A heterotopic primate model for facial composite tissue transplantation.

University of Maryland School of Medicine, Department of Surgery, Baltimore, MD 21201, USA.
Annals of Plastic Surgery (Impact Factor: 1.46). 03/2008; 60(2):209-16. DOI: 10.1097/SAP.0b013e318061b792
Source: PubMed

ABSTRACT The purpose of this study was to develop a nonhuman primate model for heterotopic composite tissue facial transplantation in which to study the natural history of facial transplantation and evaluate immunosuppressive regimens.A composite oromandibular facial segment transplant based on the common carotid artery was evaluated. Flaps from 7 cynomolgus monkeys were transplanted to the groins of 7 recipients at the superficial femoral artery and vein. The immunosuppressive regimen consisted of thymoglobulin, rapamycin, and tacrolimus. Allograft survival ranged from 6 to 129 days. Histology performed in the long-term survivor at the time of necropsy revealed extensive inflammation and necrosis of the allograft skin; however, muscle and bone elements were viable, with minimal inflammation. This heterotopic facial transplantation model avoids the potential morbidity of mandibular resection and orthotopic facial transplantation. Our work also concurs with the work of other groups who found that the skin component is the most antigenic.

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    • "prevented acute or chronic asthma and inflammation (United State patent, 2006). It was successfully used in skin (Gupta et al., 2002; Ehling et al., 2004; Gambichler et al., 2008) and inflammatory cutaneous diseases (Carroll, et al., 2004; Rubegni et al., 2006; Kymionis et al., 2008), facial tissue transplant (Silverman et al., 2008) and Crohn's disease (Juillerat et al., 2007). It also protected cavernous nerves after crush injury (Valentine et al., 2007). "
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    ABSTRACT: Tacrolimus hydrate (FK506), isolated from Streptomyces tsukubaensis, is an immensely used immunosuppressive agent. It was evaluated for its effects on meiotic chromosomes in testes, epididymal spermatozoa and fertility in male mice. The study under different parameters constituted sub acute (seven days) administration (gavage) of FK506 at doses of 4, 8 and 16 mg/kg/day body weight. The results obtained in present study revealed that, FK506 significantly induced spermatozoa abnormalities, lowered fertility and increased embryonic loss. The observed changes related to spermatogenic dysfunction reflected statistically significant increased aberrations in the meiotic chromosomes. These aberrations seemed to be induced by the inhibitory effect of the drug on the signal transduction pathways in the cells and interference in the transcription processes and proliferation of cells. Further studies are warranted to evaluate the safe dose and duration of therapy to determine the exact mode of action of FK506 induced germ cell toxicity.
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    ABSTRACT: Partial face composite tissue allotransplantation was recently achieved in a human subject. However, the side effects of long-term immunosuppression and chronic rejection area still need concerning. This preliminary study investigated the reproducibility of swine hemi-facial transplantation for preclinical studies. Eleven out-bred miniature swine underwent hemi-facial transplant. The hemi-facial orthotopic transplant consisted of ear cartilage, auricular nerve, parotid gland and lymphoid tissue, muscle with surrounding hemi-facial skin paddle supplied by the carotid artery, and external jugular vein transplanted to recipient swine. Three different experimental designs were studied, as follows: group I (n = 4): autologous hemi-facial transplantation as a normal control; group II (n = 4): hemi-facial allotransplantation without treatment; group III (n = 3): hemi-facial allotransplantation with cyclosporine-A treatment for 4 wk. The transplanted face was observed daily for signs of rejection. Biopsy of donor skin, gland lymphoid tissue, and cartilage were obtained at specified predetermined time (d 7, 14, 28), or at the time of clinically evident rejection. The results indicated the survival of group I following autologous hemi-facial transplant was 100% and indefinite until sacrifice. Group II without treatment as the controls revealed allograft rejection by d 7 to 28. The allograft with short-term cyclosporine-A treatment revealed delayed rejection by d 38 to 49 postoperatively. The histological examination in group I revealed abundant lymphocyte infiltration, especially in lymphoid gland and alloskin at 1 wk and sacrifice. In contrast, the cyclosporine treatment group showed no significant rejection signs in 4 wk posttransplants. These results demonstrated that lymphoid tissue and alloskin are both susceptible to early rejection. The experimental results revealed this model is suitable to investigate the new strategies for preclinical facial allotransplantation studies. Monitoring and modulation of early rejection in alloskin and gland lymphoid tissue is a useful strategy to evaluate composite tissue allotransplantation survival.
    Journal of Surgical Research 05/2008; 153(2):268-73. DOI:10.1016/j.jss.2008.03.050 · 2.12 Impact Factor
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    ABSTRACT: Widespread application of composite tissue allotransplantation has been impeded by risks of rejection and conventional immunosuppression. The authors have developed a nonhuman primate composite tissue allotransplantation model that demonstrated reliable and long-term success necessary to progress to preclinical studies. Composite facial subunits (e.g., skin, muscle, and bone) were transplanted between mismatched cynomolgus monkeys. Vascular supply was based on the common carotid artery and external and internal jugular veins. Facial allografts were heterotopically transplanted to the recipient's lower abdomen with end-to-side anastomoses of the common carotid artery to the common femoral artery and of both the internal and external jugular veins to the common femoral vein. Animals received tacrolimus monotherapy. Grafts were inspected daily, submitted to biopsy regularly, and studied with magnetic resonance imaging. Thirteen transplants were performed. Two grafts based on the common carotid artery and only the internal jugular vein failed within 3 to 5 days because of venous thrombosis not related to rejection. Subsequent transplants included anastomoses of both the internal and external jugular veins to the common femoral vein without thromboses. Immunosuppression consisted of tacrolimus monotherapy and was tolerated without complications. Long-term success was achieved with rejection-free graft survival (60 to 177 days). The authors have developed the first successful model of facial composite tissue allotransplantation in a nonhuman primate. Technical requirements include preservation of both internal and external jugular venous outflow. Tacrolimus monotherapy permitted prolonged rejection-free graft survival without early complications. This model provides a platform for further investigation of composite tissue allotransplantation tolerance and requirements for indefinite survival.
    Plastic and Reconstructive Surgery 03/2009; 123(2):493-501. DOI:10.1097/PRS.0b013e3181954edd · 3.33 Impact Factor
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