BACKGROUND: Engineered tissues have been proposed for the treatment of a variety of conditions including the partial or complete replacement of human organs. To determine the basis for the rejection of these tissues, we analyzed the immune response to allogeneic human skin equivalent (HSE, also called Apligraf) in the humanized SCID mouse (hu-PBL-SCID). METHODS: Two models of hu-PBL-SCID were used for these studies. In one model, human skin or HSE was transplanted onto humanized mice so that graft survival could be analyzed. In the other model, skin grafts were allowed to heal on naive mice before humanization. This model was used to analyze the immunologic response to the vascularized skin allograft. Humanization was performed by adoptive transfer of human PBL into SCID mice by i.p. injection. RESULTS: Both human foreskin and HSE successfully engrafted onto naive SCID mice and remained stable for more than 6 months. In contrast, human foreskin was rejected by 21 days posttransplant in hu-PBL-SCID, whereas HSE consistently engrafted for more than 28 days. Treatment of HSE grafts with interferon-y for 5 days to induce maximal MHC class II molecule expression before grafting failed to induce rejection. HSE also engrafted onto hu-PBL-SCID mice that were exposed to alloantigen by prior injection with interferon-gamma-treated keratinocytes identical to those used to generate the HSE. In addition, we determined that humanization of SCID mice following engraftment and vascularization of human foreskin resulted in marked CD3+ T cell infiltrates and a lymphocyte-induced vasculitis. In contrast, the response in vascularized HSE was associated with minimal CD3+ T cell infiltration in the absence of vasculitis or morphological features of rejection. CONCLUSION: These results support the use of HSE and other allogeneic engineered tissues in humans provided that such tissues are limited in their antigen presenting capabilities. In addition, our findings suggest a critical function for the donor endothelial cell in rejection.
BACKGROUND: Engineered tissues have been proposed for the treatment of a variety of conditions including the partial or complete replacement of human organs. To determine the basis for the rejection of these tissues, we analyzed the immune response to allogeneic human skin equivalent (HSE, also called Apligraf) in the humanized SCID mouse (hu-PBL-SCID). METHODS: Two models of hu-PBL-SCID were used for these studies. In one model, human skin or HSE was transplanted onto humanized mice so that graft survival could be analyzed. In the other model, skin grafts were allowed to heal on naive mice before humanization. This model was used to analyze the immunologic response to the vascularized skin allograft. Humanization was performed by adoptive transfer of human PBL into SCID mice by i.p. injection. RESULTS: Both human foreskin and HSE successfully engrafted onto naive SCID mice and remained stable for more than 6 months. In contrast, human foreskin was rejected by 21 days posttransplant in hu-PBL-SCID, whereas HSE consistently engrafted for more than 28 days. Treatment of HSE grafts with interferon-y for 5 days to induce maximal MHC class II molecule expression before grafting failed to induce rejection. HSE also engrafted onto hu-PBL-SCID mice that were exposed to alloantigen by prior injection with interferon-gamma-treated keratinocytes identical to those used to generate the HSE. In addition, we determined that humanization of SCID mice following engraftment and vascularization of human foreskin resulted in marked CD3+ T cell infiltrates and a lymphocyte-induced vasculitis. In contrast, the response in vascularized HSE was associated with minimal CD3+ T cell infiltration in the absence of vasculitis or morphological features of rejection. CONCLUSION: These results support the use of HSE and other allogeneic engineered tissues in humans provided that such tissues are limited in their antigen presenting capabilities. In addition, our findings suggest a critical function for the donor endothelial cell in rejection.
Authors: Monika Edelbauer; Dipak Datta; Ingrid H C Vos; Aninda Basu; Maria P Stack; Marlies E J Reinders; Masayuki Sho; Katiana Calzadilla; Peter Ganz; David M Briscoe Journal: Blood Date: 2010-06-10 Impact factor: 22.113
Authors: Marlies E J Reinders; Masayuki Sho; Atsushi Izawa; Ping Wang; Debabrata Mukhopadhyay; Kerith E Koss; Christopher S Geehan; Andrew D Luster; Mohamed H Sayegh; David M Briscoe Journal: J Clin Invest Date: 2003-12 Impact factor: 14.808
Authors: Tânia Baltazar; Jonathan Merola; Carolina Catarino; Catherine B Xie; Nancy C Kirkiles-Smith; Vivian Lee; Stephanie Hotta; Guohao Dai; Xiaowei Xu; Frederico C Ferreira; W Mark Saltzman; Jordan S Pober; Pankaj Karande Journal: Tissue Eng Part A Date: 2019-12-03 Impact factor: 3.845
Authors: Jonathan Merola; Melanie Reschke; Richard W Pierce; Lingfeng Qin; Susann Spindler; Tania Baltazar; Thomas D Manes; Francesc Lopez-Giraldez; Guangxin Li; Laura G Bracaglia; Catherine Xie; Nancy Kirkiles-Smith; W Mark Saltzman; Gregory T Tietjen; George Tellides; Jordan S Pober Journal: JCI Insight Date: 2019-10-17
Authors: Sarah Bruneau; Craig Bryan Woda; Kevin Patrick Daly; Leonard Boneschansker; Namrata Gargee Jain; Nora Kochupurakkal; Alan Gabriel Contreras; Tatsuichiro Seto; David Michael Briscoe Journal: Front Immunol Date: 2012-04-02 Impact factor: 7.561