Making Heart Transplants Safer With Antibodies

Transplanted hearts functioned longer in mice when the recipients who received the organs were administered with the novel antibody treatment before the surgery. According to a recent study by Cincinnati Children’s researchers, administering an anti-inflammatory antibody treatment to the recipient and the donor organ before the surgery might help prevent the graft rejection(1^✔ ✔Trusted Source
Pre-Surgical Antibody Treatment Might Prevent Heart Transplant Rejection

Go to source). The results, which were published online in Proceedings of the National Academy of Sciences (PNAS), focus on inhibiting an innate immune response that normally takes place in response to microbial infections. It has been demonstrated that in transplanted hearts, the same response causes severe inflammation.

“The anti-rejection regimens currently in use are broad immunosuppressive agents that make the patients susceptible to infections. By using specific antibodies, we think we can just block the inflammation that leads to rejection but leave anti-microbial immunity intact,” says corresponding author Chandrashekhar Pasare, DVM, PhD, director of the Division of Immunobiology at Cincinnati Children’s.

Reducing the Activity of Memory T cells

The research team, which included first author Irene Saha, PhD, a research fellow in the Pasare Lab, and several colleagues at Cincinnati Children’s, zeroed in on how dendritic cells from the donor organ trigger an inflammatory response in the recipient’s body.

Specifically, the team found that memory CD4 T cells in the recipient activated donor dendritic cells through signals delivered by the proteins CD40L and TNFα. When this signaling pathway was blocked with gene editing techniques, the results included dampened inflammation and prolonged survival of transplanted hearts.

In the study, untreated mice rejected the donated heart within a week. But in mice that were gene edited to lack receptors for CD40L and TNFα, strong heart function persisted through day 66, when the experiment was terminated.

“We have been working on this for almost a decade,” Pasare says. “The major reason we figured out this pathway is because we focused on understanding how memory T cells in the recipient with potential reactivity to donor specific antigens induce innate inflammation. The rest of the field has focused on other concepts such as ischemia reperfusion injury, ligands from dead cells, and innate immune receptors, none of which seem to really lead to transplant rejection.”

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Pasare continues: “The key to preventing organ rejection is to take away the ability of recipient’s memory T cells to initiate inflammation when they recognize donor antigens in dendritic cells. While T cell memory is critical to fight infections, the innate inflammation initiated by memory T cells is detrimental to the survival of transplanted organs.”

Advancing the research to the next level

The co-authors believe the process they used to protect hearts from rejection may also apply to other forms of organ transplantation. However, the gene editing performed with the mice would not be considered safe for humans. So now the research team is evaluating other ways to disrupt the inflammatory response.

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“Using blocking antibodies against CD40 could be a good approach. Another option would be to create biologics or compounds that specifically target the TNF receptor superfamily in humans,” Pasare says. “I think this is a very exciting area for future drug development.”
Reference:

1. Pre-Surgical Antibody Treatment Might Prevent Heart Transplant Rejection - (https://scienceblog.cincinnatichildrens.org/pre-surgical-antibody-treatment-might-prevent-heart-transplant-rejection/)

Source-Eurekalert