IL-18 in the Heart
Indianapolis, Indiana -
It is safe to say that the actual implimentation of stem cell therapy clinically is actually more being performed for purposes of immune modulation than actually growing of new tissues. For example, mesenchymal stem cells are most advanced clinically in the USA by the company Osiris, which are administering mesenchymal stem cells in Phase III trials intravenously for treatment of graft versus host disease and Crohn's, both being immunologically mediated conditions. Indeed it is known that mesenchymal stem cells can modulate inflammation through various mechanisms such as expression of HLA-G, ability to induce antigen specific T cell death, and stimulating the generation of suppressor T cells.
Previously it has been shown that mesenchymal stem cells have activity against a variety of cardiac conditions both in animal models, as well as in various clinical trials. For example, intravenous administration of bone marrow ALLOGENEIC mesenchymal stem cells was capable of inducing an increased left ventricular ejection fraction in patients with post-infarct heart failure. Of course other types of stem cells have also been demonstrated to have therapeutic activity against heart failure, such as bone marrow derived stem cells. The question is, however, how do the stem cells mediate therapeutic effects?
One simple explanation is that the stem cells are becoming cardiac tissue. This has been demonstrated in certain animal models however it has also been argued that these models are artificial.
Another explanation is that the various stem cells produce growth factors, and also generate anti-inflammatory signals. But is the damaged heart actually associated with high levels of inflammatory signals? In a recent review, (Wang et al. BIOLOGY AND MECHANISMS OF ACTION OF INTERLEUKIN 18 IN THE HEART. Shock. 2007 Dec 13) the role of one particular inflammatory cytokine, interleukin-18, is described in the heart.
The authors review studies showing that:
1. IL-18 has immune modulatory effects independent of its ability to induce interferon gamma.
2. Post-infarct, IL-18 is made by a variety of cells that infiltrate as part of the inflammatory response. These including macrophages, EC, smooth muscle, neutrophils, and the cardiomyocytes.
3. Systemic rises in IL-18 are seen post infarct.
4. IL-18 induces apoptosis of various cellular components of the myocardium.
5. IL-18 is involved in myocardial hypertrophy.
6. IL-18 knockout mice do not undergo ventricular remodeling the same way that wild-types do. Specifically, the typical hypertrophic response is missing.
7. Administration of exogenous IL-18 induces hypertrophy of the ventricle.
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deena said...
I wonder, you mention HLA-g, you know that this blocks both dendritic cell maturation as well as T cell activation, right? It is important for scientists to look at whether the mesenchymal stem cells actually inhibit IL-18 in vivo. Osiris should retrospectively check this from their trials.
For crhon's the anti-IL-12 antibody has some effects, I wonder whether the mesenchymal stem cells used to treat crohns are helpful at inhibiting the IL-12.