SickKids scientists identify new molecular mechanism that may be responsible for initiating organ rejection
TORONTO – Researchers at The Hospital for Sick Children (SickKids) and the University of Pittsburgh School of Medicine have uncovered how innate immune system cells detect and initiate the rejection of transplanted tissue in mice. The findings, published today in Science Immunology, may one day be used to create better donor-recipient matches and develop new ways to prevent rejection of transplanted tissues.
“Approximately 50 per cent of all transplanted organs are rejected within 10 to 12 years, understanding what is happening at a molecular level is essential in being able to help reduce or eliminate organ rejection in the future,” says Dr. Jayne Danska, the Anne and Max Tanenbaum Chair in Molecular Medicine and Senior Scientist in Genetics & Genome Biology at SickKids and Professor in the Department of Immunology and the Department of Medical Biophysics at the University of Toronto.
The immune system is composed of two main branches - innate and adaptive. The innate immune system is the first component to detect foreign cells and provides signals that activate the adaptive immune system. The mechanisms underlying adaptive immune activation following organ transplantation are well studied. Little was known about how innate immunity contributes to organ rejection until now.
“We have identified a mechanism by which the innate immune system distinguishes between the recipient’s own tissues and the transplanted tissue,” says Danska. “We discovered one way that innate immune cells first detect the transplanted tissue.”
The researchers demonstrated, using mouse models, that organ transplant recipients detect a molecule on the donor tissue known as SIRP-alpha. SIRP-alpha molecules vary between different strains of lab mice and also between humans. This study showed that the type of SIRP-alpha expressed on the donor tissue determines the strength of innate immune response by a type of white blood cell called a monocyte, that can initiate organ rejection by recruiting adaptive immune cells called T cells. During this process the SIRP-alpha molecules bind to a receptor called CD47 and initiate signals that can result in rejection of the transplanted tissue. Blocking this interaction in mice prevented the activation of the monocytes. According to the researchers interrupting this innate immune recognition of foreign tissues disrupted the earliest stage of the rejection process.
“Human innate immune cells also express SIRP-alpha. Our next studies will examine the potential clinical applications of these findings. We will sequence the SIRP-alpha genes in organ donors and recipients to identify variants that are associated with lower organ rejection rates. This may be used to improve matching between donor and recipient,” says Danska. “Future studies are also needed to examine how the interaction between SIRP-alpha and CD47 leads to monocyte activation, and to explore new ways to block the activation and prevent organ rejection.”
Danska’s co-senior author of the study is Dr. Fadi Lakkis, the Frank & Athena Sarris Chair in Transplantation Biology and Scientific Director of the University of Pittsburgh’s Thomas E. Starzl Transplantation Institute (STI).
Funding was provided by National Institutes of Health, the Canadian Institutes of Health Research, the National Science and Engineering Research Council, and the American Heart Association and SickKids Foundation.
This paper is an example of how SickKids is contributing to making Ontario Healthier, Wealthier and Smarter. www.healthierwealthiersmarter.ca.
About The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized child and family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca. Follow us on Twitter (@SickKidsNews) and Instagram (@SickKidsToronto).
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