The insulin producers of the islets are called beta cells. (Cell types alpha, gamma, delta, and epsilon perform other tasks.) They are the only bodily sources of that hormone. So if their numbers decrease, trouble looms. And it declines, too, in the condition known as type 1 diabetes. This happens when, in a phenomenon called autoimmunity, the body's own immune system attacks its complement of beta cells and wipes out as many as 80%.
Without an alternative supply of insulin, someone with type 1 diabetes will die. (In type 2 diabetes, insulin is still produced, but the body's cells become resistant.) Supplemental insulin can be given by injection or through a device called an insulin pump. But a better way might be to replace the missing beta cells and somehow protect them from immune attacks.
In a few lucky patients, the beta cells have indeed been replaced – through transplantation from human donors. And Vertex Pharmaceuticals, a Boston company, is testing beta cells from stem cells for the same purpose. But neither approach includes immune protection. This means that both require the administration of immunosuppressants to prevent the rejection that follows a transplant, let alone one where autoimmunity is involved. So one of the sessions at this year's American Association for the Advancement of Science meeting in Denver explored how transplanted beta cells can be made hypoimmunogenic, in other words, invisible to a patient's immune system.
Sonja Schrepfer, who works at the University of California, San Francisco (UCSF), as well as Seattle-based Sana Biotechnology, proposes a two-pronged approach to deal with the fact that the immune system has two arms. One of them, the adaptive arm, is the basis of tissue rejection. This adaptive arm can recognize the signature of 'self' provided by an individual's HLA proteins. These molecules contain so-called hypervariable regions, which differ from individual to individual. When the immune system encounters non-self HLA proteins, it recognizes the cells they display as invaders and attacks, using shock forces called lethal T cells and antibodies.
The first part of Dr.'s approach Schrepfer therefore aims to prevent the production of HLA proteins in laboratory-grown beta cells intended for transplantation. This can be done by editing two genes involved in its production, theoretically making the cells in question invisible to the adaptive arm.
However, the lack of HLA proteins brings a cell to the attention of the other arm of immunity, the innate system. Its troops are called NK (natural killer) cells and macrophages, and one of the warning signs it responds to is the absence of any form of HLA. However, it can be prevented by overexpression of a protein called CD47, something Dr. Schrepfer also achieved this by genetically engineering their beta cells.
It seems to work. In an experiment whose results were announced just before the meeting, the team first induced diabetes in a laboratory monkey and then injected the modified beta cells into one of its muscles. The diabetes disappeared and stayed away for more than six months. Now they've moved on to humans. In a trial starting soon at Uppsala University Hospital in Sweden, human versions of the modified cells will be transplanted into the forearm of a single patient.
Disrupting beta cell HLA expression is not the only possible approach to diverting the adaptive immune system. Hasna Maachi from the Technical University of Munich, Germany, described at the meeting how she and her mentor, Matthias Hebrok, are trying to develop an alternative. This introduces a third party, called a suppressor cell, to do the repelling.
Suppressor cells 'talk' to the deadly T cells and calm them down. Dr. Hebrok's group is therefore working with Wendell Lim at UCSF, who is developing suppressor cells that are specifically activated by a protein on the surface of beta cells, to devise some kind of beta mechanism. -cell protection In this case, there is no need to build in a level of protection against the innate immune system, because it will not notice anything wrong.
The Hebrok group also works, explained Dr. Maachi out, on a way to turbocharge beta cells. This involves a protein called MAFA, which regulates the expression of the insulin gene. Suppressed levels of MAFA are a symptom of type 1 diabetes, so increasing its presence seemed like a promising approach. So far, the researchers have shown that increasing MAFA levels in beta cells derived from stem cells appears to increase the amount of insulin produced.
Figures presented by Lori Sussel of the University of Colorado suggest that type 1 diabetes affects one in 500 Americans. The global average could be closer to one in 1,000. That's both a lot of human suffering and a tempting market for anyone who can come up with something that looks like a cure, rather than a treatment. Although there is still some way to go, hypoimmunogenic beta cells may bring us closer.
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