In their experiments, described in the July 10 issue of The Lancet, the Hopkins team successfully coaxed human embryonic stem cells to become the special "flag-waving" cells that tell the immune system what is "friend" and what is "foe." In additional experiments in the lab, the researchers found that these so-called antigen presenting cells can control the responses of other immune cells, called T cells, whose job is either to attack or to co-exist with "foreign" cells.
"This is the first evidence that human embryonic stem cells can generate antigen presenting cells that could be used to educate a patient's immune system," says Linzhao Cheng, Ph.D., assistant professor in Johns Hopkins' Institute for Cell Engineering. "It's a small but important step toward future clinical use of the stem cells, but many challenges remain."
Because all human cells carry proteins that identify them as coming from a particular person, even embryonic stem cells could be rejected if their identifying proteins, or antigens, don't exactly match the recipients'.
But matching embryonic stem cells to potential recipients carries ethical dilemmas for many, since it might require destruction of more in vitro fertilized embryos to get new embryonic stem cell lines or attempting so-called therapeutic cloning (somatic cell nuclear transfer), which would use an individual's regular cells to create the early embryos from which stem cells are derived. Cheng adds that the science is far from making the latter a practical option, and notes that neither approach provides an exact match for patients.
Even the use of powerful immune-suppressing drugs, such as those used for organ and tissue transplant recipients, would require better "matches" than today's limited selection of embryonic stem cells can provide, says Cheng.
A paper by Hopkins researchers and others last fall suggests that to provide embryonic stem cells that acceptably and equitably match an equal percentage of various ethnic groups, at least 85 carefully selected stem cell lines would need to be established. There are currently just a few dozen validated lines of human embryonic stem cells, most scientists think.
Because of the stem cells' flexibility, however, some scientists are trying to make the cells "stealthy" so they might escape detection by the immune system, even if they don't perfectly match the patient. One potential stealth-inducing technique is to modify or replace the genes in the embryonic stem cell that control production of rejection-inducing proteins, but progress has been slow, Cheng says.
His team is also pursuing a second option using the embryonic stem cells to get special immune cells. Because both the immune cells and the therapeutic cells say pancreatic islet cells for a type I diabetic, or dopamine-producing neurons for a person with Parkinson's disease would be derived from the same embryonic stem cell line, they would match one another. And the immune cells then could tell the patient's immune system that the transplanted therapeutic cells "belong."
"In some clinical situations, studies have demonstrated that if you can get immune cells to recognize the transplanted tissue as 'friend,' then the chances of rejection are lower," says Cheng.
For example, transplanting bone marrow from an organ donor into the recipient, at the same time as or prior to transplantation of the needed organ say, a kidney has been associated with reduced rejection, says Cheng. The transplanted bone marrow cells co-exist with the patient's own tissue and essentially create a new corner of the patient's immune system that recognizes the transplanted organ as self.
"We're presenting the first, very early suggestion that the same idea might be applicable to future applications of embryonic stem cells," says Cheng. "There still are many challenges ahead to know whether this will apply to potential uses of embryonic stem cells, but it's important to try to address the issues of 'matching' and rejection before the cells reach the clinic."
By bathing the human embryonic stem cells in a soup of certain proteins known to encourage the cells' progression into various types of blood cells, postdoctoral fellows Xiangcan Zhan and Gautam Dravid and their colleagues coaxed the primitive cells to become antigen presenting cells, sentries that tell other immune cells whether to destroy or spare cells they meet. In additional experiments, the researchers also showed that these antigen presenting cells worked as they should, at least in the lab.
"The idea is that you would create a large number of the antigen presenting cells and related immune cells and give those to the patient before they get another cell type from the same embryonic stem cell line," says Cheng. "Then, the patient's immune system would include cells that recognize the transplanted cells, preventing their destruction."
Animal experiments to prove that these human antigen presenting cells can really induce immune tolerance will be very difficult to do, he says, since any human cell would be attacked by a mouse's immune system. Cheng says that his lab will continue looking for evidence of specific immunity and of immune tolerance induced in laboratory dishes of human embryonic stem cells.
The research was funded by the Johns Hopkins Institute for Cell Engineering, the Leukemia and Lymphoma Society, the National Heart, Lung and Blood Institute, and a one-year fellowship from GRN Roborants Co. Ltd. (to Zhan).
Authors on the paper are Zhan, Dravid, Cheng, Zhaohui Ye, Holly Hammond, Michael Shamblott and John D. Gearhart, all of the Institute for Cell Engineering at Johns Hopkins. Cheng is also an assistant professor of gynecology and obstetrics and oncology.