Stem cells for GVHD

Graft-versus-host disease is one of the more common, and significant, complications of allogeneic haemopoietic stem cell transplantation, in which T cells in the graft begin to attack several of the host's organs, especially the skin, the gut and the liver.

Treatment for the condition is usually with steroids, especially prednisone and cyclosporine, but in the more acute cases patients do not respond. Mortality for the most severe grade of GVHD is over 90 per cent.

In 2004, Professor Katarina Le Blanc from the division of clinical immunology at the Karolinska Institute in Sweden and colleagues published a case history in The Lancet outlining the use of mesenchymal stem cells to treat acute or steroid-refractory graft-versus-host disease.

Since then, a number of trials have been held throughout the world to explore this novel therapy, including a small trial at the Royal Adelaide Hospital under the direction of senior consultant haematologist Dr Ian Lewis.

In addition to his work as a consultant, Lewis runs the Therapeutic Products Facility at the Institute of Medical and Veterinary Science (IMVS), a cell processing facility licensed by the TGA to produce cellular therapeutic products such as haemopoietic cells for transplantation, skin cells for burns patients and mesenchymal stem cells.

He works alongside such well-known mesenchymal stem cell researchers as Drs Stan Gronthos and Andrew Zannettino; while the latter study the potential of MSCs in tissue repair and regeneration, Lewis is looking at them for a different purpose completely.

No one is quite sure of the exact mechanism, but MSCs are thought to suppress most immune responses, Lewis says. They appear to have both immuno-modulatory and anti-inflammatory effects, but again no one is quite sure why.

"In terms of laboratory tests they have been shown to inhibit different aspects of the immune response, such as T cell responses, they inhibit cytokine production and they also inhibit dendritic cells," he says. "They seem to interact with a lot of cells in the immune system. What actually happens in humans is not known."

So far, four Adelaide patients, all with steroid-refractory GVHD, have been treated with a mesenchymal stem cell infusion and three have responded, Lewis says. It is very early days yet, but this small trial, part of the multi-institutional Le Blanc-led trial, is raising a great deal of interest.

In addition to a potential treatment, recent studies have looked at using MSCs as a prophylaxis for GVHD. Lewis says the rationale for using MSCs as a prophylactic agent is fairly sound but a large study is required to judge its efficacy.

In the meantime, US biotech Osiris Therapeutics, which is also exploring MSCs in bone and tissue repair, is carrying out a Phase III trial of its investigational therapy Prochymal for steroid-refractory GVHD. 240 patients are being enrolled in the study following very promising Phase II results, in which 94 per cent of evaluable patients had a response and 74 per cent achieved a complete response.