Patterns of Rejection in Murine, Porcine, and Human Vascularized Composite Allografts Based on Clinical, Histologic, and Immunohistochemical Analysis

M. J. Grzelak, J. W. Etra, F. A. Chang, G. J. Furtmüller, A. R. Ahmadi, F. Nägele, Y. Guo, K. Kambarashvili, A. Jain, S. A. Beck, C. F. Brayton, I. B. Sander, W. A. Lee, G. Brandacher

Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD

Meeting: 2019 American Transplant Congress

Abstract number: 307

Keywords: Graft failure, Histology, Mice, Miniature pigs

Session Information

Session Name: Concurrent Session: Basic & Clinical Science - VCA

Session Type: Concurrent Session

Date: Monday, June 3, 2019

Session Time: 2:30pm-4:00pm

Presentation Time: 3:30pm-3:42pm

Location: Room 209

*Purpose: The side effects of chronic immunossupression limit the more extensive use of Vascularized Composite Allotransplantation (VCA), and because reliable pre-clinical animal models will be instrumental in the development of safer immunosuppressive regimens, the aim in this study was to assess the relevance of murine and porcine VCA models by comparing their clinical and histologic rejection patterns to those of human VCA patients.

*Methods: The VCA models compared in this study included murine and porcine hindlimb transplant models as well as human patients with upper extremity transplants. Clinical rejection patterns were compared by photographic documentation, and histologic rejection patterns were compared based on H&E stains of graft biopsies. Due to the similarities between porcine and human VCA rejection, porcine rejection patterns were further characterized according to immunologic cell types based on immunohistochemical (IHC) staining. Analysis of IHC slides involved cell counting software (ImageJ) and percent area calculations (Fiji).

*Results: Porcine clinical skin rejection is similar to human clinical rejection and progresses from mild erythema to necrolysis. In contrast, murine rejection has unique features such as fur loss and early edema. Porcine histologic rejection is also similar to human rejection based on H&E characterization, whereas murine histologic rejection follows a unique pattern of early, severe edema and a lower density of inflammatory infiltrates. Finally, IHC analysis of porcine rejection reveals distinct differences in cellular components between rejection grades. T cells rise in grades 2 and 3, B cells rise in grade 3, and Macrophages rise in grade 4. Regulatory T cells rise in grade 3 and markedly decrease in grade 4. This pattern resembles previously published data on human VCA rejection.

*Conclusions: While the murine model is a cost-effective way to test initial theories and perform high throughput studies, the porcine model is superior due to its strong correlation with human VCA rejection patterns. Based on IHC analysis, during the porcine rejection process the presence of T cells, B cells, Macrophages, and Tregs shifts dramatically. Future research should be devoted to exploring the effects of tailoring the immunosuppressive regimen to the components of the current rejection grade.

To cite this abstract in AMA style:

Grzelak MJ, Etra JW, Chang FA, Furtmüller GJ, Ahmadi AR, Nägele F, Guo Y, Kambarashvili K, Jain A, Beck SA, Brayton CF, Sander IB, Lee WA, Brandacher G. Patterns of Rejection in Murine, Porcine, and Human Vascularized Composite Allografts Based on Clinical, Histologic, and Immunohistochemical Analysis [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/patterns-of-rejection-in-murine-porcine-and-human-vascularized-composite-allografts-based-on-clinical-histologic-and-immunohistochemical-analysis/. Accessed May 12, 2025.

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