By Sofia Sandalli | Wed, 23 Oct 2019
Organ transplantation not only underlies several bioethical issues and poses difficulties in regards to the socio-economic context of organ procurement, but is also one of the most complex and challenging medical procedures.
The main problem resides in transplant rejection, which occurs when the recipient mounts an immune response against the transplanted organ, often resulting in the immediate need to remove the organ from the patient. Transplants occur successfully when there is sufficient similarity between the cell-surface proteins of donors and recipients: the recipient’s immune system will recognise the foreign cells as ‘self’ and will be less likely to flag an immune response against them.
Successful transplants are further accomplished with the use of anti-rejection drugs, which, as the name suggests, prevent the patient from rejecting the transplanted organ. However, since these drugs work by suppressing the immune system, they put the recipient at risk for infections and tumour formation. The optimal solution would be to perform a successful organ transplant without the use of anti-rejection drugs. But is it possible? And if yes, how?
There is evidence that this could be possible thanks to immunomodulatory strategies, which rather than suppressing the immune system, simply alter its activity. It was through such mechanisms that John Hopkins Medicine researchers were successfully able to transplant brain stem cells in mice without anti-rejection drugs. What is particularly significant about this investigation—which was led by Shen Li and published in the journal Brain on September 16th—is that it dealt with the transplant of glial cells, cells of the nervous system that safeguard neurons through the formation of a protective substance called myelin. Glial cell dysfunctions are associated with a range of neurological disorders, caused by genetic mutations in the genes encoding for myelin. These include multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and various devastating disorders in infants and adolescents.
There is evidence that this could be possible thanks to immunomodulatory strategies, which rather than suppressing the immune system, simply alter its activity
The John Hopkins Medicine researchers achieved their results by manipulating the so-called ‘costimulatory signals’ of T cells, where T cells are central components of the immune system and costimulatory signals are stimuli that trigger their initiation of an immune response. More specifically, they used two antibodies called CTLA4-Ig and anti-CD154, which, by binding to the surface of T cells, prevent them from mounting an attack against foreign cells.
This immunomodulatory technique had been used before, but never for the transplant of brain cells. Firstly, the researchers injected mice with glial cells that had been genetically engineered to glow and thus, remain visible. They then proceeded to transplant the glowing glial cells into three kinds of mice: normal mice, mice that were genetically engineered to not produce glial cells and mice that had been bred to have deficient immune systems. To block immune responses against the inserted glial cells, they treated some mice with CTLA4-Ig and anti-CD154 antibodies, while others were left untreated as a control. The fluorescent, transplanted cells were monitored with specialised equipment that imaged the mice brains. Researchers saw that whereas in untreated mice the transplanted cells immediately deteriorated, in the mice treated with antibodies, the cells survived for over 200 days. This proves that the mice successfully accepted the transplant. On top of that, another successful observation was that the inserted glial cells produced myelin, taking on their normal function of safeguarding brain neurons.
Although these are only preliminary results and a great amount of research into the transplant of glial cells for brain repair has yet to be conducted, in the long-term, this scientific development could contribute towards the treatment of patients with neurological disorders and towards the execution of organ transplants without the need for immunosuppressant drugs.