Chemokine-Binding Viral Protein M-T7 Prevents Chronic Rejection in Rat Renal Allografts

Abstract

M-T7 is a myxoma virus-encoded protein that has been found to bind and disrupt human chemokine gradients. This study examined whether purified M-T7 could prevent chronic rejection in a rat renal allograft model. Fisher F344 renal allografts were transplanted into Lewis rats. Recipients were randomly grouped into two groups: control animals treated with cyclosporine alone and animals treated with cyclosporine combined with low-, medium- and high-dose M-T7 viral protein. The survival rate was not significantly different between allograft groups. Renal allografts treated with high-dose M-T7 demonstrated a significant reduction in tubular atrophy, glomerular atrophy, vascular hyalinization, cortical scarring, and lymphocyte infiltration. Morphometric analyses demonstrated that the high-dose M-T7 group also showed a significantly decreased amount of glomerulosclerosis and transplant arteriosclerosis. These data demonstrate for the first time that the immunoregulatory viral protein M-T7 can effectively attenuate chronic rejection in rat renal allografts.

Comparative Analysis of Plaque Growth after Arterial Stent Implant with Anti-Inflammatory Chemokine and Serine Protease Inhibitors Treatment

“…Plaque area, was measured by morphometric analysis using an Olympus CCD color video camera attached to an Olympus microscope, and the ImagePro application program calibrated to the microscope objective [26][27][28][29][30][31]33]. Both the mean total cross-sectional intimal area and the mean intimal thickness after normalized to the medial thickness were calculated for each arterial section.…”

“…These inflammatory moderators function at femptomolar to picomolar concentrations when secreted by the originating viruses [23,24]. Two such proteins, Serp-1 that inhibits uPA/uPAR [23][24][25][26][27][28] and M-T7 [26,[29][30][31] that blocks the C terminal GAG binding domain of C, CC and CXC class chemokines [26,[29][30][31] have been purified individually and studied as anti-inflammatory reagents in a wide range of animal models with demonstrated reduction in inflammatory cell invasion and plaque growth. One protein, Serp-1 has been successfully tested in clinical trial for treatment of patients with unstable coronary syndromes (Unstable angina and NSTEMI) who have received stent implants [26,32].…”

“…Harvested arterial sections were processed and stained with hematoxylin and eosin (H & E) or Masson's trichrome stains as previously described [25][26][27][28][29][30][31]33]. Plaque area, was measured by morphometric analysis using an Olympus CCD color video camera attached to an Olympus microscope, and the ImagePro application program calibrated to the microscope objective [26][27][28][29][30][31]33].…”

Viral Anti-Inflammatory Proteins Target Diverging Immune Pathways with Converging Effects on Arterial Dilatation, Plaque and Apoptosis

“…When utilized as purified protein isolates, these anti-inflammatory proteins suppress disease progression in animal models of inflammatory vascular disease, specifically atherosclerosis and transplant rejection (10,11,(13)(14)(15)(16)(17)(18)(19)(20). Serp-I is a secreted 55kD serpin (serine proteinase inhibitor) that inhibits uPA, tPA, plasmin, and factor Xa (16,(18)(19)(20).…”

“…Serp-2 is a 34kD cross-class serpin that inhibits caspase I and 8 and granzyme B (15,21). M-T7 represents a separate protein class, inhibiting rabbit interferon gamma (IFNy) (13,14,17,22) and a broad spectrum of C, CC, and CXC chemokines in a non-species dependent manner (13,14,17,22). In multiple animal models, Serp-1 reduced plaque growth and transplant vasculopathy (10, 11, 16, 18-20, 22, 23) and Serp-1 has been successfully tested in a clinical trial in patients with unstable coronary syndromes after stent implantation (24).…”