A Metalloporphyrin-Based Superoxide Dismutase Mimic Inhibits Adoptive Transfer of Autoimmune Diabetes by a Diabetogenic T-Cell Clone

Abstract

We present here the first report of a metalloporphyrinbased antioxidant that can prevent or delay the onset of autoimmune diabetes. Type 1 diabetes is an autoimmune process whereby T-cells recognize pancreatic ␤-cell antigens and initiate a leukocyte infiltrate that produces proinflammatory cytokines and reactive oxygen species (ROS), ultimately leading to ␤-cell destruction. Because islet ␤-cells have a reduced capacity to scavenge free radicals, they are very sensitive to ROS action. Metalloporphyrin-based superoxide dismutase (SOD) mimics scavenge ROS and protect cells from oxidative stress and apoptosis. To investigate the effect of SOD mimics and the role of oxidative stress in the development of autoimmune diabetes in vivo, we used a diabetogenic T-cell clone, BDC-2.5, to induce rapid onset of diabetes in young nonobese diabetic-severe combined immunodeficient mice (NOD.scid). Disease was significantly delayed or prevented altogether by treatment of recipient mice with an SOD mimic, AEOL-10113, before transfer of the BDC-2.5 clone. To investigate the mechanisms of protection, in vitro assays for T-cell proliferation and ␥-interferon (IFN-␥) production were carried out using the T-cell clone BDC-2.5. We found that the SOD mimic significantly inhibited antigen-presenting cell-dependent T-cell proliferation and IFN-␥ production in vitro. In addition, pretreatment of lipopolysaccharide (

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

“…Our further synthetic efforts in searching for a potential therapeutic based on the SAR led us to Mn(III) ortho N-alkylpyridylporphyrins as the most potent candidates for forwarding them into animal models where superoxide-mediated damage is involved. Thus remarkable effects were observed in cancer, radiation, diabetes, ALS, Alzheimer's disease etc [13][14][15][16][17][18][19][20][21][22][23]. Further, along with our mechanistic studies we observed a dramatic impact of the positive charges of the Mn porphyrin on the O 2 •− dismutation; the rate constants are more than two orders of magnitude higher when compared to the neutral or negatively charged porphyrins [3,4].…”

“…In all previous studies the data obtained with E. coli parallel the trends obtained in in vivo animal model studies [1][2][3][4][5][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]37]. Here we compare the effect of Mn II Br 8 TM-3-PyP 4+ , its metal-free porphyrin HBr 8 TM-3-PyP 3+ , and the para analogue Mn II Br 8 TM-4-PyP 4+ on the aerobic growth of an SOD-deficient E. coli strain.…”

The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

“…An essential role for ROI in T cell function was initially demonstrated by reports indicating that antioxidants inhibit proliferation and IL-2 production when administered during the early stages of T cell activation (17,18). Subsequent in vivo studies found that antioxidant treatment of mice decreased the proliferation and cytokine production of Ag-specific T cells in both autoimmune and infectious models (19,20). These findings suggest that ROI generated in response to receptor stimulation act as positive mediators involved in lymphocyte activation.…”

Gene- and cell-based therapeutics for type I diabetes mellitus

“…[112][113][114][115][116][117] Some of these antiapoptotic proteins fused to protein-transduction domains can successfully prevent apoptosis and significantly improve islet yield and survival following isolation. 30,118,119 We and others have also shown that the inclusion of synthetic mimetics of free-radical scavengers seem to prevent islet degeneration possibly limiting the initiation of apoptotic processes. 105,119 Islets also take up oligonucleotides quite efficiently (unpublished observations).…”

“…30,118,119 We and others have also shown that the inclusion of synthetic mimetics of free-radical scavengers seem to prevent islet degeneration possibly limiting the initiation of apoptotic processes. 105,119 Islets also take up oligonucleotides quite efficiently (unpublished observations). Knowledge of the primary transcripts whose protein products are involved in apoptosis activation or suppression of insulin production can be targeted with antisense oligonucleotides during the isolation procedure.…”