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.