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 D. Brand, Andrew Baker, David S. Wilkes

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13 Scopus citations

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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Keywords

  • Autoimmunity
  • Cytokines
  • Posttransplant lymphoproliferative disorder
  • Rodent
  • Type V collagen

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Yoshida, S., Iwata, T., Chiyo, M., Smith, G. N., Foresman, B. H., Mickler, E. A., Heidler, K. M., Cummings, O. W., Fujisawa, T., Brand, D. D., Baker, 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