Composite Tissue Allograft Transplantation Research Articles

The intragraft vascularized bone marrow component plays a critical role in tolerance induction after reconstructive transplantation

The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not completely understood. In this study, vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation (CBMT) or vascularized bone marrow (VBM) transplantation from Balb/c (H2d) to C57BL/6 (H2b) mice were compared. Either high- or low-dose CBMT (1.5 × 108 or 3 × 107 bone marrow cells, respectively) was applied. In addition, recipients were treated with costimulation blockade (1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2, respectively) and short-term rapamycin (3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks). Similar to high-dose conventional bone marrow transplantation, 5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival (>120 days). In contrast, significantly shorter median survival was noted in the low-dose CBMT group (~64 days). Consistently high chimerism levels were observed in the VBM transplantation group. Notably, low levels of circulating CD4+ and CD8+ T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients (>30 days) but not in low-dose VBM transplant recipients. Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro. Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.

AMD3100 (Plerixafor) as a Single-Dose Stem Cell Mobilizing Agent in Vascularized Composite Tissue Allograft Transplantation in a Canine Haploidentical Model

Swearingen, Bruce J. MD; Graves, Scott S. PhD; Storb, Rainer MD; Mathes, David W. MD, FACS Author Information

BASIC PRINCIPLES OF MODELLIND OF FACIAL COMPOSITE TISSUE ALLOGRAFTS

The article presents the results of anatomical studies aimed to develop modelling of facial allografts taking into account the peculiarities of blood supply. The allografts should meet both aesthetic and functional needs of the recipient for further use in clinical practice. There were selected 3 facial composite tissue allografts out of 50 modifications, which are more suitable for required parameters. On basis of these data, there was successfully performed the facial composite tissue allograft transplantation on the patient.

AN ALGORITHM FOR THE FACIAL COMPOSITE TISSUE ALLOGRAFT TRANSPLANTATION.THE FIRST RUSSIAN EXPERIENCE

The article presents the first Russian experience in a facial composite tissue allograft transplantation. An algorithm for the interaction of government agencies such as the Ministry of Healthcare and the The Ministry of Defence of the Russian Federation was being reviewed . The basic aspects of the preparation and conduct of the operation, followed by immunosuppressive therapy were being presented.

Achieving Tolerance in a Mismatched VCA Transplant While Reducing The Risk of GVHD: Goal of Transient Chimerism.

Background: Vascularized composite tissue allograft (VCA) transplantation offers the opportunity to restore form and function. Life-long immunosuppression limits clinical applicability. A promising method is the development of mixed chimerism. We've shown that a non-myeloablative stem cell transplant can lead to tolerance in a mismatched dog model (450cGy TBI). This protocol has been limited by skin graft-versus-host disease (GVHD). We observed animals that after an initial period lost their stem cell allograft but remained tolerant to the VCA while those that retained full donor cell chimerism inevitably developed GVHD. The hypothesis for this study was that our transplant protocol could be used to induce tolerance to a recipient VCA without the need for persistent donor cell chimerism. Methods: 5 haploidentical canine recipients received a non-myeloablative conditioning regimen of 350cGy TBI, mobilized donor stem cell and VCA transplantation, followed by a short course of immunosuppression (MMF: 56 days/Cyclosporine: 70 days). Peripheral blood chimerism was evaluated by PCR techniques weekly. VCA rejection was followed clinically and confirmed histologically after biopsy. Results: All 5 tolerated the conditioning regimen. Two rejected their stem cells early (<5 weeks). One rejected the stem cells at post-operative day (POD) 35 and rejected the VCA transplant following the cessation of immunosuppression. The other was euthanized for persistent fevers at POD 84 with no sign of VCA rejection. One fully engrafted, converted to 100% donor chimerism, and had long-term tolerance to the VCA but developed skin GVHD. 2 dogs demonstrated a prolonged period of transient chimerism (7 to 10 weeks post-transplant) before rejecting their donor stem cells without acute rejection of their donor VCAs. Later in the study both of these animals demonstrated evidence of chronic rejection. Neither developed skin GVHD. Conclusions: We demonstrate that our non-myeloablative protocol allows for selective rejection of donor stem cells and elimination of GVHD risks without acute rejection of the VCA transplant while persistent donor chimerism can lead to GVHD.

