In mice, an inflammation-blocking approach
boosted organ survival from about a week to more than two
months
CINCINNATI, Aug. 13,
2024 /PRNewswire/ -- A new study from scientists at
Cincinnati Children's suggests there may be a way to further
protect transplanted hearts from rejection by preparing the donor
organ and the recipient with an anti-inflammatory antibody
treatment before surgery occurs.
The findings, published online in PNAS, focus on blocking
an innate immune response that normally occurs in response to
microbial infections. The same response has been shown to drive
dangerous inflammation in transplanted hearts.
In the new study – in mice -- transplanted hearts functioned for
longer periods when the organ recipients also received the novel
antibody treatment. Now the first of a complex series of steps has
begun to determine whether a similar approach can be safely
performed for human heart transplants.
"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.
Making memory T cells a bit more forgetful
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."
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."
Next steps
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.
"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."
About the study
Cincinnati Children's co-authors also included Amanpreet Singh Chawla, PhD, a former
postdoctoral fellow in the Pasare lab; Ana
Paula Oliveira, PhD, a postdoctoral fellow in the Hagan Lab;
Eileen Elfers, BS, a research
assistant in the Katz lab; Kathrynne
Warrick, BS, an MSTP student in the Pasare Lab; Hannah Meibers, PhD, a former graduate student
in the Pasare Lab; Thomas Hagan,
PhD, Division of Infectious Diseases; and Jonathan Katz, PhD, Division of
Immunobiology.
Funding sources for this study included grants from the National
Institutes of Health (R01 AI123176, R01 AI155426, and U54
DK126108). The work also was supported by the Veterinary Services
Facility, Research Flow Cytometry Core, and the Bioinformatics
Collaborative Services Core at Cincinnati Children's.
View original content to download
multimedia:https://www.prnewswire.com/news-releases/pre-surgical-antibody-treatment-might-prevent-heart-transplant-rejection-302221466.html
SOURCE Cincinnati Children's Hospital Medical Center