Down-Regulation of Diabetogenic T-Cells

Brumeanu, Teodor-Doru

Abstract

Insulin-dependent diabetes mellitus (IDDM, diabetes type I) is a chronic autoimmune disease resulting from T-cell mediated destruction of pancreatic beta-cells. The role of autoreactive Th1 cell subset in IDDM pathogenesis has been widely demonstrated. Non selective immunosuppressive drugs and other approaches aimed at blocking the diabetogenic T-cell immune response remain clinically ineffective. Using a genetic approach, the investigators have generated a dimeric peptide/MHC class-II chimera (DEF), which exhibits remarkable potency to deviate the peptide-specific T-cells toward a Th2 protective response in vivo. DEF is composed of the extracellular domains of the alpha- and beta-chains of I-E(d) dimerized through the Fc portion of IgG 2 alpha linked at the C-termini of the beta-chains. The immunodominant CD4-T-cell epitope of the influenza type A/PR/8/34 hemagglutinin (HA110-120) is covalently linked at the N-termini of the beta-chains. In contrast to other immunotherapeutic strategies i.e., anti-CD4, anti-CD8, or anti-MHC class II Abs, which require high doses and increase the susceptibility to infections, the DEF approach is aimed at down-regulating selectively the diabetogenic T-cells. The model for IDDM consists of double transgenic mice expressing influenza virus A/PR/8/34 hemagglutinin protein (HA) in the pancreatic beta cells, and the HA-specificT-cells. Preliminary results have indicated a potential anti-diabetogenic effect of DEF in this double transgenic mouse model of IDDM. The major goal for Phase I is to evaluate the curative efficacy of DEF in IDDM mice with overt diabetes, and to determine the capacity of DEF for preventing/delaying the onset of IDDM in prediabetic mice. Satisfactory results will lead to the generation of a human DEF-like molecule (hu-DEF) consisting of the HLA-DR*0401 allele, and the most common diabetogenic peptide in humans, GAD-derived p270-283 peptide (LPRLIAFTSEHSHF). The DEF approach may open new avenues for the development of more efficient immunotherapeutic agents in IDDM.