Cell therapy to prevent transplant rejection shows promise
20 May 2011
The approach would involve taking a blood sample from the transplant patient before surgery and isolating his or her immune cells. The cells would be grown in the laboratory under conditions that 'teach' the cells not to reject the transplant, before being re-injected into the patient.
The research is described in three papers published today in the journal 'Science Translational Medicine', including studies from the University of Oxford and King's College London that were part-funded by the Wellcome Trust.
"We have developed a new approach to generate cells called regulatory T cells that can control rejection of transplanted tissue in mice," says Dr Andrew Bushell of the Nuffield Department of Surgical Sciences at the University of Oxford.
Professor Robert Lechler, Vice-Principal for Health at King's and Executive Director of King's Health Partners, describes the studies as "a promising step forward that could lead to dramatic advances in preventing organ rejection and improving the quality of life of transplant patients."
Transplantation is very effective, but patients need to take powerful drugs for the rest of their lives to make sure the donated organ is not rejected by the body's immune system. Although these drugs have been crucial in making transplantation possible, their long-term use can lead to an increased risk of infection, cancer, damage to blood vessels and metabolic complications.
"Achieving a state where transplanted organs survive for a long time without immunosuppression is the holy grail in this field," said Dr Bushell. "Many research groups across the world are trying to solve this problem because developing better ways to prevent transplant rejection is a big unmet clinical need. Regulatory T cells may provide part of the answer."
It is known that among the body's immune cells, which patrol the body looking for any infections or foreign invaders, there is a population of cells called regulatory T cells, or Tregs. These cells dampen down immune responses when they are no longer needed and help to maintain the normal status quo in the body's immune system.
The Oxford team, along with colleagues from the Karolinska Institute in Sweden and University College London, have developed a new technique for generating Treg cells that can recognise donated tissue or organs and protect them from being attacked by other cells of the immune system.
The team used a humanised mouse model to study their effects. They first isolated human T cells and cultured them in the lab with cells from the tissue being transplanted, in the presence of a drug called cilostamide.
Cilostamide, which is already used widely in people with vascular problems, blocks a biological pathway and encourages the growth of Treg cells. By culturing the immune cells with others from the donated tissue, the Tregs are taught to recognise the donor tissue and turn off rejection.
The researchers then showed that the human regulatory T cells produced using this method could control transplant rejection in a mouse model with a human-like immune system.
In a similar study, researchers at King's College London have developed a method to select the Tregs that regulate only the activity of immune cells that would target a transplanted organ, leaving the remaining cells to function normally. They also used a humanised mouse system, where a mouse lacking its own immune system is given human immune cells and Tregs, to show that these 'specific' Tregs can prevent rejection of human skin grafted onto the mouse.
The researchers say that these results are encouraging. Ultimately, the approach could extend the life of a transplanted organ and, in turn, could alleviate the organ shortage problem.
"Different research groups are beginning to discover different ways of generating Treg cells," explains Dr Bushell. "The next steps for the field include working out which approach is best and understanding how these T cells regulate the immune response."
Dr Bushell is keen to stress that these cell therapies are not treatments that are just around the corner for transplant patients. However, the Oxford and King's College groups are members of an EU-funded European consortium that is working on the various issues necessary to allow trials of cell therapy in human transplantation to begin within the next three to five years.
Image: Colour-enhanced scanning electron micrograph of a meshed skin graft over a burn. Credit: David Gregory and Debbie Marshall, Wellcome Images.
References
Feng G et al. Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection. Sci TM 2011;3(83):83ra40
Sagoo P et al. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci TM 2011;3(83):83ra42
