We all hate rejection. It hurts us somewhere deep inside. And those of us who’ve had an organ transplant hate it most of all. Because the only way to make all that pain go away is by taking a hearty (sometimes heroic) dose of anti-rejection drugs.
Rejection is driven by our body’s immune system, a collection of cells (T cells) that recognise and destroy foreign cells: germs, poisons, other bits that find their way into us. All cells have proteins called antigens on their surface. As soon as these antigens enter our body, the immune system recognises that they are not from our body and attacks them.
When we receive an organ transplant, our immune system may detect that the antigens on the cells of the organ are not from our body or not “matched.” Mismatched organs, or organs that are not matched closely enough, can trigger rejection. To help prevent reaction, doctors type, or match both the organ donor and the person who is receiving the organ. The closer the match the antigens are between the donor and recipient, the less likely that the organ will be rejected.
Anti-rejection drugs work by slowing down our body’s immune system. But you can’t let up: it’s like pressing our foot down on a spring: the moment you take it away, it bounces back to exactly where it was. So once you have a transplant, you must take the drugs for as long as the transplant lasts (which can be decades).
The trouble is, anti-rejection drugs have side effects:
- With our immune system supressed, we catch every bug that’s passing by and because we have almost no resistance, the damage it can cause is massively exaggerated (where a person with a normal immune system may get a mild sniffle, we can easily end up with pneumonia)
- The drugs do things to us (give us moon heads, thin easy-tear skin, bruises from bumps a 90-pound weakling would brush aside, scramble our brains and our emotions and lots more).
But all this may change over the next few years (key dramatic, super up-beat music).
Re-writing the anti-rejection script
Last week I had the pleasure of interviewing Melbourne scientist from the Monash University Department of Anatomy and Developmental Biology. Dr Heng and her colleagues from the Departments of Anatomy and Developmental Biology, and Immunology and the CSIRO are re-writing the anti-rejection script: this time eliminating the cause of rejection rather than stamping on the spring.
Put simply, they have found a way to make every donor kidney a perfect match for the recipient using the body’s own mechanism for teaching the immune system to recognise what is foreign versus local. Of course it involves the wonder building blocks of all cells, stem cells.
How it works
During the normal course of events our immune system creates the T cells it needs from our bone marrow stem cells. Dr Heng and her colleagues have found a way to introduce foreign bone marrow stem cells from the donor into the recipient’s bone marrow. The stem cells mix with the locals and when they are converted into T cells, they have been “educated” to see all donor cells as a perfect match. When the transplanted organ arrives there are no alarms; no attack; and no rejection. This technique is called “tolerance induction”, whereby the recipient becomes tolerant to the donor organ.
The technique involves using a small dose of Busulfan (a chemotherapy drug usually given before a stem cell transplant for leukaemia) to slightly reduce the number of the recipient’s bone marrow stem cells, making space for the donor stem cells. The stem cells are then transplanted into the recipient’s bone marrow combined with a small amount of anti-rejection drug for a few days to stop the donor stem cells being rejected. The recipient is now ready for the transplant.
Good for the life of the transplant
The technique specifically replaces “long term” stem cells, to generate long lived, educated T cells that they expect to last at least as long as the recipient has their transplant.
Low impact and radiation-free
Dr Heng noted that a variant of this approach has been trialled in the US, using larger doses of chemotherapy drugs or radiation, which may not be suitable for the sick or elderly (both groups are heavily represented on transplant lists). This new approach is a radiation free, way of producing the educated T cells.
Good for aged transplant recipients
Dr Heng started this research in 2009, and the team has conducted successful pre-clinical trials with both young and aged mice, despite age-related cell degeneration in the aged mice. From a clinical viewpoint, this is especially important, as the majority of transplant recipients are older patients whose immune recovery might be dangerously slow and would benefit from a radiation-free, low impact conditioning technique that enables organ transplant without compromising their immune system.
The details were published in the 10 July 2014 edition of the American Journal of Transplantation.
When can we line up?
Not for a few years. There are many tests and trials to complete before it becomes a standard clinical treatment for transplants. But the fact that the team is using drugs that are in use worldwide means there are no drug safety hurdles. I’m betting it will certainly be the norm in my lifetime (I’m 62).
Of course, since the whole objective is to make each donor organ a perfect match for the recipient, this treatment is limited to live donor transplants. Deceased donor transplants happen within hours of death, so there would (currently) be no time to condition the recipient’s stem cells.
Those who follow this blog know that I’ve had two transplants, one from my wife (bless her) and one from a deceased donor (bless him/her too). Neither did particularly well, because it seems I can reject almost anything, regardless of the level of performance enhancement provided by anti-rejection drugs.
If this technique was available in 1995, I would now be swanning around with my wife’s kidney tucked safely under my right rib, the world as my oyster. Sadly it was not to be. But very soon, a whole new population of donor kidney (/ liver/ lungs/heart and most other body bit) recipients will be doing just that. All thanks to wonderful, smart people like Tracy Heng and her colleagues.