Novel Treatment for Lupus in Mice

Scientists have found a new approach to treating lupus, an autoimmune disease that ravages kidneys. Injecting specific protein snippets into mice halts and even undoes some of the damage, they report in the 15 May issue of the Journal of Immunology. But to try the treatment in patients, they will have to identify the mouse proteins' human equivalents first.

Systemic lupus erythematosus (SLE) is an immune reaction against material from the body's cellular nuclei leaking out of dying cells. After detecting this debris, which includes DNA and histones (the proteins around which DNA is wrapped), T cells make B cells produce antibodies, which bind to the bulky DNA, forming tangles that can become wedged in tiny blood vessels. Other immune cells are lured to the clog, causing severe inflammation that can damage the kidneys, other organs, and the skin. In severe cases, patients must undergo dialysis or a kidney transplantation to survive.

Immunologist Syamal Datta and his team at the Northwestern University Medical School in Chicago had previously identified four short histone fragments that push T cells to start the autoimmune reaction in mice. For reasons ill understood, the body tolerates these peptides, instead of mounting an immune response, when it is flooded with them. To try to exploit this phenomenon as a potential treatment, Datta injected large amounts of the peptides into young female mice of a strain prone to succumb to SLE. The team found that just four injections over 6 weeks significantly delayed the disease's onset: At 36 weeks of age, more than 80% of the untreated animals had kidney damage, compared to only 10% of the mice given the most potent of the four peptides, a fragment of histone H4. Monthly H4 peptide injections even reversed some of the kidney damage in rare long-term survivors of kidney inflammation, prolonging their life-span.

The next step, Datta says, is to find which fragments of the human histones trigger lupus, then test whether injecting high doses in patients will help them. "If you find the right peptide, you can really influence a large repertoire of B and T cells and have a profound effect on the disease," at least in mice, says immunologist Bevra Hahn of the University of California.

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