What role plays trained immunity in transplanted organ rejection? NIAID grant of over $15 million

A consortium of Mount Sinai, Massachusetts General Hospital and Radboudumc has received over $15 million to investigate the role of trained immunity in organ rejection after transplantation. Trained immunity - the ability of the innate immune system to withhold infections - may be a new lead to combat rejection.

More than 40,000 organ transplants are performed each year in the United States. An estimated 30 percent of organs are lost to rejection within the first five years. Why is that? The adaptive immune system is almost always looked to as an explanation. This part of the immune system uses T cells - a type of white blood cell - to deal with threats. A transplanted organ is such a threat because it does not belong to one's own body. Therefore, to inhibit that immune response, immunosuppressants are used. This indeed improves the survival of the transplanted organs, but cannot ultimately prevent rejection of many of these organs. Moreover, the dampening of the immune system, among other things, also leads to an increased risk of infections and cancer.

Trained immunity
In recent years, it has become clear that the innate immune system - which mounts a rapid but non-specific defense against threats - also plays a crucial role in organ transplantation. Transplantation triggers a response in which cells of the innate immune system become more inflammatory. Thus, they can begin to support the adaptive immune response (see article in Immunity). The "training" of innate immune cells is called "trained immunity" and plays a role in various diseases. However, the role of that trained immunity in organ rejection has not yet been well studied (see article in Nature Reviews Immunology). Researchers now hypothesize that trained immunity promotes transplant rejection by enhancing the innate and adaptive rejection response. This means that trained immunity represents an attractive therapeutic target for improved graft survival.

Promising strategy
"It is a promising strategy to prevent transplant rejection, and we can now start investigating that strategy with this grant," says Willem Mulder, affiliated with Radboudumc and TU/e and co-applicant of the National Institute of Allergy and Infectious Diseases (NIAID) grant. The research is being conducted by scientists at Mount Sinai, Massachusetts General Hospital and Radboudumc. The goal is to analyze how trained immunity drives transplant rejection and develop tools to diagnose and regulate trained immunity in transplantation. Mulder, together with nephrologist Raphael Duivenvoorden and other colleagues at the Radboudumc, will specifically try to elucidate the role of trained immunity in kidney transplant patients. In addition, the regulation of trained immunity in mouse transplant models will also be studied and whether trained immunity-inhibiting nanobiologics can achieve heart transplant survival in non-human primates.

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