One of the reasons why fat stem cells seem to have therapeutic activity in animal models and early clinical trials is likely associated with their ability to modulate the immune system.  Specifically, the mesenchymal stem cell component of the fat is very interesting since administration of both mouse and human mesenchymal stem cells into animal models of multiple sclerosis has resulted in beneficial effects in the disease process.

How to mesenchymal stem cells affect multiple sclerosis?  There is some evidence that mesenchymal stem cells produce the enzyme indolamine 2,3 deoxygenase, which depletes local tryptophan and causes death of nearby T cells.  The importance of this enzyme is seen in studies in which stem cell mediated inhibition of multiple sclerosis is reversed by addition of a chemical inhibitor of indolamine 2.3 deoxygenase. In addition to inhibition of activated T cells, indolamine 2,3 deoxygenase causes production of various small molecules that can directly induce T cell apoptosis.  This enzyme is one of the mechanisms by which tumors escape immune attack and is also involved in the ability of the fetus (which has different genes than the mother) to grow up inside the mother without immunological rejection.

Mesenchymal stem cells express molecules such as HLA-G which are known to send inhibitory signals to T cells and prevent their activation.  Additionally, HLA-G is known to bind to immunoglobulin-like transcripts (ILTs) on dendritic cells and induce immune suppressive activities. We previously discussed that subsets of T regulatory cells express HLA-G.

Of course, besides indolamine 2,3 deoxygenase and HLA-G, mesenchymal stem cells modulate the immune system by secretion of cytokines.  Notable cytokines that have been implicated include TGF-beta, IL-10 and leukemia inhibitory factor (LIF).  Interestingly, the cytokines that are immune modulatory actually start getting produced in higher quantities when the mesenchymal stem cell is under allogeneic immunological pressure, such as in a mixed lymphocyte reaction (Nasef et al. Leukemia inhibitory factor: Role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol 2008 May-Jun;253(1-2):16-22).  This would make sense since why would mesenchymal stem cells constitutively secrete immune suppressants? They would theoretically secrete them only when they are needed by the host, which is what seems to be the case.

Today we wanted to mention a new type of mesenchymal stem cell mediated immune modulatory mechanism: cleavage of the interleukin-2 receptor protein CD25.  The clinically used antibody daclizumab binds to anti-CD25 and has had some promising effects in multiple sclerosis patients.  In a recent paper (Ding et al. Mesenchymal Stem Cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of Matrix Metalloproteinase-2 and -9. Diabetes 2009 Jun 9) it was demonstrated that mesenchymal stem cells can cut and thereby inactivate CD25 on T cells via expression of MMPs 2 and 9.

The investigators took the study one step further and shown that while the mesenchymal stem cells could provide prolongation of allogeneic tissue survival, this was associated with their ability to reduce expression of CD25.

This paper is very interesting not only for the finding that mesenchymal stem cells can modulate this interesting area of T cell biology, but also because it suggests modulation of MMP activity by other means may be a useful method of controlling the immune system.  For example, numerous MMP inhibitory compounds have been developed for treatment of cancer (cancer needs angiogenesis, angiogenesis needs MMPs) but not many, well to my knowledge none, have worked in Phase III.  This means that there is a possiblity that MMP modulators that are feasible from a clinical trial perspective may already be in existance. 

Another interesting question that this study begs is whether the MMPs involved in angiogenesis of cancer are also involved in cleaving CD25 off immune cells and therefore may be one of the mechanisms by which cancer reduces the immune response.

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.