Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) is characterized by low or absent levels of endogenously produced insulin, as a consequence of the autoimmune destruction of pancreatic (3-cells. The US incidence of IDDM in children up to 14-year-old is estimated in the range of 12 to 20 per 100,000, with an increasing incidence worldwide. At present, there is no an effective therapy to prevent or cure the disease in humans. We have genetically engineered a dimeric MHC class II (I-Ed)/Fc, namely DEF, molecule containing a CD4 T cell epitope (HAl10-120) of hemagglutinin (HA) of influenza A/PR/8/34 virus. DEF molecule exerts different immunomodulatory effects on the specific T cells depending on the dose: low doses polarize resting and activated T cells toward Th2 phenotype, and high doses induce central tolerance and peripheral energy. We propose to evaluate the protective and curative capacity of DEF in an animal model for autoimmune diabetes. The animal model consists in double transgenic (dTg) mice expressing HA of influenza virus in the pancreatic (3-cells, and at the same time the specific T cell receptor (TCR- HA) for the immunodominant epitope HA1 10-120. The dTg mice develop insulitis, hyperglycemia, and hypoinsulinemia early in life. We will investigate the immunomdulatory mechanisms responsible for the prophylactic and curative capacity of low and high doses of DEF in dTg mice. Human DEF-like molecules may represent a new approach for the prevention and treatment of type 1 diabetes.
| Casares, Sofia; Hurtado, Alicia; McEvoy, Robert C et al. (2002) Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide-MHC class II chimera. Nat Immunol 3:383-91 |
| Casares, S; Bona, C A; Brumeanu, T D (2001) Enzymatically mediated engineering of multivalent MHC class II-peptide chimeras. Protein Eng 14:195-200 |
| Casares, S; Stan, A C; Bona, C A et al. (2001) Antigen-specific downregulation of T cells by doxorubicin delivered through a recombinant MHC II--peptide chimera. Nat Biotechnol 19:142-7 |
| Casares, S; Bona, C A; Brumeanu, T D (2001) Modulation of CD4 T cell function by soluble MHC II-peptide chimeras. Int Rev Immunol 20:547-73 |
