NEW YORK (Reuters Health) - Autoreactive T cells in type 1 diabetes may specifically target insulin in islet cells of the pancreas, according to two reports in the May 12th issue of Nature.
One of the studies involved NOD mice, an animal model of type 1 diabetes. Like wild-type mice, NOD mice have two insulin genes, insulin 1 and insulin 2, which differ from each other by 2 of 51 amino acids.
According to Dr. George S. Eisenbarth, at the University of Colorado Health Sciences Center in Denver, and his co-authors, most CD4 T cells that infiltrate NOD islets react to insulin, specifically the insulin B chain 9-23 peptide amino acids (insulin B:9-23).
The group generated transgenic NOD mice with a mutation in B:9-23 that preserved insulin’s metabolic activity, while eliminating T-cell reactivity to this amino acid sequence.
Female mice lacking both native insulin genes failed to produce insulin autoantibodies. At 23 to 26 weeks of age, the pancreas was normal with no insulitis or evidence of diabetes. However, mice expressing at least one of the two normal insulin genes did develop insulitis.
The authors also found that when splenocytes from wild-type NOD mice were transferred into immunodeficient NOD.SCID mice, 75% of recipients were diabetic after 8 weeks. However, when spleen cells from the insulin gene double-knockout mouse were transferred into NOD.SCID mice there was a significant delay in the development of diabetes (p < 0.02).
These results raise the possibility that B:9-23 could be used to induce “regulatory tolerance” in NOD mice, Dr. Eisenbarth told Reuters Health.
“The immune system wants to respond to pieces of insulin (B:9-23) in NOD mice, because the T cell receptor is designed to ‘see’ that piece of insulin,” the researcher explained. “One can use that to create T cells that actually regulate and turn off other T cells if the antigen is presented to them in the right way.”
In other words, B:9-23 could be given orally, “not to lower blood sugar but to entrain white blood cells to give a protective response,” he added. If this works, a corresponding autoreactive segment of human insulin, A:1-15, may be able to do the same thing in humans.
In the second paper, Dr. David A. Hafler, at Harvard Medical School in Boston, and his associates obtained complementary findings to those of Dr. Eisenbarth’s team, using pancreatic draining lymph nodes from three subjects with autoimmune diabetes and three control subjects. Two diabetic subjects had disease spanning 15 to 29 years, while the third had disease duration of 1.5 years.
“We cloned the cells without any preconceived notion as to what was driving them, growing them at one cell per well, and generated hundreds of clones,” Dr. Hafler said in an interview with Reuters Health. “We then asked if some clones were extended, suggesting that they were more important, and what they were reacting to.”
While T-cell clones from the three controls expressed heterogeneous T-cell antigen receptors, over half of those from the two subjects with long-term autoimmune diabetes expressed identical antigen receptors, “a remarkable number,” Dr. Hafler said.
These identical clones recognized the insulin A:1-15 peptide, as Dr. Eisenbarth had posited.
While cautioning that their results need to be replicated in a larger trial, and other autoantigens are likely, Dr. Hafler’s team writes, they “provide perhaps the most conclusive evidence possible from in vitro experiments that insulin is a critical antigen in the etiology of human type 1 diabetes.”
Source: Nature 2005;435:220-228. [ Google search on this article ]
MeSH Headings:Animals, Laboratory: Animals, Transgenic: Invertebrates: Mice, Inbred Strains: Mice, Transgenic: Mice, Inbred NOD: Animals, Inbred Strains: Organisms, Transgenic: etiologyCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
