Interferon gamma as a "danger signal"

Boston, MA -

Although stem cell therapy has demonstrated some benefit in a variety of cardiac conditions, heart transplantation is still the only option for many patients with end-stage heart failure.  The problem with heart transplantation is that firstly there are not enough donors, and secondly, the patients have to take immune suppressive drugs for the rest of their lives. 

Understanding how to "trick" the immune system into accepting a foreign graft, a procedure called "immunological tolerance" would be very beneficial not only to transplant patients but also to the stem cell community.  The most advanced regenerative stem cell therapy, mesenchymal stem cell therapy, have progressed rapidly because these cells are immune modulatory, therefore mesenchymal stem cells can be transplanted across allogeneic barriers without the need for immune suppression.  For example, Osiris Therapeutics demonstrated simple intravenous injection of mesenchymal stem cells was able to improve ejection fraction of patients after a heart attack, without needing to provide immune suppression.  This is because mesenchymal stem cells induce generation of T regulatory cells, as well as express various immune modulatory compounds such as HLA-G, so that they do not get rejected by allogeneic immunological pressures. 

See mesenchymal stem cells evade the immune system, home to the area of tissue injury, and mediate therapeutic effects.  But what about if you take mesenchymal, or for that matter embryonic stem cells, differentiate them into a new heart, and then transplant the heart???  The heart obviously will still get rejected because it is allogeneic.  So the problem of inducing immunological tolerance is very important not only for transplant patients and their doctors, but also for stem cell scientists.  Unfortunately this problem is very much ignored by everyone, especially in the area of embryonic stem cells.

In a recent paper (Hoerbelt et al. The effects of tolerance on allograft damage caused by the innate immune system. Transplantation 2008 Feb 15;85(3):314-22) the importance of the T cell generated cytokine interferon gamma was assessed on the induction of tolerance.  The researchers used 4 groups of recipients:

Group 1: Syngeneic heart and interferon gamma + cyclosporin
Group 2: SLA-1 different heart + interferon gamma + cyclosporin
Group 3: SLA-1 different heart and kidney + interferon gamma + cyclosporin (procedure known to induce tolerance)
Group 4: No transplant, only interferon gamma injected

The interferon gamma administration caused rapid rejection of the hearts in Group 2 AND induced rejection of the syngeneic heart !! Yes, the syngeneic heart, which normally would be accepted forever...because its syngeneic...actually was rejected !

Group 3 still had tolerance induction occurring.

These data suggest an important point:  Type I cytokines such as Interferon Gamma may take a tissue injury (such as the one caused during the syngeneic transplant) and accelerate it to cause full-blown rejection.  Specifically, these findings appear to support a close collaboration between the innate (syngeneic ischemic reperfusion injury) and adaptive (IFN-gamma) immunity.

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