Manipulating T-Cell Autoimmunity May Prevent Diabetes

Low-avidity ligands at high doses and intermediate-affinity ligands at intermediate doses were highly protective against diabetes. Manipulating T-cell mediated autoimmunity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) can prevent the development of diabetes in a mouse model, according to a report in the May 22nd advance online publication of Nature Medicine.

The findings imply that "future vaccines for the prevention of autoimmunity will have to target multiple antigenic specificities as opposed to just dominant ones," Dr. Pere Santamaria from University of Calgary, Alberta, Canada told Reuters Health. "Another very important aspect of our work is that it establishes IGRP as a remarkably dominant autoantigen in murine autoimmune diabetes, involving numerous epitopes," Dr. Santamaria said.

Dr. Santamaria and colleagues investigated the antidiabetogenic properties of altered peptide ligands targeting CD8+ T cells that recognize an epitope of IGRP in a mouse model of autoimmune diabetes.

Low-avidity ligands at high doses and intermediate-affinity ligands at intermediate doses were highly protective against diabetes, the authors report, whereas high-avidity ligands afforded no protection at any dose.

Protection was associated with the enhanced recruitment of noncytolytic, low-avidity IGRP-reactive CD8+ T cells to islets, the report indicates, whereas deletion of high-avidity IGRP-reactive T cells failed to provide protection.

The combined response of islet-associated T cells against all IGRP epitopes was significantly higher in diabetic mice than in prediabetic mice, the researchers note. Altered ligand treatment reduced the frequency and magnitude of response against the ligand administered, but increased the responses against other IGRP epitopes.

"Our findings suggest that complete elimination of a dominant T-cell subpopulation by using high doses of high-affinity altered peptide ligands is an inefficient way to halt the progression of cellularly complex, polyclonal autoimmune responses," the investigators write.

"Rather," the authors conclude, "we argue that effective prevention of such diseases with altered peptide ligands requires the selective elimination of high-avidity clonotypes and the unopposed recruitment of their low-avidity, nonpathogenic counterparts."
"Additional work is underway to investigate how low-avidity autoreactive cells mediate protection," Dr. Santamaria said. "There are two general possibilities. One is that they do it simply by occupying space, denying it to the much more aggressive high-avidity cells. The other is that these cells have active immunoregulatory properties."

Nat Med 2005.

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