91av

SMART molecules that can target rogue immune cells are being lined up to
fight autoimmune diseases. The new molecules could tackle a vast range of
disorders, from diabetes to arthritis.

All cells display chopped-up proteins, or peptides, on their surfaces to help
the immune system’s T cells sniff out invaders. T cells normally ignore the
body’s own peptides. But if they become less choosy, autoimmune disease can
result.

For example, insulin-dependent diabetes develops when T cells become
sensitised to a peptide found in the pancreas and attack the cells that make
insulin. In multiple sclerosis, T cells target myelin basic protein, which is
found in the cells that insulate nerve fibres.

Teodor Brumeanu of the Mount Sinai School of Medicine in New York already
knew that rogue T cells can be suppressed by coupling the target peptide to an
MHC molecule—a protein that helps T cells recognise peptides. When
injected into mice, this MHC-peptide complex desensitises the T cells. But the
effect is only temporary. “You have to inject repeatedly. As soon as you stop
they come back,” says Brumeanu.

Brumeanu and his colleague Sofia Casares decided to see if they could kill
off the rogue T cells by attaching a toxic drug used for chemotherapy to the
MHC-peptide complex. They engineered mice to produce T cells that target a
peptide from the viral protein haemagglutinin (HA). Then they injected an
“immunotoxin” consisting of the HA peptide bound to an MHC molecule and four
molecules of the drug.

The immunotoxin halved the number of HA-targeting T cells in the animals’
spleen and thymus. Injecting the drug alone had no effect on the T cells.
Further tests showed the animals’ T cells were indeed being killed off. A more
powerful toxin should be even more effective, says Brumeanu.

By attaching the right peptide, it should be possible to develop immunotoxins
to tackle any autoimmune disease. Though there is still debate about which
peptides the immune system targets in some diseases, there are many good
candidates, he says.

One potential complication is that not all T cells that recognise the body’s
own proteins are bad. “Everyone is chock-full of autoreactive T cells,” says
Emanual Maverakis of the La Jolla Institute for Allergy and Immunology in San
Diego. “Only a small percentage of them are responsible for disease.”

For example, everyone has T cells that react to myelin basic protein, the
protein targeted in multiple sclerosis. But these apparently help to protect
nerve sheaths by preventing inflammation. Whether killing the good with the bad
will cause unwanted side effects remains to be seen.

Casares has already made two immunotoxin molecules for use against diabetes.
She plans to test these in diabetic mice before trying them on people.