Recent research from Cincinnati Children’s has found a potential method to enhance protection for transplanted hearts against rejection. This involves administering an anti-inflammatory antibody treatment to both the donor organ and the recipient before surgery takes place.
The study, published in PNAS, highlights a new approach to inhibiting a natural immune response that typically arises during microbial infections. Interestingly, this immune response has also been linked to harmful inflammation in transplanted hearts.
In experiments with mice, it was observed that transplanted hearts survived longer when the organ recipients received the innovative antibody therapy. This marks the initiation of a complex sequence of steps to assess whether this strategy can be safely applied in human heart transplants.
“Presently, anti-rejection treatments mainly involve broad immunosuppressants that increase infection risk for patients. Our goal with specific antibodies is to target only the inflammation associated with rejection, while preserving the body’s ability to fight infections,” explains the study’s lead author, Chandrashekhar Pasare, DVM, PhD, who leads the Division of Immunobiology at Cincinnati Children’s.
Reducing memory T cells’ reactions
The research team, led by first author Irene Saha, PhD, focused on how dendritic cells from the donor organ provoke inflammation in the recipient’s body.
They identified that memory CD4 T cells from the recipient activated donor dendritic cells via signals from proteins CD40L and TNFα. When researchers blocked this signaling pathway using gene editing, they observed reduced inflammation and increased survival rates of the transplanted hearts.
Untreated mice rejected the transplanted hearts within a week. However, mice that were gene-edited to lack receptors for CD40L and TNFα maintained strong cardiac function up to day 66 of the study.
“We’ve been researching this area for nearly ten years,” says Pasare. “We discovered this pathway by focusing on how memory T cells in recipients, which can react to donor-specific antigens, contribute to innate inflammation. Other research has concentrated on different aspects such as ischemia reperfusion injury and innate immune receptors, none of which seemed to directly cause transplant rejection.”
Pasare adds: “To prevent organ rejection, it’s crucial to inhibit the capacity of the recipient’s memory T cells to trigger inflammation upon recognizing donor antigens in dendritic cells. While T cell memory is important for combating infections, the inflammation induced by memory T cells can be detrimental to the health of transplanted organs.”
Future Directions
The team believes that this method of preventing rejection may also apply to other types of organ transplants.
However, the gene editing used in mice is not considered safe for human application. Thus, the research team is exploring alternative ways to mitigate the inflammatory response.
“Using blocking antibodies against CD40 might be a viable approach. Additionally, creating biologics or compounds that precisely target TNF receptor superfamily in humans is another potential strategy,” notes Pasare. “This represents an exciting opportunity for future drug development.”
Study Contributors
Additional co-authors from Cincinnati Children’s include Amanpreet Singh Chawla, PhD; Ana Paula Oliveira, PhD; Eileen Elfers, BS; Kathrynne Warrick, BS; Hannah Meibers, PhD; Thomas Hagan, PhD; and Jonathan Katz, PhD.
This research was funded by grants from the National Institutes of Health (R01 AI123176, R01 AI155426, and U54 DK126108) and received support from various facilities at Cincinnati Children’s, including Veterinary Services, Research Flow Cytometry Core, and Bioinformatics Collaborative Services Core.
