Possible reason for severe side-effects of Northwick Park clinical trial

Jan 25 2007

A possible reason why the Northwick Park clinical trial of the drug TGN1412 caused multiple organ failure in human volunteers is revealed in research presented at a conference near Paris.

The research shows that stimulating the molecule CD28 on cells that mediate the immune response, known as T cells, can have an adverse effect if these immune cells have been activated and altered by infection or illness in the past.

The scientists found that when they artificially stimulated CD28 on these previously activated 'memory' T cells, this caused the cells to migrate from the blood stream into organs where there was no infection, causing significant tissue damage. CD28 is an important molecule for activating T cell responses and the TGN1412 drug tested on the human volunteers strongly activates CD28.

Around 50% of adult human T cells are memory cells, having been activated by infections and illnesses during the course of a person's life. However, animal models, such as those used to test TGN1412 before tests were carried out on humans, do not have many memory T cells because they are deliberately kept in a sterile environment where they are shielded from infections.

The research, by scientists from Imperial College London, King's College London, and the Babraham Institute, is presented at the Club de la Transplantation conference in Cernay la Ville, near Paris.

Dr Federica Marelli-Berg, lead author of the research from the Department of Immunology at Imperial College London, explained: "The drug TGN1412 appeared to be relatively safe when it was tested in animal models. However, when the drug was tested on human volunteers, some experienced very severe side-effects.

"Our research suggests that this is because the human subjects' memory T-cells lost their sense of direction and started migrating into several areas of the body where they were not supposed to go, and caused damage."

The researchers reached their conclusions after memory T cells in which CD28 had been previously stimulated were injected into healthy mice. These cells immediately migrated from the blood into many organs including the kidney, the heart and the gut, where they are not normally found unless there is an infection.

TGN1412 was developed to treat chronic inflammatory conditions, including rheumatoid arthritis, leukaemia and multiple sclerosis, which are caused by the body's immune system attacking itself. It was thought that by targeting CD28, the drug could over-stimulate the rogue T cells, making them burn out and die.

The study was funded by the British Heart Foundation.

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