About 24,000 kidney transplants are performed in the US each year, yet more than 90,000 people are waiting for a transplant. Even when patients get a transplanted kidney, organ rejection is a common complication in the first year after a transplant, affecting 1 in 3 people.                                                        

Sometimes finding a perfect match for a kidney can turn into an endless search – with blood, tissue, and antibody compatibility needed between donor and recipient. A study recently published in the journal Transplantation shows researchers may be able to help increase the number of kidney transplants thanks to a new transplant procedure working between mismatched donors and recipients. 

Rhesus monkeys at the Wisconsin National Primate Research Center are playing a starring role in a study to improve the success of kidney transplants. Animal care experts and pathologists worked with transplant surgeon Luis Fernandez and other researchers to test the new procedure. Fernandez directed the University of Wisconsin Hospital and Clinics liver transplant program until last year and is now a transplant division chief at Loyola Medicine in Chicago. Also on the research team were preclinical and clinical experts from the University of Wisconsin–Madison School of Medicine and Public Health, Texas Southwest Medical Center, Pharming Technologies BV in Leiden, The Netherlands, and Leiden University Medical Center.

The researchers focused on complement activation, implicated in delayed graft function. They used a high-dose complement blockade therapy called C1INH (or rhC1INH in rhesus monkeys) to discover it worked well in preventing delayed graft function and antibody-mediated kidney rejection. Furthermore, the researchers used donor kidneys from deceased animals to make up for the lack of available deceased human kidney donors (approximately 20% of human donor kidneys are discarded due to the length of storage time or advanced donor age).

Of all the mismatched kidney transplant recipients, four out of five monkeys treated with a saline control developed delayed graft function complications, whereas only one in eight rhC1INH-treated recipients experienced difficulties. The other seven animals in the treatment group underwent successful transplants with fully functioning kidneys.

The study results support high-dose C1INH complement blockade therapy in mismatched transplant recipients as an effective strategy to reduce kidney injury and inflammation, prevent delayed graft function, delay antibody-mediated rejection development, and improve transplant outcomes.

The research team thanks the veterinary and SPI staff at the Wisconsin National Primate Research Center for their “extraordinary care for the animals during the observation period.”

Right now, kidney transplant recipients are required to undergo a lifelong regimen of immunosuppressive medications so their white blood cells won’t reject the new organ. But scientists at the Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin-Madison (UW) are working to create conditions in recipients that will allow their bodies to accept transplants without the need for drugs.

In an ongoing study utilizing nonhuman primates, hematopoietic stem cells (HSC; cells that can become any other blood cell) are driven from the bone marrow of the potential donor into the blood. They are then collected from the blood and frozen, using methods like those used in humans to harvest cells for transplantation into cancer patients. Next, the kidney is transplanted from donor to recipient. Then, the recipients undergo targeted treatments for two weeks with immune-depleting agents and radiation to prevent rejection. After the last radiation treatment, the donor’s set-aside blood containing the HSCs is infused into the recipient.

If these cells are accepted along with the kidney, this is called a state of mixed chimerism; the resulting immune system is part-donor and part-recipient. The subjects are then placed on immunosuppressive drugs for eight months, during which time the investigators examine whether the transplanted kidney is doing its job, and whether the infused HSCs are actually multiplying.

“We are seeing that the donor HSCs survive and differentiate to join the components of the recipient’s immune system,” said Dixon B. Kaufman, MD, PhD, one of the researchers and chair of the UW Division of Transplantation. “This combined system appears to be much more accommodating to the new organ than what we observe in traditional transplantation.”

A critical next step, according to the researchers, is to come up with a new standard of care that works for most, if not all patients, as everyone’s immune system reacts differently to disease, surgery and postoperative care.  

“We hope to provide a successful system for other major organ transplants (as well),” Kaufman said. “Saving lives, along with reducing the cost to patients and the healthcare system with a one-and-done transplant approach, where the patient need not take a regimen of drugs, nor have to worry about a second organ transplant if the first gives out, is the holy grail of this work.”

A collaborative research team at the Yerkes National Primate Research Center and Georgia Tech is studying non-invasive imaging as a way to detect immune rejection of transplanted organs, thanks to a $2.4 million, five-year grant from the National Institute of Allergy and Infectious Diseases.