CD4+CD25+ T regulatory cell–depleted splenocytes enhance chimerism in graft recipients

The discovery and development of immunosuppressant therapies have dramatically improved the survival of organ transplant recipients. However, as a consequence of our efforts to prevent immunologic rejection of a graft, patients now experience an array of debilitating complications from long-term immunosuppressant therapy, including opportunistic infections and risk of malignancy [ [1] Fishman J.A. Issa N.C. Infection in organ transplantation: Risk factors and evolving patterns of infection. Infect Dis Clin North Am. 2010; 24: 273 Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar ]. Hence, research into immunosuppressant therapies has improved graft and patient survival at the cost of quality of life. An alternative to chronic immunosuppressant therapy is to induce graft tolerance in the recipient by inducing donor-specific tolerance [ [2] Bui A.H. Lipshutz G. Kupiec-Weglinski J. Donor-specific tolerance. in: Hewitt C.W. Lee W.P.A. Transplantation of composite tissue allografts. Springer, New York2008: 89 Crossref Scopus (1) Google Scholar ], which allows the recipient's immune system to function at full capacity, with the transplanted graft maintaining complete immunologic “immunity” [ [3] Hayashi Y. Yamazaki S. Kanamoto A. et al. Splenocytes can replace chimeric cells and maintain allograft tolerance. Transplantation. 2007; 84: 1168 Crossref PubMed Scopus (10) Google Scholar ]. In a theoretical sense, this would allow the abandonment of immunosuppressant therapies. Chimeric acceleration by donor CD4+CD25+T-reg depleted fraction in splenocyte transplantationJournal of Surgical ResearchVol. 178Issue 1PreviewWe have established a splenocytic chimera model that can induce donor-specific tolerance and reconstitute the recipient immune system by donor splenocytes. Full-Text PDF

The First (Double) Hand Transplantation in Turkey

In September 2010, a bilateral hand allotransplantation was performed on a 28-year-old man who had suffered amputations at the level of 1/3 of the proximal forearm on the right and 1/3 of the distal forearm on the left 2 years previously. This was the first hand transplantation case in Turkey. Preoperative organization, legal difficulties, technical aspects of the operation, and immunosuppressive regimen are detailed herein. The early results of the first composite tissue allograft (CTA) transplantation are also reported. The results were encouraging for all future types of CTA transplantation, including hand and face. Following the early promising outcome of the first case of hand transplantation in Turkey, we have accelerated preparation of regulations for CTA transplantation, including hand and face allotransplantation.

Immunological tolerance to composite tissue allograft transplantation in a DLA-identical canine model

Immunological tolerance to composite tissue allograft transplantation in a DLA-identical canine model

An Optimized Dual-Surgeon Simultaneous Orthotopic Hind-Limb Allotransplantation Model in Rats

Composite tissue allograft (CTA) transplantation is a promising treatment in reconstructive surgery for complex tissue injuries in humans. However, continued research is required to optimize the risk to benefit ratios. In this study, we describe, in detail, an optimized simultaneous dual-surgeon orthotopic hind-limb transplantation model in direct comparison to a single-surgeon model. In this study 75 hind-limb CTAs were performed, employing either a dual-surgeon model (n = 60) or a single-surgeon model (n = 15) for the transplantation of two hind-limbs. Operative times, complication rates, and costs were compared. The dual-surgeon approach showed a significant reduction of 45.4% in overall operative time (p < 0.05). Overall complication rate was 8%. The dual-surgeon model was ∼30.5% more cost-effective than the traditional single-surgeon approach. Benefits of the proposed simultaneous dual-surgeon orthotopic rat hind-limb CTA model include decreased operating times, decreased complication rates, and reduced financial costs when compared with the established single-surgeon model.

The Impact of Current Immunosuppression Strategies in Renal Transplantation on the Field of Reconstructive Transplantation

Composite tissue allograft (CTA) transplantation, such as the clinical face and hand transplants, has now been performed in multiple centers across the world. The transplants have successfully treated complex injuries that have either failed conventional approaches or where autologous reconstruction could not restore both form and function. CTA transplantation has the potential to improve outcomes over traditional techniques. However, the widespread application of CTA transplantation continues to be limited by the need for chronic immunosuppression. Due to the small numbers of CTA transplants performed, any modification in the immunosuppression used will likely be based from the solid organ literature. The renal transplantation literature has served as the basis for the current selection of CTA drug regimens and in this article we review the evidence in the renal transplant literature for the selection of immunosuppressive regimens. The study then compares the regimens used in both the face and hand transplantation with those regimens currently used for renal transplantation.

