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Kidney Transplant Tolerance Signatures Provide Clues to Curbing Excess Immunosuppression

NEW YORK (GenomeWeb) – Immune-related expression profiles in kidney transplant recipients may help predict which of those individuals accept the new organ without having to endure a lifetime of immune-suppressing drugs.

Researchers from Northwestern University, the University of Virginia, and elsewhere used a combination of microarrays and/or RT-qPCR to assess gene expression and microRNA profiles in kidney graft samples from seven kidney transplant "tolerant" individuals, who received engineered donor stem cells and did not require chronic immunosuppression post-surgery.

The team's findings, published online today in the Journal of the American Society of Nephrology, revealed a rise in B cell receptor signaling and anti-inflammatory pathways in the donor-tolerant group relative to pre-implantation donor samples, samples from individuals experiencing organ rejection, and organ recipients who required immunosuppression to continue staving off acute rejection.

Along with providing insights into the immune regulatory processes that contribute to kidney transplant tolerance, the investigators noted that some of the expression changes identified might serve as markers for favorable kidney transplant outcomes.

"The data generated from this study can help not only longitudinally monitoring our tolerant patients, but also could help identify those patients on chronic immunosuppression (the vast majority of the kidney transplant recipients) … [who] could therefore be potentially considered for minimization of their immunosuppression," corresponding and first author Lorenzo Gallon, a nephrology, hypertension, and organ transplantation researcher at Northwestern University, said in a statement.

Although ongoing immunosuppressive therapy is a helpful tool for transplant recipients who might be prone to acute organ rejection, he and his colleagues explained, it can also have a range of serious side effects such as increased infection risk, potential kidney toxicity, heart disease, or even cancer.

In an effort to curb immunosuppressive drug use as much as possible, members of the team have been pursuing chimerism — successful comingling of bone marrow cells from an organ recipient with those infused from the organ donor after bioengineering to produce "facilitating cells," known as FCRx.

"We previously demonstrated full door chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx)," the authors noted.

For the current study, they focused on seven kidney transplant recipients in which this FCRx approach was associated with donor organ tolerance in the absence of immunosuppression.

Using array- or RT-qPCR-based profiling, they compared gene and miRNA expression profiles in post-transplant graft tissue from these individuals with pre-surgery kidney samples from donors. They also evaluated samples from 10 kidney transplant recipients receiving immunosuppressive therapy and 10 individuals who experience transplant rejection.

Consistent with the observed organ tolerance, the team did not see the same rejection-related expression of antigen presentation, T cell, and B cell immune pathways in the FCRx-treated recipient individuals as were present in the rejection samples. And while some genes did show altered expression in the graft samples from transplant recipients compared with pre-surgery samples, expression profiles from the same organ were largely consistent before and after transplant.

Even so, the researchers noted, there were some notable expression differences between donated kidney samples from transplant-tolerant individuals and those from organ recipients who were acute rejection-free, but reliant on immunosuppressive drugs.

Among the almost 1,400 genes that were differentially expressed in the FCRx-treated recipient kidney samples, they saw an uptick in B cell receptor signaling gene expression and lower-than-usual expression of genes in regulatory genes related to pro-inflammatory pathways.

Such differences were echoed by the miRNA expression shifts between the FCRx, rejection, and ongoing immunosuppression transplant samples, the authors explained, noting that their integrative miRNA and gene expression analyses "identified the induction of regulators with demonstrated roles in the down-regulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with [standard immunosuppression without rejection] samples."