Enhanced allograft survival and modulation of T-cell alloreactivity induced by inhibition of MMP/ADAM enzymatic
V L Eaton1, N M Lerret, M M Velásquez-Lopera
1Department of Pathology, Rush University Medical Center, Chicago, IL, USA.
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.
Insights
Broad-spectrum inhibition of matrix metalloproteinases (MMP) and disintegrin-type metalloproteinases (ADAM) significantly improved allograft survival by reducing immune cell infiltration and tissue damage. This suggests MMPs and ADAMs are key targets for preventing allograft rejection.
Area of Science:
- Immunology
- Biochemistry
- Transplantation Biology
Background:
- Matrix metalloproteinases (MMP) and disintegrin-type metalloproteinases (ADAM) are upregulated during allograft rejection.
- Previous studies indicated contrasting roles for MMP-2 and MMP-9 in allograft survival.
Purpose of the Study:
- To investigate the impact of broad-spectrum MMP/ADAM inhibition on allograft rejection pathogenesis.
- To evaluate MMP/ADAM inhibitors as potential therapeutic targets for allograft transplantation.
Main Methods:
- Heterotopic BALB/c cardiac allografts were transplanted into C57BL/6 recipients.
- Recipients were treated with MMP/ADAM inhibitors (GM6001 or doxycycline).
- Allograft survival, cellular infiltration, tissue remodeling, immune cell chemotaxis, and T-cell alloreactivity were assessed.
Main Results:
- Systemic MMP/ADAM inhibition significantly enhanced allograft survival.
- Inhibitor-treated allografts exhibited reduced cellular infiltration and tissue remodeling compared to controls.
- In vitro and ex vivo studies showed decreased immune cell chemotaxis and enhanced T-cell alloreactivity with inhibitor treatment.
Conclusions:
- MMPs and ADAMs play a critical role in allograft rejection.
- Broad-spectrum MMP/ADAM inhibition demonstrates therapeutic potential for preventing allograft rejection.
- Targeting MMPs and ADAMs could offer novel strategies for transplant medicine.
