Metalloproteinase inhibition has differential effects on alloimmunity, autoimmunity, and histopathology in the transplanted lung

Shigetoshi Yoshida, Takekazu Iwata, Masako Chiyo, Gerald N. Smith, Brian H. Foresman, Elizabeth A. Mickler, Kathleen M. Heidler, Oscar W. Cummings, Takehiko Fujisawa, David Brand, Andrew Baker, David S. Wilkes

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Abstract

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-α, and interleukin-1β. 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.

Original languageEnglish (US)
Pages (from-to)799-808
Number of pages10
JournalTransplantation
Volume83
Issue number6
DOIs
StatePublished - Mar 1 2007

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Metalloproteases
Autoimmunity
Tissue Inhibitor of Metalloproteinase-1
Allografts
Matrix Metalloproteinases
Tissue Inhibitor of Metalloproteinase-2
Lung
Collagen Type V
Inbred WKY Rats
Delayed Hypersensitivity
Pathology
Bronchiolitis Obliterans
Antigens
Matrix Metalloproteinase Inhibitors
Lung Transplantation
Inbred F344 Rats
Autoantigens
Interleukin-1
Genetic Therapy
Hyperplasia

All Science Journal Classification (ASJC) codes

  • Transplantation

Cite this

Yoshida, S., Iwata, T., Chiyo, M., Smith, G. N., Foresman, B. H., Mickler, E. A., ... Wilkes, D. S. (2007). Metalloproteinase inhibition has differential effects on alloimmunity, autoimmunity, and histopathology in the transplanted lung. Transplantation, 83(6), 799-808. https://doi.org/10.1097/01.tp.0000258600.05531.5d

Metalloproteinase inhibition has differential effects on alloimmunity, autoimmunity, and histopathology in the transplanted lung. / Yoshida, Shigetoshi; Iwata, Takekazu; Chiyo, Masako; Smith, Gerald N.; Foresman, Brian H.; Mickler, Elizabeth A.; Heidler, Kathleen M.; Cummings, Oscar W.; Fujisawa, Takehiko; Brand, David; Baker, Andrew; Wilkes, David S.

In: Transplantation, Vol. 83, No. 6, 01.03.2007, p. 799-808.

Research output: Contribution to journalArticle

Yoshida, S, Iwata, T, Chiyo, M, Smith, GN, Foresman, BH, Mickler, EA, Heidler, KM, Cummings, OW, Fujisawa, T, Brand, D, Baker, A & Wilkes, DS 2007, 'Metalloproteinase inhibition has differential effects on alloimmunity, autoimmunity, and histopathology in the transplanted lung', Transplantation, vol. 83, no. 6, pp. 799-808. https://doi.org/10.1097/01.tp.0000258600.05531.5d
Yoshida, Shigetoshi ; Iwata, Takekazu ; Chiyo, Masako ; Smith, Gerald N. ; Foresman, Brian H. ; Mickler, Elizabeth A. ; Heidler, Kathleen M. ; Cummings, Oscar W. ; Fujisawa, Takehiko ; Brand, David ; Baker, Andrew ; Wilkes, David S. / Metalloproteinase inhibition has differential effects on alloimmunity, autoimmunity, and histopathology in the transplanted lung. In: Transplantation. 2007 ; Vol. 83, No. 6. pp. 799-808.
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AU - Smith, Gerald N.

AU - Foresman, Brian H.

AU - Mickler, Elizabeth A.

AU - Heidler, Kathleen M.

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N2 - 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-α, and interleukin-1β. 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.

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