Currently, medical professionals use blood tests and biopsies – removing a small sample of the organ tissue – to monitor how well a new kidney or liver is adapting to its new home. But with each biopsy, the patient must endure a small surgery so the organ can be accessed yet again. These follow-up procedures can result in hemorrhaging and infection – a major problem for anyone, but especially someone still recovering from the trauma of a transplant.

Andrew Adams, MD, PhD, a researcher at the Yerkes National Primate Research Center and an assistant professor of surgery in Emory University School of Medicine, is part of the team working to identify a non-invasive method for monitoring organs post-transplant.

“Patients often require multiple biopsies to assess response to treatment, thus putting them at risk of complications each time they undergo a separate procedure,” says Adams. “In addition, a biopsy only samples a small part of the transplanted organ.” In other words, just because part of the organ is adapting, doesn’t mean all of it is.

Adams and his colleague at Georgia Tech, Phil Santangelo, are studying the use of positron emission tomography (PET) to monitor post-transplant progress. PET is already used to diagnose heart disease and monitor cancer. Using a variant called “immunoPET,” the researchers can see particular types of immune cells infiltrating the transplanted organ, alerting them to the possibility of rejection. The researchers are conducting the study with mice and nonhuman primates first and hope the results will prove successful so they can advance to human clinical trials.

Reviewed August 2019

Imagine a day where we’re able to treat some of the world’s most debilitating neurological disorders, like Parkinson’s, strokes and brain injuries. While this day may seem far removed, scientists at the Southwest National Primate Research Center (SNPRC) are taking steps toward making the dream a reality.

Dr. Marcel Daadi of SNPRC is developing a more effective method for delivering neural stem cells to the brain in an effort to move forward stem cell therapies to treat neurological disorders. His research has already developed stem cells capable of becoming the type of cells Parkinson’s patients lose over time, or dopaminergic cells. An MRI-guided technique to implant these cells would move scientists one step closer to delivery of this therapy to patients.

“Stem cell-based therapy is emerging as a promising treatment for a variety of diseases and injuries. The first step in evaluating the potential of different therapeutic stem cell lines is to develop a safe and effectively reproducible delivery system,” Dr. Daadi explained.

Injection parameters have been well studied in drug delivery methods; however, they simply cannot be directly applied to stem cell-based therapy and the technology for stem cell delivery is undeveloped and limited.

Dr. Daadi and his colleagues developed an operational technique for delivering stem cells with low invasiveness and high accuracy in placement of the stem cells to the basal ganglia part of the brain. The basal ganglia controls motor skills compromised in Parkinsons disease.

The team tested the technique on baboons at SNPRC and not only showed effective targeted delivery but also revealed the cells were not released at a steady rate but instead dispersed in small bursts. This is a significant finding as it demonstrated how injected cells disperse in the host brain and stimulates new ideas on how we can prepare the cells to function at their best.

“We wouldn’t have been able to see this phenomenon using standard stereotaxic delivery,” Dr. Daadi said. “With iMRI, we can visualize in real time the cells being injected to the target area. A non-invasive MRI approach is becoming a necessity in clinical applications to enhance the safety of patients and the efficacy of the therapeutic approach. We can create the best cells, but if we can’t transplant them to the patient in a consistent and predictable way so that the patient can accept and thrive from them, then the therapy is simply ineffective.”

Since the early 1990s, a team at Yerkes National Primate Research Center has been developing and refining a costimulation blocker that will prevent the immune system from rejecting transplanted organs. The Food and Drug Administration approved the drug, belatacept, or Nulojix as it’s commonly known, in 2011 for kidney transplants. Ever since, the team has been working to expand the applications of this research to other organs.

As a result of the research team’s success, the National Institute of Allergy and Infectious Disease awarded it a $12.6 million grant to continue these efforts.

“Our research is aimed at extending the benefits of costimulation blocker-based regimens to a larger group of transplant patients, and helping them to have longer, healthier lives,” says Christian Larsen, a Yerkes researcher and professor of surgery at Emory University School of Medicine.

The team’s newest line of research has identified biomarkers on immune cells that may predict whether or not immune cells that are resistant to belatacept will reject the transplant. To determine the predictive ability of these biomarkers, the team will continue working with the nonhuman primates at the Yerkes Research Center.

In addition, researchers will be investigating possible solutions for targeting those costimulation blocker-resistant cells and strategies for preserving the immunity of the organs post-transplant. Such research is key for helping people who have organ transplants live a normal life span.

Reviewed August 2019