Bone Healing After Secondary Surgery on Hand Allografts Under Sirolimus-Based Maintenance Immunosuppression

Composite tissue allograft transplantation is a recognized option for reconstruction in upper limb amputees. Sirolimus is an immunosuppressive drug that prevents organ rejection and improves kidney function, but its use has been associated with impaired healing. Two recipients of bilateral hand allografts underwent arthrodeses of 6 joints as secondary procedures while being treated with sirolimus. We found no clinical or radiologic evidence of bone healing delay or bone nonunion. The functional evaluation revealed an improvement in the performance of activities of daily living after the transplant and secondary procedures. We conclude that bone surgery can be performed safely in recipients of hand allografts who are receiving sirolimus-based immunosuppressive therapy.

Ethical Considerations in Face Transplantation: Ethical Issues Related to Inclusion Criteria for Face Transplant Candidates

On November 15, 2004, Cleveland Clinic Foundation’s Institutional Review Board (IRB) granted me the world’s first approval to perform face transplantation in humans. This approval was granted based on over 20 years of work in the field of composite tissue allotransplantation, both in the experimental laboratory as well as in the anatomy laboratory, on cadaver models. The process of approval took over 1 year and a number of meetings in front of the IRB committee, which consisted of about 20 members of different specialties including medicine, transplantation, infectious disease, and surgery; however, also experts in different fields—lawyers, social workers, as well as lay representatives, all having the right to ask questions about the validity of such a new procedure. When it comes to surgical breakthroughs, there is always a lot of controversy around the topic. It is quite understandable that the announcement of Cleveland Clinic having received approval for facial transplantation in humans, in 2004, raised considerable interest from media all over the world, and from this perspective, I must say that the international and national media interest was almost larger than when we actually performed the first US face transplantation in December 2008. Interestingly, there was a lot of support from the media perspective, since it was obvious that our IRB approval was based on years of work in the field of composite tissue allograft transplantation. Also, the medical society supported the idea that, for patients who had lost their faces and were severely disfigured, introduction of new reconstructive options which went beyond what was currently available, was something to be accepted with interest and excitement. The major opponents, however, of the idea of facial transplantation, were experts in ethics. One of them, Dr. Art Caplan, questioned the value of face transplantation and had numerous public interviews where he criticized the idea, as well as having warned society that now patients would be unwilling to donate organs and would be tearing up their drivers’ licenses since, in the United States, organ donation is voluntary and a statement indicating agreement to be an organ donor is displayed on drivers’ licenses. Interestingly, from the surgeons’ perspective, this type of approach could be ethically questionable, specifically when it comes to statements made ex cathedra, without really dealing with disfigured patients and seeing their disability, daily suffering, and inability to maintain physiological functions, as well as normal social lives. This introduces the ethical questions which we had raised during the work on our IRB approval protocol, as well as on the consent form for face transplant candidates. As for any medical procedure, when it comes to a decision about elective and novel surgery, there is always the M. Siemionow (&) Department of Plastic Surgery, Cleveland Clinic, 9500 Euclid Avenue/Desk A-60, Cleveland, OH 44195, USA e-mail: siemiom@ccf.org Arch. Immunol. Ther. Exp. (2011) 59:157–159 DOI 10.1007/s00005-011-0121-6

Perioperative Ischemic Injury and Fibrotic Degeneration of Muscle in a Forearm Allograft

Allografts of the forearm are still uncommon in the field of composite tissue allograft transplantation. In November 2007, a right-hand allograft and a left-hand/full-length forearm allograft were transplanted in a 30-year-old man who lost both hands and the vision in his left eye due to an explosion. The patient underwent alemtuzumab and steroid induction therapy. Tacrolimus, mycophenolate mofetil, and low doses of steroids were given to prevent rejection. The allografts were rejected 3 times, but these episodes were controlled successfully. The immunosuppressive regimen was switched from tacrolimus to sirolimus because of increased serum creatinine. The left allograft showed a flexion contracture due to muscle fibrosis that was conjectured to be associated with a perioperative ischemic injury and permitted only a Moberg-type key pinch. In contrast, an excellent grade of function was observed in the right allograft. The Disabilities of the Shoulder, Arm, and Hand score improved from 70.83 to 36.6 and intrinsic musculature returned to both allografts. The patient was able to work 2 years after transplantation. This is the first report of an ischemic injury related to the successful allotransplantation of a composite tissue.

