New research has found a way to suppress the rejection of natural killer (NK) cells, the first-line fighters of the immune system, with important implications for fields such as natural cell therapy, transplantation surgery, and for improving immunotherapy for the fight against cancer by finding and killing free cancer cells.
NK cells, a type of white blood cell, are the first-line fighters of immune stress, able to quickly detect and destroy any cell that does not have a legitimate “identity”, including the body’s own cells, or at least a “permanent resident” in the body. Such identity information is expressed in the form of a highly personalized molecule called MHC-I.
To prevent rejection, transplants are manually removed to “hide” their foreign identity, but without an identity, the transplanted cells are still targets of aggressive NK cell attacks. So there has long been no good solution to this rejection reaction.
The researchers took a cue from the way cancer cells evade the body’s immunity. Some cancer cells have high levels of the CD47 protein, which turns off the natural immune function of immune cells by activating a molecular switch called SIRPα within the immune cells. So, using genetic engineering, the researchers also made cells that expressed significant levels of the CD47 protein.
“All of the research literature suggests that NK cells have no immune checkpoint mechanism, but we clearly saw the SIRPα switch on cells from human patients that we saw in the lab, so we could clearly show that our genetically modified cells, by overexpressing the CD47 protein, were able to shut down NK cell attacks. ” said Sonja Schrepfer, professor of transplant surgery at the University of California, San Francisco, one of the researchers.
Schrepfer said, “Most studies looking for NK cells are done in lab-grown cell lines, whereas we are directly studying cells from human patients, and I think there must be a difference between the two.”
They found that NK cells present the SIRPα molecular switch only when they are stimulated by specific immune signaling molecules, cytokines. The researchers found that NK cells exhibit this switching effect only in an inflammatory environment, which may be designed to allow NK cells to control the level of immunity and avoid damage from over-immunization.
“NK cells have been a major obstacle to research in the field of cellular therapy. Cell therapy has gained more and more attention in recent years, and instead of injections, the finished product is simply implanted into the patient for treatment. So this research has great promise.” Lewis Lanier, professor of microbiology and immunology, said.
This study documents in detail how cells with CD47-expressing proteins can turn off NK cells from hunting them down. Some other approaches can turn off some of the NK cells, but their experiments completely inhibited them for the first Time, the study says. And they found that the sensitivity of NK cells to produce an inhibitory response to the CD47 protein was also species-dependent, just as NK cells identify with each of their own cells.
They created some adult human stem cells with the CD47 protein from the macaques, implanted them in the macaques, and the results successfully inhibited the macaques’ rejection of these cells.
The researchers say that for future studies they will experiment with another approach – such as adding human CD47 protein to pig heart cells and then implanting them in humans – in the hope of stopping the body’s rejection reaction.
CAR T-cell therapies and other regenerative drug therapies for cancer now rely on taking cells from the patient themselves, modifying them in the lab and then implanting them back into the patient to stop rejection, but that’s laborious and costly,” Schleipfer said. Our goal is to create cell production solutions that can evade immunity and create products that can be bought and used directly in grams, so that any patient can be used to treat the disease.”
The study was published in early January in the Journal of Experimental Medicine.
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