Bristol, UK -

An interesting study was published by Gordon et al (Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration, Neurosci Lett 2008 Dec 19;448(1):71-3) describing the use of human bone marrow derived mesenchymal stem cells in the treatment of EAE, a mouse model of multiple sclerosis.

Previously people have demonstrated that administration of mouse mesenchymal stem cells into mice with EAE results in remission of disease.  In this current paper an interesting, and very relevant variation of the previous study was made….human stem cells were used.  This is important since human mesenchymal and mesenchymal-like stem cells are being developed by companies such as Osiris and Medistem as “universal donor” cells.  This means that theoretically these cells are not rejected by the immune system.  So the authors of this paper wondered whether the human cells would survive in the mouse, and whether they would actually mediate a therapeutic effect.

The investigators induced EAE through administration of the peptide MOG 35-55 together with an adjuvant in order to elicit immune responses against myelin.  They injected 1 million mesenchymal stem cells intraperitoneally and found a statistically significant reduction in disease score.  Disease score is measured on a scale of 0-5 (0 – Normal; 1 – Tail flaccidity or hind limb weakness; 2 – Partial hind limb paralysis; 3 – Complete hind limb paralysis, spastic paresis, impaired righting reflex; 4 – Complete hind and fore limb paralysis; 5 – Dead).

On day 50 the disease score seemed to have went in remission (about 0.5) in the mice receiving mesenchymal stem cells but was still active (2) in the control mice.  Interestingly tracking of the cells showed that few mesenchymal stem cells were found in the brain on day 50.

This paper was really nicely written and provides some good background references for people interested in this area.  It is available for free online at this link.

Cleveland, Ohio -

The possibility of stem cells treating multiple sclerosis is very enticing. 

This comes from two angles.  The first is that various type of stem cells either directly can heal injured nervous system tissue or produce various growth factors that allow the injured tissue to heal itself.  For example, it has been published that mesenchymal stem cells can differentiate into oligodendrocytes, which make myelin.  It has also been reported that stem cells produce growth factors such as IGF-1, which when administered into injured central nervous system tissue cause its repair.  The second reason why stem cell therapy for multiple sclerosis is appealing is that various types of stem cells, such as mesenchymal stem cells, are known to have immune modulating properties.  In other words, since multiple sclerosis is mediated by an abnormal T cell response, there is a possibility that therapy using cells such as mesenchymal stem cells may actually not only heal the damage that has occurred, but also address the root cause of the damage.

There was a recent paper (Bai et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis) which used human bone marrow mesenchymal stem cells to treat mice which were induced to have a disease that is similar to multiple sclerosis.

The scientists used two types of mouse multiple sclerosis.  The first is a progressive type, in which the MOG peptide was used to ”immunize” B6 mice, and the second is a relapse-remitting type in which another myelin component called PLP was used to “immunize” SJL mice.  What this means is that the mice develop an immune response against components of the myelin, and subsequently exhibit a disease that resembles clinical multiple sclerosis.

Administration of human bone marrow derived mesenchymal stem cells into these mice resulted in reduction in disease progression, as well as healing at the cellular level.  Increased numbers of oligodendrocytes (the cells that make myelin) were observed in the mice that recieved stem cell therapy. Interestingly, the autoimmune response seemed to be suppressed, well at least the inflammatory component of it, since reduction of interferon gamma and interleukin-17 was seen, which are both associated with poor patient prognosis, whereas elevated levels of interleukin-4, an antiinflammatory agent were seen in the treated mice.

This paper was particularly interesting since it demonstrated that human mesenchymal stem cells work in mice, not only for modulating the immune system but also for accelerating repair.  Although not assessed, it is possible that the mesenchymal stem cells were also increasing levels of T regulatory cells.  This is something that should be performed in future studies.

Wuerzburg, Germany -

Autoimmune diseases such as multiple sclerosis appear to be caused by the immune system attacking components of the body that they should not be attacking.  For example, in multiple sclerosis the T cells are recognizing part of the myelin sheath and produce chemicals (cytokines) which attract macrophages and microglial cells, which cause demyelination.  The lack of myelin leads to poor signaling between neurons, thus causing some of the pathology associated with the disease.

The immune system usually does not attack the body because the immune cells that recognize the body are killed in the thymus.  Unfortunately some immune cells escape the thymus and circulate in the body.  These cells are autoreactive and can cause diseases such as multiple sclerosis, or type 1 diabetes, or rheumatoid arthritis.  Usually the body protects itself from these cells by virtue of another type of immune cell, called the T regulatory cells, which inhibits immune cells that attack the body.

In many patients with autoimmune diseases the T regulatory cells higher are found in lower numbers, or have lower activity.  Patients with autoimmunity who respond to various therapies actually have an increase in numbers of T regulatory cells.  

The subject of T regulatory cells has been controversial in the past, primarily due to lack of molecular characterization of these cells.  At the turn of this Century, immunologists have started characterizing T regulatory cells as CD4 positive and CD25 positive.  These are proteins that are used to distinguish T regulatory cells from other cells.  

A recent publication in the April 28th Journal of Leukocyte Biology (Huang et al. T cell suppression by naturally occurring HLA-G-expressing regulatory CD4+ T cells is IL-10-dependent and reversible. J Leukoc Biol 2009 Apr 28) describes what appears to be a new type of T regulatory cell capable of suppressing autoreactive immune responses, which is very important in disease such as multiple sclerosis.

The authors of the paper demonstrated that a population of cells exists that express CD4 but also the molecule HLA-G.  These cells are apparently a type of “natural T regulatory cell”.

Natural T regulatory cells are made (mature) in the thymus like “normal” T cells, and recognize proteins of the body.  This way if a conventional T cell starts to attack a tissue of the body, the “natural T regulatory cell”is already in existence and can inhibit the attack (see Piccirillo et al. Naturally-occurring CD4⁺CD25⁺ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin. Immunol. 16:81–88). This is in contrast to “inducible T regulatory cells”, which are known to initially be conventional T cells, but after consistant immune activation take an inhibitory profile.

The new cell described in the paper appears to be capable of inhibiting activation of conventional T cells in vitro through production of the cytokine interleukin-10 but not TGF-beta.  This type of HLA-G expressing natural T regulatory cell is interesting because it is another possible way in which the body protects itself from autoimmune diseases.

It will be important to see if this cell works or doesnt work in multiple sclerosis patients and how relevant it is to the disease in a clinical situation.  This type of research is important since if the cell appears to be critically important (eg if you take out the cell in animals with multiple sclerosis the multiple sclerosis accelerates), then one could develop methods of amplifying the cell outside of the body (ex vivo) and putting them back in, or small molecule drugs could be developed that are orally available that could be used as a medicine for multiple sclerosis or other autoimmune diseases.