease mediated through CD4+CD25+Foxp3+ regulatory T cells. Blood 110, 3793–3803 (2007). | | (Link)
  2. Fujita, S., Yamashita, N., Ishii, Y., Sato, Y., Sato, K., Eizumi, K., Fukaya, T., Nozawa, R., Takamoto, Y., Yamashita, N., Taniguchi, M. & Sato, K. Regulatory dendritic cells protect against allergic airway inflammation in a murine asthmatic model. Journal of Allergy and Clinical Immunology 121, 95–104 (2008). | |
    (Link)