Facial Subunit Composite Tissue Allografts in Nonhuman Primates: I. Technical and Immunosuppressive Requirements for Prolonged Graft Survival

Barth, Rolf N.; Bluebond-Langner, Rachel; Nam, Arthur J.; Stanwix, Matthew G.; Shipley, Steven T.; Bartlett, Stephen T.; Rodriguez, Eduardo D.

doi:10.1097/prs.0b013e3181954edd

Cited by 46 publications

(28 citation statements)

References 28 publications

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“…To test this hypothesis, we developed a nonhuman primate model of heterotopic facial allotransplantation to study the unique immunobiology of VCA and investigate approaches that may decrease or eliminate the long-term immunosuppressive requirements ( Figure 1) (10,11). Our model utilized selectively mismatched cynomolgus macaques that provided a method for detection of donor macrochimerism.…”

Section: Introductionmentioning

confidence: 99%

Vascularized Bone Marrow-Based Immunosuppression Inhibits Rejection of Vascularized Composite Allografts in Nonhuman Primates

Barth

Rodriguez

Mundinger

et al. 2011

American Journal of Transplantation

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Vascularized composite allograft (VCA) transplantation (also referred to as composite tissue allotransplantation) has demonstrated clinical success in cases of hand, arm and face transplantation despite prior belief that skin provides an insurmountable barrier to allograft rejection. These overall good outcomes are facilitated by substantial immunosuppressive requirements in otherwise healthy patients, yet still demonstrate frequent rejection episodes. We developed a nonhuman primate model of facial segment allotransplantation to elucidate the unique pathophysiology and immunosuppressive requirements of VCA with addition of concomitant vascularized bone marrow (VBM). Heterotopically transplanted facial segment VCA with VBM treated only with tacrolimus and mycophenolate mofetil (MMF) demonstrated prolonged rejection-free survival, compared to VCA without VBM that demonstrated early rejection episodes and graft loss. While VCA with VBM demonstrated sporadic macrochimerism, acute and chronic rejection and graft loss occurred after discontinuation of immunosuppression. These data support an immunomodulatory role of VBM in VCA that reduces immunosuppressive requirements while providing improved outcomes.

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Section: Introductionmentioning

confidence: 99%

Vascularized Bone Marrow-Based Immunosuppression Inhibits Rejection of Vascularized Composite Allografts in Nonhuman Primates

Barth

Rodriguez

Mundinger

et al. 2011

American Journal of Transplantation

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“…43,46 In two animals (group 2), tacrolimus therapy at a serum goal level of 20 to 30 ng/ml was combined with a novel anti-CD28 co-stimulatory blocking antibody (scFvCD28) 47-49 administered at a dosage of 2 mg/kg by means of daily intravenous infusion from postoperative days 1 to 28. Tacrolimus was converted to once-daily intramuscular dosing after 28 days, with trough target levels of 10 to 20 ng/ml.…”

Section: Immunosuppressive Regimensmentioning

confidence: 99%

“…Unfortunately, both preclinical and clinical protocols have shown high rates of rejection, infection, failed bony union, and vasculopathy. 28 -42 We developed a nonhuman primate model of facial vascularized composite tissue allotransplantation that achieved long-term rejection-free survival 43,44 and extended this model to vascularized composite tissue allotransplants containing vascularized long bone, skin, and muscle ( Fig. 1).…”

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confidence: 99%

Nonhuman Primate Model of Fibula Vascularized Composite Tissue Allotransplantation Demonstrates Donor-Recipient Bony Union

Mundinger

Nam

Hui-Chou

et al. 2011

Plastic and Reconstructive Surgery

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In contrast to successes in extremity vascularized composite tissue allotransplantation, the authors' nonhuman primate fibular vascularized composite tissue allotransplantation model showed early skin loss, replacement of donor bone marrow, and chronic rejection. Donor-recipient bone union did occur and supports the potential for reconstruction of bony continuity defects using isolated vascularized bone allotransplants.

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“…3). A heterotopic model of facial transplantation has also been developed by a group at the University of Maryland involving part of the mandible, overlying soft tissue, skin, and vasculature (Silverman et al 2008;Barth et al 2009). …”

Section: Vascularized Composite Allograftsmentioning

confidence: 99%

Primate Models in Organ Transplantation

Anderson

Kirk

2013

Cold Spring Harbor Perspectives in Medicine

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Large animal models have long served as the proving grounds for advances in transplantation, bridging the gap between inbred mouse experimentation and human clinical trials. Although a variety of species have been and continue to be used, the emergence of highly targeted biologic-and antibody-based therapies has required models to have a high degree of homology with humans. Thus, the nonhuman primate has become the model of choice in many settings. This article will provide an overview of nonhuman primate models of transplantation. Issues of primate genetics and care will be introduced, and a brief overview of technical aspects for various transplant models will be discussed. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed.A nimal experimentation has long provided a rational basis for the translation of treatments and techniques from the bench to the bedside. In general, all first-in-human trials require preparative animal experimentation to allow patients to make truly informed decisions about their participation. Properly designed animal studies in relevant species provide the necessary background experience with a novel approach to reasonably anticipate the efficacy or, at the very least, safety of a planned intervention. As such, they serve as a foundation on which human trials can be ethically designed, particularly in fields such as immunology, in which the complexity of the interactions involved has prevented the development of any sufficiently predictive in vitro model. Although animal models are far superior to in vitro models in projecting the potential of an approach, it must be recognized that they do not mimic clinical transplantation precisely, and thus cannot be expected to forecast the ultimate experience in humans.The mouse model has formed the backbone of medical research and development for many years owing to the relative ease of breeding and genetic manipulation of the animals at a comparatively low cost. For immunology research, the mouse immune system offers sufficient homology for pathway determination and mechanistic studies, and indeed represents the ideal platform for this type of endeavor. In contrast, the large animal models (dog, pig, and primate) are significantly more expensive and, with the exception of inbred miniature swine (Sachs 1992;Mezrich et al. 2003), exhibit increased genetic diversity, making definitive mechanistic studies much more difficult, if not impossible. However, this complexity makes large animals suited to preclinical studies, in which the addition of often-unanticipated variables allows for the examination of practicality, safety, and generalized efficacy. In general, mice define pathways, and large animal models help establish whether a particular pathway's effect is suffi-

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Facial Subunit Composite Tissue Allografts in Nonhuman Primates: I. Technical and Immunosuppressive Requirements for Prolonged Graft Survival

Cited by 46 publications

References 28 publications

Vascularized Bone Marrow-Based Immunosuppression Inhibits Rejection of Vascularized Composite Allografts in Nonhuman Primates

Vascularized Bone Marrow-Based Immunosuppression Inhibits Rejection of Vascularized Composite Allografts in Nonhuman Primates

Nonhuman Primate Model of Fibula Vascularized Composite Tissue Allotransplantation Demonstrates Donor-Recipient Bony Union

Primate Models in Organ Transplantation

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