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Characterization of Clinical and Histological Rejection of Male Genital Tissues Using a Novel Microsurgical Rat Penile Transplantation Model

Fidder, Samuel A.J. MD1,2; Furtmüller, Georg J. MD1; Simons, Brian DVM, PhD3; Oh, Byoung Chol DVM, PhD1; Chicco, Maria MBBS1; Etra, Joanna W. MD1; Brayton, Cory DVM, DACVP4; Cooney, Carisa M. MPH1; Vasilic, Dalibor MD2; Kern, Barbara MD1; Lough, Denver MD, PhD1; Lee, WP Andrew MD1,5; Redett, Richard J. MD1; Brandacher, Gerald MD1; Cooney, Damon S. MD, PhD1

doi: 10.1097/TP.0000000000002812
Original Basic Science–General
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Background. Penis transplantation represents an exciting new avenue for restoration of male urogenitalia. However, little is known about the specific immunological features of penile transplants, limiting their application in complex urogenital reconstruction. To properly study this emerging form of transplantation, adequate preclinical models are a necessity. The purpose of this study is to establish a clinical and histological rejection classification of urogenital tissue transplants using a new rat heterotopic penile transplant model that includes preputial skin.

Methods. Syngeneic and allogeneic heterotopic penile transplantations were performed on Lewis and Brown Norway rats using a new model designed by our group. Grafts were clinically and histologically monitored at postoperative days (POD) 3–30.

Results. Six syngeneic and 25 allogeneic transplants were performed. All syngeneic and tacrolimus-treated grafts survived until endpoint. Allogeneic graft rejection is shown to follow a 4-stage clinical progression with all untreated allografts developing epidermal sloughing at POD7 and full rejecting between POD14 and POD16. Histological samples were used to develop a specific 4-grade rejection classification analogous to the 2007 Banff Criteria for skin-containing allografts.

Conclusions. Graft skin and urethral lining tissue are first rejection targets followed by tunica albuginea and corpora cavernosa in a distal to proximal pattern. We established a robust and reproducible murine model to study the immunobiology of male genital tissue in the context of transplantation and developed a novel 4-grade clinical and histological rejection scale based on graft skin and urethral lining as the main targets of rejection.

1 Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.

2 Department of Plastic and Reconstructive Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

3 Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD.

4 The Department of Molecular & Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD.

5 UT Southwestern Medical School, Dallas, TX.

Received 25 March 2019. Revision received 19 April 2019.

Accepted 10 May 2019.

The authors declare no conflicts of interest.

S.F. participated in research design, performed all of the operations and research, and wrote the article. G.F. participated in research design, assisted with the operations and research, and edited the article. B.S. participated in the histological data analysis and writing and editing of the article. B.O. assisted with performance of research and provided technical support. M.C. participated in the performance of the research. J.E. participated in material support and writing of the article. C.B. participated in histological data analysis. C.C. participated in writing of the article. D.V. participated in research design and provided administrative support. B.K. participated in the performance of the research. D.L. participated in writing of the article. W.L. provided administrative support and participated in writing and editing of the article. R.R. provided administrative support and participated in writing and editing of the article. G.B. participated in research design, provided administrative support, and participated in writing of the article. D.C. participated in research design, provided administrative support, and participated in writing of the article. S.F. and G.F. contributed equally to this work. G.B. and D.C. are co-senior authors.

Correspondence: Gerald Brandacher, MD, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross Research Bldg, Room 749D, Baltimore, MD. (brandacher@jhmi.edu).

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