New research from investigators at Cincinnati Children’s Hospital Medical Center may have uncovered a method to further protect heart transplant patients and lower the rate of rejection by providing patients with an anti-inflammatory antibody prior to surgery. The results of the team’s mouse study, published in the journal PNAS, focused on blocking the innate immune response that often occurs due to microbial infection, which has also been shown to cause serious inflammation in transplanted hearts after surgery.
“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,” said corresponding author Chandrashekhar Pasare, DVM, PhD, director of the division of immunobiology at Cincinnati Children’s.
The results showed that the transplanted hearts of the mice used in the study functioned for longer periods when they received the anti-inflammatory antibody prior to transplant. The research team will now move forward to find whether this approach can be translated to an effective approach for humans.
The team’s approach examined how dendritic cells from the donor organ triggered inflammatory immunity responses in organ recipients. Their research showed that memory CD4 T cells in the heart recipient triggered dendritic cells in the transplanted organ via signals delivered by the proteins CD40L and TNFα.
Based on this finding, the investigators then employed gene editing to block this signaling pathway and observed lowered inflammation and prolonged survival. The differences in survival among the mice in the study was stark: untreated mice rejected the donated heart within one week, whereas mice that had immune response signaling blocked by gene editing to eliminate the CD40L and TNFα receptors maintained healthy heart function through 66 days, the length of the experiment.
“We have been working on this for almost a decade. 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,” Pasare noted. “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.”
The key to the success of their study, Pasare added, was their approach of removing the ability of memory T cells to initiate inflammations as a response to antigens in dendritic cells of the donor organ. The researchers noted that this approach may also be applicable to other types of organ transplant patients.
Having identified the signaling pathway of inflammatory response in heart transplants, the team is now searching for different methods to disrupt this pathway in people, noting that the gene editing performed in the mice to achieve this would not be safe for humans.
“Using blocking antibodies against CD40 could be a good approach,” Pasare said. “Another option would be to create biologics or compounds that specifically target the TNF receptor superfamily in humans.”
