Elimination of T cell reactivity to pancreatic b cells and partial preservation of b cell activity by peptide blockade of LFA-1:ICAM-1 interaction in the NOD mouse model
Abby L. Dotson1, Lesya Novikova2, Lisa Stehno-Bittel2, and Stephen H. Benedict1,3
The autoimmune disease insulin dependent (type 1) diabetes mellitus (T1D) is driven by self-reactive T cells that infiltrate pancreatic islets of Langerhans and induce destruction of beta cells leading to dysregulation of blood glucose levels. As with any autoimmune disease, a long sought goal is to control only the self-reactive T cells, leaving the remainder of the T cell population free to protect the host. One approach for achieving this, that has not reached full potential, is blockade of the second signal required for T cell activation while allowing the first (antigen-specific) signal to occur. The present work explores the hypothesis that use of small peptides to block interaction of second signals delivered through the counter receptor pair LFA-1:ICAM-1, will induce attacking T cells that are receiving the antigen signal to become anergic or undergo apoptosis. A second hypothesis holds that in their capacity as adhesion molecules, inhibition of LFA-1:ICAM-1 interaction will interfere with cell migration. Injection of the peptides into NOD mice at 13 weeks of age eliminated detectable T cell reactivity against pancreatic antigens and reduced cellular infiltration into islets and these responses remained at five weeks after cessation of therapy. Islets in treated animals had retained stronger density of insulin staining. In in vitro studies the peptides induced nonresponsiveness during activation of T cells from NOD mice and from human peripheral blood.