Metalloproteinase inhibition has differential effects on alloimmunity, autoimmunity, and histopathology in the transplanted lung.
BACKGROUND
Upregulation of matrix metalloproteinases (MMPs) has been associated with chronic lung allograft rejection known as bronchiolitis obliterans syndrome. It has been suggested that MMP inhibition could prevent the rejection response. However, the effect of MMP inhibition on lung allograft rejection has not been reported.


METHODS
Utilizing a rat model of lung transplantation, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were overexpressed by gene therapy in F344 rat lung allografts prior to transplantation into WKY recipient rats. Separately, WKY rats that received F344 lung allografts were treated systemically with COL-3, a global MMP inhibitor.


RESULTS
TIMP-1 and TIMP-2 had differential effects on delayed type hypersensitivity (DTH) responses to donor antigens and type V collagen, an autoantigen involved in the rejection response. Neither TIMP-1 or TIMP-2 affected the onset of rejection pathology. COL-3 suppressed DTH responses to donor antigens and type V collagen, abrogated local production of tumor necrosis factor-alpha, and interleukin-1beta. Although it did not prevent rejection pathology, COL-3 (30 mg/kg) induced intragraft B cell hyperplasia suggestive of posttransplant proliferative disorder (PTLD).


CONCLUSIONS
These data identify a complex role for MMPs and TIMPs in the immunopathogenesis of lung allograft rejection, and indicate their effects are not limited to matrix remodeling.
Yoshida
Shigetoshi
S
Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Iwata
Takekazu
T
Chiyo
Masako
M
Smith
Gerald N
GN
Foresman
Brian H
BH
Mickler
Elizabeth A
EA
Heidler
Kathleen M
KM
Cummings
Oscar W
OW
Fujisawa
Takehiko
T
Brand
David D
DD
Baker
Andrew
A
Wilkes
David S
DS
D000818:Animals; D015551:Autoimmunity / Q000276:immunology* / Q000502:physiology; D024062:Collagen Type V / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D013754:Tetracyclines / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000502:physiology; D014184:Transplantation, Homologous / Q000276:immunology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D024062:Collagen Type V; D053583:Interleukin-1beta; D061965:Matrix Metalloproteinase Inhibitors; D013754:Tetracyclines; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; C117155:tetracycline CMT-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases