"For the first time, we have an insight into the earliest steps that start the rejection response," study coauthor Fadi Lakkis of the University of Pittsburgh's Thomas E. Starzl Transplantation Institute, says in a statement. "Interrupting this first recognition of foreign tissues by the innate immune system would disrupt the rejection process at its earliest inception stage and could prevent the transplant from failing."
Using positional cloning, a method that can identify genetic mutations, Lakkis and colleagues discovered that SIRP-alpha, a cell-surface receptor that varies across individual mice, was responsible for activating the innate immune response—the body's first-line, nonspecific defense mechanism. When the researchers transplanted tissue from one mouse into a host animal with different SIRP-alpha receptors, the molecule bound to the CD47 receptor on the recipient's monocytes, a type of innate immune cell, and generated a rejection response.
Since human cells also express SIRP-alpha, sequencing this gene to identify donors with matching molecules could help reduce rejection rates, Lakkis says in the statement.
"One can imagine these interactions being critical in providing a constant trigger that poises the immune response to reject the organ, and thus new therapies that limit the function of these receptors may promote organ survival," Anita Chong, a professor of surgery at the University of Chicago who was not involved in the study, told the Pittsburgh Post-Gazette. "This is a possibility, although much work needs to be done to test whether this molecular pathway will actually impact the outcome of organ transplants in the clinic."