Stem Cells: Immunosuppressive or Immunostimulatory?

Although attractive as a therapeutic approach for autoimmune diseases, mesenchymal stem cells are now known not to be exclusively immunosuppressive. A paper published by Dazzi (et al, 2011) warned that the laboratory findings showing that MSCs can prevent the induction of several autoimmune diseases does not necessarily translate to usefulness in inhibiting the pathogenesis of human disease. It is clearly impossible to begin stem cell treatment prior to autoimmune disease developing and the activity of mesenchymal stem cells in human patients is more complicated than in the laboratory. In fact, autoimmune diseases themselves recruit endogenous MSCs to sites of inflammation, such as swollen joints in autoimmune arthritis, or lesions in multiple sclerosis, and these MSCs contribute to the disease progression. Therefore, injecting stem cells into the body of a patient with an inflammatory autoimmune disease may actually worsen the prognosis which is just one of the reasons it is inadvisable to undergo experimental treatment in an unregulated clinic overseas.

Drugs to Promote Stem Cell Activity

More research is needed on the various chemicals and signals provided by the body that trigger either an immunosuppressive or immunostimulatory response by stem cells. Some of those under investigation include interferon-gamma, tumor-necrosis factor alpha, toll-like receptor (TLR) ligands, and cytokines. The evidence arising from such research may allow clinicians to develop stem cell treatments administered alongside pharmaceuticals which induce favorable chemical environments for the stem cells to exert their desirable action. Without control of these mechanisms the administration of mesenchymal and other stem cells is something of a gamble for patients with autoimmune disease.

Dangers of Immunosuppression

Despite those concerns over MSCs not behaving in an immunosuppressive fashion, some research actually indicates that this immunosuppression itself could be problematic. The potential for mesenchymal stem cells (MSCs) to inadvertently contribute to tumor growth is also vitally important for patients and clinicians to consider. Research carried out by Djouad (et al, 2003) used injected B12 melanoma cells with or without simultaneously injected MSCs to observe the effects on tumor growth. They found that the immunosuppressive qualities of MSCs were permissive for tumor development, which did not occur in those mice just receiving injections of the melanoma cells and no MSCs. This clearly has significant consequences for those undergoing treatment for autoimmune disease and other conditions.

The body’s immune system ordinarily consumes cancerous cells when functioning correctly, thereby preventing tumor growth, but this research in mice suggests that under conditions which suppress immunity cancer cells may be permitted to grow unchecked. Caspi (2008) has called this ‘the penalty for success’ in a paper concerned with the possibility of using stem cells for cancer treatment and the possibility of negative consequences for autoimmune disease development as a result of dysregulation imposed by the stem cells.

Alternatives to Stem Cell Treatments for Autoimmune Disease

In spite of considerable research into stem cell transplants for autoimmune disease it may be that a pharmaceutical treatment already in general use for cancer patients offers a credible alternative to such experimental therapy. Collaboration between researchers at The Johns Hopkins University School of Medicine, and Biogen-Idec has resulted in evidence that a commonly used anti-cancer agent, also used for myeloablation prior to bone marrow transplant is also effective for autoimmune diseases even without subsequent stem cell transplantation. The review carried out by Dezern (et al, 2011) looked at the rates of remission for patients with aplastic anaemia, treated with cyclophosphamide either alone or in combination with stem cell transplants, as well as other patients with autoimmune disease treated with cyclophosphamide alone. This particular pharmaceutical is extremely toxic to lymphocytes but spares haematopoietic stem cells due to the present of aldehyde dehydrogenase in these cells which deactivates cyclophosphamide.

Cancer Drugs and Autoimmune Disease

The patients in this review experienced durable remission from their autoimmune disease in most cases after cyclophosphamide treatment (50mg/kg per day for four days) with an overall response rate (i.e decrease in disease activity and reduction of immune-modulating drugs) of 94%. An average of three years later found that 44% of the patients had suffered no disease progression. This figure however includes patients assessed at between 1-120months casting doubt on the relevance of the statistic for actual rates of remission at the three year mark. Whether or not this is favorable in comparison to use of the anti-cancer drug combined with stem cell therapy is still under some debate and the treatment still means that patients’ immune systems are compromised in the short term. The cost-effectiveness of treatment, and the removal of experimental stem cell treatment from the therapeutic plan for autoimmune disease may however, make it more likely to be used in a clinical setting.

References

Zhou Y, Yuan J, Zhou B, Lee AJ, Lee AJ, Ghawji M Jr, Yoo TJ., The therapeutic efficacy of human adipose tissue-derived mesenchymal stem cells on experimental autoimmune hearing loss in mice, Immunology. 2011 May;133(1):133-40.

Dezern AE, Petri M, Drachman DB, Kerr D, Hammond ER, Kowalski J, Tsai HL, Loeb DM, Anhalt G, Wigley F, Jones RJ, Brodsky RA., High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other autoimmune diseases, Medicine (Baltimore). 2011 Mar;90(2):89-98.