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Human Periprosthetic Tissues Implanted in Severe Combined Immunodeficient Mice Respond to Gene Transfer of a Cytokine Inhibitor
Shang-You Yang, MD1; Sam Nasser, MD1; David C. Markel, MD1; Paul D. Robbins, PhD2; Paul H. Wooley, PhD1
1 Department of Orthopaedic Surgery, Wayne State University, University Health Center 7C, 4201 St. Antoine Boulevard, Detroit, MI 48201. E-mail address for S-Y Yang: syang@wayne.edu
2 Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, W1246, Biomedical Science Tower, Pittsburgh, PA 15213
View Disclosures and Other Information
In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the National Institutes of Health and a VA Merit Grant. In addition, one or more of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity (consultant for Tissuegene, a company working on arthritis gene therapy). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the Department of Orthopaedic Surgery, Wayne State University, Detroit, Michigan, and the Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2005 May 01;87(5):1088-1097. doi: 10.2106/JBJS.D.02052
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Abstract

Background: Periprosthetic tissue formation and local inflammation that are associated with wear debris contribute to the pathogenesis of aseptic loosening of a prosthesis. This study evaluated a retrovirus-mediated gene therapy with use of a novel xenograft-based animal model.

Methods: Human periprosthetic tissues obtained from patients during revision arthroplasty performed because of aseptic loosening of a prosthetic joint were transplanted into the left quadriceps and paravertebral muscles of severe combined immunodeficient (SCID) mice. The engrafted tissues were recovered seven, fifteen, or thirty days after implantation for histological and molecular analyses. The periprosthetic tissues were incubated with retroviruses encoding for human interleukin-1 receptor antagonist (hIL-1Ra) or bacteria ß-galactosidase (LacZ) at 37°C for three hours prior to implantation to evaluate their responses to gene modification.

Results: The human periprosthetic tissues were well accepted in SCID mice for up to thirty days, with angiogenesis occurring in the majority of the implanted tissue sections. The histological appearance was consistent between the recovered graft tissue and the original donor tissue. Strong expression of interleukin-1, tumor necrosis factor, and interleukin-6 was detected in the xenografts with use of immunohistochemical stains. Histological analysis revealed that interleukin-1 receptor antagonist gene modification significantly decreased the total number of inflammatory cells (p < 0.01) in engrafted human tissue containing implant wear debris. Real-time reverse transcription-polymerase chain reaction and immunohistochemical staining showed declining expression levels of interleukin-1 and tumor necrosis factor following interleukin-1 receptor antagonist gene transfer in comparison with LacZ-transduced or virus-free controls.

Conclusions: Human periprosthetic tissue can survive in the SCID mouse host for up to thirty days and responds to the interleukin-1 receptor antagonist gene transfer with the amelioration of inflammation.

Clinical Relevance: The human periprosthetic tissue-SCID mouse chimera has been characterized in this study as a useful model to explore the properties of human periprosthetic tissue in vivo, laying the foundation for potential clinical application of gene therapy in aseptic loosening.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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