Keeping clean may not always be wise
Wednesday, 07 February, 2007
No-one in my house suffers from asthma, which is really rather lucky. However, I have long been concerned that all the research that establishes over-clean houses as a potential trigger for the disease actually shows up my limitations as a housekeeper. Now it seems it is possible that scrupulous hygiene and a sterile environment may have inadvertently lead to the catastrophic events in the TGN1417 clinical trial. German biotech company TeGenero designed the drug, TGN1417 to stimulate an increased immune reaction and treat chronic inflammatory conditions, including rheumatoid arthritis, leukaemia and multiple sclerosis, which are caused by the body's immune system attacking itself.
Preclinical research on mice, rats and monkeys showed no sign of danger and the drug proceeded to human trials. The Phase I clinical trials were conducted by Parexel in leased space at Northwick Park and St. Mark's Hospital, London, on 13 March 2006. There, despite all relevant and legal protocols having been followed, the drug provoked devastating immune reactions in the six human volunteers leading to multiple organ failure and ongoing medical problems. Now, researchers from Imperial College London, King's College London and the Babraham Institute lead by Dr Federica Marelli-Berg, have proposed a reason for the severe side effects of Northwick Park clinical trial. The research, presented at the Club de la Transplantation conference in late January, 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 artificially stimulating CD28 on previously activated 'memory' T cells 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 the animals are deliberately kept in a sterile environment where they are shielded from infections.
Marelli-Berg said: "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.
So it is possible that keeping the experimental animals in clean, sterile environments where they were not exposed to many infections may have kept their T cells immature and precluded the devastating cytokine storm that was experienced by the human volunteers. An immunologist at the National Institute for Biological Standards and Control in London, Stephen Inglis, is working on a laboratory test using human immune cells that shows the same overactivation and proliferation seen in the volunteers. Although still being refined and developed, he hopes that similar tests could become a routine part of preclinical testing of new drugs that target the immune system. If successful this procedure could help ensure that clinical trials become safer for participants.
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