Organ transplantation has undoubtedly been one of the greatest medical innovations of the last century. The development of modern immunosuppressive drugs has significantly reduced the rates of organ rejection, but these drugs often have dramatic side effects for the patient. A team from Yale has now developed an entirely new way of reducing organ transplant rejection by "hiding" the donated organ using targeted nanoparticles.
One of the most potent form of immune cells responsible for the body rejecting a transplanted organ is activated by proteins known as human leukocyte antigens (HLAs). These proteins are found on the surface of endothelial cells, which line an organ's blood vessels.
Previous research has shown that small interfering RNA (siRNA) can stifle the expression of these HLAs, lowering the chances of the body rejecting the new organ, but up until now there have been a couple of problems with this form of treatment. General administration of siRNA can negatively affect healthy organs in other parts of the body, and the effects of siRNA tend to only last a few days while a new organ needs several weeks to settle into the body.
The novel drug delivery system developed by the team at Yale uses polymer-based nanoparticles to send the siRNA to the desired graft locations and then slowly release the siRNA over several weeks.
In the study the team transplanted a small part of a human artery loaded with these siRNA nanoparticles into a mouse inoculated with human T-cells. The results were significantly positive, notably silencing the expression of HLA proteins for up to six weeks. The study also showed no damage to other organs meaning the delivery mechanism was successfully localized.
"If we delay the start of the rejection response, it should be milder and more easily controlled and lead to less late rejection," says co-author on the study, Jordan Pober.
The team is now moving the research focus to kidney transplants, the most common type of organ transplant. A system known as normothermic machine perfusion, developed at Cambridge University, looks to be the best way to deliver these nanoparticles to a donated organ before transplantation.
The process involves pumping oxygenated red blood cells through an organ after it is removed from a deceased donor in order to repair any damage. The plan is to add the new nanoparticles to the red blood cells during this process in the hope it will deliver the siRNA to the organ's endothelial cells prior to implantation in the new patient. If successful, this could significantly reduce the rate of organ rejection in the recipient.
The study proposes a variety of uses for this new nanoparticle delivery method, allowing for the targeting of many different immunomodulatory proteins across a broad assortment of transplanted organs.
The study was recently published in the journal Nature Communications.
Source: Yale University
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