Enhanced Allograft Survival and Modulation of T-Cell Alloreactivity Induced by Inhibition of MMP/ADAM Enzymatic Activity

Abstract

Recent studies have shown significantly increased expression of matrix metalloproteinases (MMP) and disintegrin-type metalloproteinases (ADAM) during allograft rejection. In this regard, our previous studies have demonstrated contrasting roles for MMP-2 and MMP-9 during allograft rejection: MMP-2-deficiency enhanced allograft survival while MMP-9-deficiency decreased allograft survival. The aim of this study was to determine the effect of broad-spectrum MMP/ADAM inhibition on the pathogenesis of allograft rejection. Toward this, heterotopic BALB/c cardiac allografts were transplanted into C57BL/6 recipients treated with MMP/ADAM inhibitors, GM6001 or doxycycline. Systemic MMP/ADAM inhibition significantly enhanced allograft survival. Functioning allografts recovered from MMP/ADAM inhibitor-treated recipients showed lower cellular infiltration and tissue remodeling than rejected allografts recovered from control recipients. In addition, decreased chemotaxis of CD4+ and CD8+ T cells, B cells and macrophages was observed in vitro in the presence of MMP/ADAM inhibitors. Enhanced T-cell alloreactivity was also observed ex vivo in MMP/ADAM inhibitor-treated recipients and in vitro in the presence of MMP/ADAM inhibitors. These observations were associated with enhanced cytokine, chemokine and growth factor production. These results indicate that MMPs and ADAMs play a critical role in the pathogenesis of allograft rejection and may represent novel therapeutic targets for the treatment and/or prevention of this disease.

Matrix metalloproteinases in kidney homeostasis and diseases

“…MMP-2 null mice have decreased T cell alloreactivity and inflammatory cytokine release, while MMP-9 null mice have increased alloreactivity and cytokine release (14). Broad-spectrum inhibition of MMPs leads to decreased inflammatory cell chemotaxis and improves cardiac graft survival (26). However, these results may be tissue specific, as MMP-9 null mice have improvement in survival of tracheal allografts (30).…”

Anti-Inflammatory Activity of Tetracyclines: Applications to Human Disease

“…Inhibition of other in vitro T cell activation responses by tetracyclines have also been demonstrated, such as chemotaxis, up-regulation of CD40 ligand, and cytokine production, most notably that of IFN [61][62][63][64]. In most assays, significant inhibitory effects are observed at clinically achievable drug concentrations (5-15 μM).…”

“…In vitro experiments have shown B cell proliferation and chemotaxis to be inhibited by doxycycline, in some studies at concentrations as low a 1 μg/ml [64,67]. In addition, in vitro immunoglobulin (Ig) production is decreased by as much as 86% by minocycline or doxycycline (5-10 μg/ml), Ig class switching is inhibited, and expression of B cell differentiation genes is reduced [67,68].…”

Letter by Pinto and Heymans Regarding Article, “Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice”

“…Use of a broad spectrum MMP inhibitor significantly reduced T-cell infiltration and improved survival of the cardiac allograft, whereas MMP-9 gene-inactivated mice had significantly increased cellular infiltration and impaired cardiac allograft survival. 4 Whether TIMP-1 deficiency or overexpression also alters cardiac allograft function and survival warrants further investigation.…”

“…Use of a broad spectrum MMP inhibitor significantly reduced T-cell infiltration and improved survival of the cardiac allograft, whereas MMP-9 gene-inactivated mice had significantly increased cellular infiltration and impaired cardiac allograft survival. 4 Whether TIMP-1 deficiency or overexpression also alters cardiac allograft function and survival warrants further investigation.What about the role of MMP-9 in other cardiac diseases? Independent studies clearly showed that deficiency of MMP-9 but also of MMP-2 significantly reduced inflammation and improved cardiac function after myocardial infarction or hypertension (reviewed in Vanhoutte et al 5 ).…”