Enhanced allograft survival and modulation of T-cell alloreactivity induced by inhibition of MMP/ADAM enzymatic activity.
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.
Eaton
V L
VL
Department of Pathology, Rush University Medical Center, Chicago, IL, USA.
Lerret
N M
NM
Velásquez-Lopera
M M
MM
John
R
R
Caicedo
M
M
DeCresce
R P
RP
Jaramillo
A
A
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; D004151:Dipeptides; D036341:Intercellular Signaling Peptides and Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D003094:Collagen; D051722:ADAM Proteins; D018093:Gelatinases; D004318:Doxycycline