Long-Term Reversal of Established Autoimmunity upon Transient Blockade of the LFA-1/Intercellular Adhesion Molecule-1 Pathway

Abstract

Transgenic models and administration of mAbs directed against the LFA-1/intercellular adhesion molecule 1 (ICAM-1) pathway have shown that these costimulatory molecules play a key role in generating effector cells mediating inflammatory responses. In this report, durable remission of recent diabetes in nonobese diabetic (NOD) mice was induced by transient expression of an immunoadhesin gene encoding the soluble form of ICAM-1 (sICAM-1/Ig). A single i.v. injection of an adenovirus vector encoding the immunoadhesin gene led to 70% diabetes remission as opposed to 0% in mice injected with a control adenovirus vector. Despite the rapid decline of sICAM-1/Ig serum levels, diabetes remission remained stable in 50% of NOD mice for >6 mo. sICAM-1/Ig expression also led to long-term protection against diabetes in prediabetic NOD mice. sICAM-1/Ig in vitro induced an agonistic effect of T cell activation in a TCR-transgenic model, increasing T cell proliferation and IL-2 secretion. Importantly, protected mice were not immunosuppressed because they rejected skin allografts normally and developed immunity against the adenovirus vector. Rather, sICAM-1/Ig induced active tolerance, as assessed by the persistence of diabetogenic T cells in protected mice and the reversal of protection by immunosuppression with cyclophosphamide.

NKT Cell Defects in NOD Mice Suggest Therapeutic Opportunities

“…Thus LFA-1 may play a role in trafficking to or retention of CD4+ NKT cells by the liver, or their proliferation once there. In contrast Moriyama et al [59] and Bertry-Coussot et al [60] have shown that the transient blockade of LFA-1/ICAM pathway leads to induction of tolerance and long term reversal of established autoimmunity in NOD mice. However in our natural history study, we have shown that like NKT cell expression, LFA-1 expression is also reduced in various organs and upon immunization of the NOD mice with interventions that prevent the disease, increase both NKT cell as well as LFA-1 transcript expressions.…”

The Inhibition of Autoreactive T Cell Functions by a Peptide Based on the CDR1 of an Anti-DNA Autoantibody Is via TGF-β-Mediated Suppression of LFA-1 and CD44 Expression and Function

“…The expression of two of these, LFA-1 and CD44, was shown to be up-regulated in lupus and was correlated with disease activity (19,20). LFA-1 on T cells interacts with ICAM-1 on APC, and a blockade of this interaction induced the remission of diabetes in NOD mice (23). CD44 was shown to support proliferation by apposition of protein kinases for the initiation of signaling via the TCR/CD3 complex (30).…”

“…The blockade or down-regulation of these adhesion and costimulatory molecules has been shown to be beneficial in various autoimmune diseases, including lupus (23)(24)(25)(26).…”

Galectin-8 binds to LFA-1, blocks its interaction with ICAM-1 and is counteracted by anti-Gal-8 autoantibodies isolated from lupus patients

“…For instance, loss of LFA-1 expression in a lupus mouse model (MRL/MPJ-Fas (Ipr) signifi cantly inhibits the development of infl ammatory disease (Kevil et al, 2004) and treatment of NZB/NZW F-1 lupus mice with blocking LFA-1 antibodies inhibits autoantibody production characteristic of lupus (Connolly et al, 1994). LFA-1-blocking antibodies also inhibit the development of autoimmune diseases such as diabetes (Bertry-Coussot et al, 2002), experimental autoimmune encephalitis (EAE) (Gordon et al, 1995) and glomerulonephritis (Nishikawa et al, 1993) in different animal models. All these data indicate that incremented LFA-1 function promotes autoimmune disorders, whereas the contrary occurs when LFA-1 function decreases.…”