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70 5-aminolevulinic acid combined with ferrous iron ameliorate graft-versus-host-induced systemic sclerosis in the mouse
  1. M Fujino1,
  2. C Liu2,
  3. X Yang3,
  4. P Zhu4,
  5. S Li2,
  6. H Ito5,
  7. K Takahashi5,
  8. T Tanaka5,
  9. M Nakajima5,
  10. J Zhuang4,
  11. H Zou3 and
  12. XK Li2
  1. 1National Institute of Infectious Diseases, National Institute of Infectious Diseases, Tokyo, Japan
  2. 2National Research Institute for Child Health and Development, Division of Transplantation Immunology, Tokyo, Japan
  3. 3Fudan University, Institute of Rheumatology- Immunology and Allergy, Shanghai, China
  4. 4Guangdong General Hospital- Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Guangzhou, China
  5. 5SBI Pharmaceuticals Co.- Ltd, SBI Pharmaceuticals Co.- Ltd, Tokyo, Japan

Abstract

Background and aims Scleroderma or systemic sclerosis (SSc) is a clinically heterogeneous rheumatologic autoimmune disease characterised by skin, internal organs and blood vessels, and there is no effective therapy. The purposes of current study are to develop a model of GvHD-induced scleroderma that more fully represents human condition, and to investigate the effects of 5-aminolevulinic acid (5-ALA), an intermediate of heme synthesis, enhance HO-1 activity to cleave heme to form biliverdin, CO, and iron on this model.

Methods Scl-GvHD was induced by injection of lymphocytes from B10.D2 mice into BALB/c mice deficient in mature T and B cells (recombination activating gene 2 null mice).

Results We successfully established an scl-GvHD model, which is similar to the human disease particularly in the skin, progressive inflammation and fibrosis of internal organs including lung, kidney, and liver. We found that treatment with 5-ALA and iron (Fe2+) significantly reduced progressive inflammation and fibrosis in the skin and ear. Furthermore, by quantitative real-time PCR analysis, 5-ALA and Fe2+ suppressed the inflammatory cytokines and TGF-β, type I collagen mRNAs expression. These results indicate that combination treatment with 5-ALA and Fe2+ exhibited a protective effect on tissue fibrosis and inflammation of scl-GvHD model mice.

Conclusions The model of GvHD-induced SSc has shown most of symptoms of human disease and is likely to contribute to better understanding of the disease mechanism. Furthermore, efficacy of the 5-ALA has important implication for clarifying the mechanism of HO-1 activity in autoimmune diseases, and may provide a favourable opportunity for clinical therapy.

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