Drs. Laura Mulloy and Anatolij Horuzsko
Drs. Laura Mulloy and Anatolij Horuzsko. [Source: Michael Holahan]

A humanized mouse model that mimics a patient’s immune system is better than current approaches for identifying an optimal living organ donor, according to scientists at the Medical College of Georgia (MCG) in Augusta, USA.

They call their approach an “immunobiological algorithm” that provides a comprehensive prospective on how a patient’s immune system will react to tissue from each potential living donor, says Anatolij Horuzsko, senior author and an immunologist at the college.

“That is the take-home message,” says co-author Laura Mulloy. “Not only is it a better match, it’s less drugs and expense for the recipient, and a better chance of success for both recipient and donor.” Mulloy is chief of the MCG Division of Nephrology, and Horuzsko’s longtime collaborator.

The current standard, HLA, or human leukocyte antigen, testing is used to compare a potential recipient and donor’s lineup of a handful of proteins on the surface of their cells that provide cues to how aggressively the recipient’s immune system is likely to respond to the new organ.

A comparison of the two approaches was published recently in the journal Frontiers in Immunology. The best donor identified per HLA testing ultimately triggered the strongest immune response, which translates to an increased risk for organ rejection and the need for more medication to try to keep that immune response at bay.

In 2020, there were 33,310 deceased donor transplants compared with 5,726 living donor transplants, according to the United Network for Organ Sharing (UNOS). The kidney is the most commonly transplanted organ from a living donor, according to UNOS. Less commonly, segments of liver, which can regenerate, and uterus or other segments of organs, are donated by living individuals, they say.

“We create a situation very close to reality with a kidney transplant or any type of organ transplant,” says Horuzsko. “We see the response of T cells, CD8+ T cells, killer cells, many factors which potentially have a killing effect on the transplanted kidney,” he says, noting the comprehensive assessment shows the response of antigens that have not even been named, but whose collective immune response is clear.

“That’s the beauty of this,” says Mulloy, “It’s more comprehensive, specific testing.”

Horuzsko’s team developed this system from scratch over the past five years. A humanized mouse model is created for each potential donor. Then, each potential donor’s blood is given to the corresponding mouse and the varying immune responses measured. An additional model is given the patient’s own blood as a control.

While living organ donors remain a small portion of organ donors overall, a single individual may have multiple, often family members, willing to donate a kidney, Mulloy notes.

A major problem with the limitations of current testing is that while HLA typing can show an antigen mismatch between donor and recipient, it doesn’t tell you how much or little immune response that mismatch will produce between the two individuals, Horuzsko says, noting potentially tremendous individual variations in immune response. Mismatches can range from catastrophic to insignificant.

“Your immune system may not be as reactive as mine,” he says. “Current analysis does not tell me how vigorous the resulting immune response might be.”

Evidence indicates about 18% of kidney transplant rejections result from these mismatches and about 38% result from antigens which are not part of HLA typing.

The researchers say their humanized mouse model could be used in the evaluation of any type of organ transplant as well as for stem cell transplants for cancer, autoimmune disease and other conditions when donor cells are used.

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