Solving the Transplant Puzzle: Preventing Organ Rejection but Maintaining Pathogen-Specific Immune Response

Investigators in Switzerland may have taken a step toward solving a serious conundrum in the field of organ transplantation: How to suppress the immune system enough to prevent organ rejection but still maintain the ability to fight off pathogens that can lead to life-threatening infections.

A team from the Biozentrum at the University of Basel has determined that T cells can be engineered to specifically fight infections while leaving allogeneic tissue transplants (heart and skin), at least in mice, untouched.

By manipulating levels of coronin 1, an immunoregulatory protein, in mice, investigators were able to achieve allograft-specific tolerance without compromising pathogen-specific immunity.

“We found that mice deficient in coronin 1, a regulator of naive T cell homeostasis, fully retained allografts while maintaining T cell-specific responses against microbial pathogens,” investigators wrote in the study, published recently in Immunity. “Mechanistically, coronin 1-deficiency increased cyclic adenosine monophosphate (cAMP) concentrations to suppress allo-specific T cell responses.”

Investigators deleted the gene coding for coronin 1 in T cells of the mouse models, which prevented the cells from actively attacking the transplants, and then infected the mice with either Staphylococcus aureus or Candida albicans and monitored immune response.

"By removing coronin 1 [in mouse models], we observed that the T cells not only massively suppressed the immune response to the transplanted organ but even actively prevented its rejection," first author Rajesh Jayachandran, MBBS, Phd, said in a statement. "At the same time, we were astonished that coronin 1-depleted T cells continue to fight infections."

It was not within the scope of the study to extrapolate results out to humans, but Jean Pieters, PhD, professor of biochemistry at Biozentrum who led the study team, told Contagion^® further research will be conducted.

“[O]ur next step is to further unravel the mechanisms underlying allo- and infection-specific T-cell responses,” Dr. Pieters said. “Whether these findings may result in the development of therapies to allow retention of transplanted organs while retaining the ability to fight infections remains a task for the future.”

But being able to direct the immune system to selectively suppress foreign material could revolutionize organ transplantation if proven to be successful in humans.

“The data suggest a [sea] change in how we look at transplant,” Michael G. Ison, MD, MS, FIDSA, FAST, professor in the divisions of Infectious Diseases and Organ Transplantation at Northwestern University Feinberg School of Medicine, who was not involved in the study, told Contagion^®. “Currently, all drugs that prevent rejection either remove the T cells or make them less reactive. This prevents rejection but increases the risk of infection; typically, the more potent the immunosuppression, the higher the risk of infections. If the approach [presented by the Swiss team] is proven to work in human transplant recipients, this would allow the use of a novel approach to prevent rejection without inherent risk of infection. This would markedly improve outcomes.”