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.
"The immunodepletive induction protocol with antithymocyte globulin (ATG), methylprednisolone, and maintenance therapy with FK506 and rapamycin was used for heterotopic transplantation of facial allografts in cynomolgus monkeys . Under this protocol, long-term facial VCA survival ranging from 6 to 129 days posttransplant was achieved but tolerance was not induced, indicating that further development of immunosuppressive protocols is needed for nonhuman primate VCA models. "
[Show abstract][Hide abstract] ABSTRACT: The preclinical experimental models of vascularized composite allografts (VCAs) have been rapidly developed for the assessment of immunomodulatory protocols for clinical application. Recently, researchers have focused on immunomodulatory protocols which overcome the immunologic barrier between the allogeneic donor and recipient and may lead to tolerance induction. In order to test the feasibility of chimerism induction, experimental VCAs have been performed in different models including rodents, large animals, and nonhuman primates. These models differ in the complexity of transplanted tissue and in their responses to immunomodulatory protocols. In most applications, VCA contains multiple-tissue components; however, each individual component of CTA possesses unique immunologic characteristics that ultimately contribute to the chimerism induction and successful outcome of the VCA. Heterogenic character and complexity of tissue components in different VCA models determine the quality and robustness of donor-specific chimerism. As introduced in experimental studies, variable immunomodulatory options have been studied to achieve tolerance to VCA in rodents and large animal models allowing for widespread application in clinic. In this paper, based on our own experience, we have analyzed the current knowledge of tolerance-inducing strategies via chimerism induction in VCA experimental models in the context of immunomodulatory protocols and VCA complexity and their relevance and applicability to clinical practice.
"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). "
[Show abstract][Hide abstract] 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.
AFRICAN JOURNAL OF BIOTECHNOLOGY 01/2011; 10(3). · 0.57 Impact Factor
[Show abstract][Hide abstract] 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 · 1.94 Impact Factor
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