There is some evidence to suggest that pregnant women with multiple sclerosis experience a diminished frequency and severity of relapse in the last trimester of pregnancy.  This has prompted investigators to assess whether hormones such as progesterone are capable of inhibiting multiple sclerosis in animal models.  Indeed this seems to be the case. 

For example, Garay et al (Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neuroimmunomodulation 2008;15(1):76-83) used the B6 mouse model of multiple sclerosis (immunized with peptide from myelin oligodendrocyte protein 40-54) to demonstrate that administration of progesterone before induction of pathology led to suppressed disease severity index, inhibition of demyelination and increased expression of the sodium-potassium-ATPase gene in motor neurons.  Another study, (Correale et al. Steroid hormone regulation of cytokine secretion by proteolipid protein-specific CD4+ T cell clones isolated from multiple sclerosis patients and normal control subjects. 1998 Oct 1;161(7):3365-74) demonstrated that culture of T cells in progesterone upregulated ability to generate interleukin-4, a Th2 cytokine.  This is shown in the figure below.

Now we on the one hand we know that hormones affect immunological cells, but do hormones such as progesterone alter the ability of stem cells to modulate immune responses?  It appears that they do.  Ivanova-Todorova et al published (HLA-G expression is up-regulated by progesterone in mesenchymal stem cells. Am J Reprod Immunol. 2009 Jul;62(1):25-33) that treatment of mesenchymal stem cells with progesterone increased expression of the immune modulatory protein HLA-G.  This implies that ex vivo treatment of mesenchymal stem cells with progesterone may be useful in augmenting their ability to alter immune responses.  Additionally, it would be interesting to see if in vivo synergy may be obtained by treating patients with hormones and concurrently administering stem cells.

The ability to augment therapeutic activity of mesenchymal stem cells is very appealing since these cells are already in Phase III clinical trials by the company Osiris Therapeutics for treatment of Graft Versus Host Disease.  Once these cells are approved for marketing purposes (anticipated to be next year), then physicians will be able to use them on a more widespread basis and in many situations for off-label uses.  This will cause a great interest in methods of augmenting their efficacy, including methods as mentioned above.

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.