Mesenchymal Stem Cells Inhibiting Homeostatic Proliferation
Felix Platter -Spital, Switzerland -
Immune regulatory effects of mesenchymal stem cells include suppression of allogeneic lymphocyte proliferation, stimulation of T regulatory cells, and secretion of soluble immune suppressive molecules such as soluble HLA-G.
In a recent paper (Bocelli-Tyndall et al. Human bone marrow mesenchymal stem cells and chondrocytes promote and/or suppress the in vitro proliferation of lymphocytes stimulated with the cytokines IL 2, IL 7 and IL 15. Ann Rheum Dis. 2008 Jul 22) a new way in which mesenchymal stem cells modulate the immune system is demonstrated. The investigators stimulated T cell proliferation in an antigen-independent manner in order to mimic homeostatic expansion. Various cell to cell ratios of mesenchymal stem cells to articular cartilage were added to T cells that were stimulated with the cytokines IL-2, 7, and 15, which are associated with T cell proliferation that does not require TCR signaling.
It was found that higher ratios of mesenchymal stem cells to articular cartilage cells was associated with inhibition of in vitro "homeostatic" proliferation. This means that conceptually mesenchymal stem cells may be useful at inhibiting homeostatically expanding T cells. This is important since homeostatic proliferation after lymphodepletion results in the generation of memory-like cells that are costimulatory signal independent, meaning tolerance induction because difficult, if not impossible.
Future experiments assessing ability of mesenchymal stem cells to inhibit homeostatic proliferation may result in the establishment of the mesenchymal stem cell as a potent adjuvant in tolerance-inducing protocols.
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jonnyboy said...
You mean TGF-beta would inhibit the allogeneic lymphocyte proliferation, right?
Interesting point since TGF-beta also stimulates the production of T regulatory cells, and if IL-6 is there...Th17 cells.
This is a very strong point you brink up since as you may know TGF-beta rears its ugly head not only in mesenchymal stem cells but also is an autocrine inhibitor of hematopoietic stem cell proliferation. There is actually a patent in this database I found where they show that blocking antibodies to TGF-beta can stimulate early hematopoietic stem cell proliferation.
Even cooler perhaps is that TGF-beta is one of the mechanisms by which tumors suppress the immune system. So companies such as NovaRx are using allogeneic cancer cell lines in which TGF-beta is inhibited with antisense as a tumor vaccine. This approach may sound interesting, but it is even more interesting that there is an independent guy in miami, podack i think his name is, who is also trying this approach
TGF beta is also associated with fibrosis, so it may not always be a good thing when you are thinking about inhibiting pathological immune responses. But then again everything seems to be so context specific.
Thomas said...
Mesenchymal stem cells have potent abilities to suppress immune responses in certain situations. There was a neat paper that was recently published in the Journal Transplant Immunology, which provides in vivo data showing that donor derived mesenchymal stem cells synergize with low dows mycophenolate (MMF) to induce tolerance in an allogeneic rat cardiac transplant model. The reference is (Popp et al. Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. Transplant Immunology 2008 Aug 30).
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Harry Banaharis said...