Embryonic stem cell rejection problem fixed, study says

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One of the toughest problems facing embryonic stem cell therapy, immune rejection of transplanted cells, may have been solved, according to a UC San Diego-led research team.
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4 E2 \, X/ ?! B- p" T0 _The cells can be made invisible to the immune system by genetically engineering them to make two immune-suppressing molecules, according to the study. Researchers tested the approach in mice given a human immune system. Immune functioning in the rest of the animal remained active.
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If the approach works in people, patients receiving transplanted tissue or organs made from embryonic stem cells wouldn’t have to take harsh immune-suppressing drugs, said study leader Yang Xu, a UC San Diego professor of biology.+ {4 Y7 R  x" [1 e$ @! b0 k4 c: P
Researchers placed genes in the stem cells to produce the two molecules, called CTLA4-lg and PD-L1, naturally made in the body. The mice accepted transplants of heart and skin cells derived from the engineered stem cells. They rejected transplants derived from regular embryonic stem cells.
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The study was published online Thursday in the journal Cell Stem Cell. Its findings will have to be confirmed for safety and effectiveness before human trials can be considered, which will take years.% A0 L8 S* r0 `  q
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Three scientists given the paper for comment had mixed reactions. While they praised the work’s scientific prowess, two said genetically engineering the transplanted cells could cause serious side effects that might preclude their use.
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The researchers employed “a clever strategy” to use the immune system’s natural regulatory systems, said Mitchell Kronenberg, president of the La Jolla Institute for Allergy & Immunology.* k0 o2 I( {# S2 ~9 f

  {4 ^1 ?  F0 R; c; t1 w% \“This is an especially promising approach, because it avoids the toxic side effects of the drugs now used to suppress the rejection response, and therefore this is an important step forward in showing the feasibility of using human embryonic stem cells from unrelated donors,” Kronenberg said.
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- l7 X' m- i& _; pMore skeptical were Jeanne Loring, a stem cell researcher at The Scripps Research Institute, and Craig M. Walsh, associate director of the Institute for Immunology at UC Irvine.- i: P; a& Y, K; v' c7 z
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Loring said that while the embryonic stem cell experiment was “clever,” it wouldn’t have much impact on human therapies.6 e1 n3 ?9 K, n. J

) G/ Y7 ~4 P, A1 @3 X“The FDA would be concerned about the combination of gene and cell therapy, and making the cells invisible to the immune system would disable the body’s ability to recognize and reject cells that become cancerous,” Loring said by email.9 z* r  U& z) e% Q: p
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Loring is investigating an alternative approach using artificial embryonic stem cells called induced pluripotent stem cells. These cells can be made from the person to be treated, so they presumably wouldn’t elicit an immune response.
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Loring said she would have been much more interested in the study if it had tested the induced pluripotent cells.
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9 `+ V3 ]& v' W  e( o$ LWalsh said the results weren’t surprising, because the molecules are well known to suppress the activity of T cells in transplants.: ]! C! b- o; f3 m5 X

: h7 P$ P  j. J6 Q. y' L: ]+ C“I am concerned that the use of these two therapeutics would cause immunosuppression, which could lead to a loss of tumor surveillance and increased susceptibility to infections,” Walsh said, also by email.
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: n4 h7 y) a3 X  l8 OThe paper said those dangers could addressed. One approach would be to include a “suicidal” gene in the cells, triggered when the antiviral drug gangciclovir is given. Tumors with this gene have been eliminated in animal models with this method, the paper stated.
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