Anti-αβ-T-Cell Receptor Antibodies in the Setting of Laryngeal Transplantation

Inhibiting T-cell activation is critically important to the induction of transplantation tolerance. Monoclonal antibodies directed against the αβ-T-cell receptor have been shown to cause selective immunodepletion of this T-cell population and can provide long-term allograft acceptance. This article discusses the role of this promising immunosuppressive agent in scientific research and clinical utilization. Specifically, the article focuses on its efficacy and mechanism of tolerance induction in solid tissue and composite tissue allograft transplantation with a particular focus on laryngeal transplantation.

Improvement in Renal Function After Late Conversion to Sirolimus-Based Immunosuppression in Composite Tissue Allotransplantation

Improvement in Renal Function After Late Conversion to Sirolimus-Based Immunosuppression in Composite Tissue Allotransplantation

Methods of Assessment of Cortical Plasticity in Patients Following Amputation, Replantation, and Composite Tissue Allograft Transplantation

The brain is always adapting to new inputs from the environment. New noninvasive techniques are available to scrupulously study cortical plasticity. Several studies have proven that these modifications of neural pathways occur because of denervation from injury such as amputation. Changes that occur rapidly are likely because of unmasking of established synapses that are latent, whereas changes that occur over long periods of time are more likely because of establishment of new neural connections. Cortical reorganization that occurs from traumatic amputation has been shown to be reversible with replantation and transplantation. With the new field of composite tissue transplantation, such as hand or face, it is critical to be aware of these changes to choose potential patients and to modify their rehabilitation, on the basis of our understanding of the cortical reorganization that occurs over time.

Experimental Facial Transplantation Surgery

Facial composite tissue allograft transplantation represents a novel frontier in the reconstruction of complex human facial defects. To develop more refined surgical techniques and yield fine results, it is definite to make a suitable animal model. Rabbit is a medium-sized animal and considered to have many advantages than any other animal, but published reports are very few and contain less detailed description. We made an easy and accessible facial transplantation approach and tried to ascertain its virtue of use as an appropriate transplantation model. The facial-scalp flap including ipsilateral ear was harvested and transferred as a single unit with unilateral common carotid artery and external jugular vein. Most allografts survived with perfect viability without vascular problems in the early postoperative period, and rejection response was also identified by clinical and histopathologic analysis. The total mean time of transplantation was 2 hours +/- 10 minutes. We documented that this model is well qualified for use as a standard transplantation training model and future research work in every aspect.

Transplantation of Composite Tissue Allografts

Transplantation of Composite Tissue Allografts

Immunodepletive Anti-α/β-Tcr AntiBody in Transplantation of Composite Tissue Allografts: Cleveland Clinic Research Experience

The immunologic characteristics of composite tissue allografts (CTA), which contain skin, lymphoid elements and bone with bone marrow, raise new challenges for transplant immunologists. Owing to the heterogeneity of transplanted tissues in limb or face transplant models, researchers are focusing on the new tolerance-inducing strategies facilitating CTA acceptance. A number of immunosuppressive protocols have been designed to develop tolerance in experimental models; however, only a few protocols have been introduced to clinical transplantation. In this review, based on own experiences, we discuss the major strategies for tolerance induction in limb and face allograft models in experimental studies. This review is focused on tolerance induction strategies by establishment of donor-specific chimerism using different immunomodulatory protocols, including nonselective T-cell depletion with polyclonal antibody antilymphocyte serum and selective inhibition of alphabeta-T-cell receptors on the alloreactive T cells.

Tolerance and Future Directions for Composite Tissue Allograft Transplants: Part II

After studying this article, the participant should be able to: 1. Discuss the definition and basic aspects of tolerance as applied to clinical practice. 2. Understand the role of donor bone marrow cells for tolerance induction in composite tissue allograft. 3. Understand the role of passenger leukocytes in allograft acceptance and rejection. 4. Understand the tolerogenic role of dendritic cells and regulatory cells in composite tissue allograft transplants. 5. Understand modern approaches to transplantation tolerance and their applicability to composite tissue allograft transplants. The introduction of composite tissue allograft transplants into clinical practice has become reality because of well-established microsurgical techniques. However, the success of composite tissue allograft transplants is still dependent on chronic immunosuppression. Clinically applicable protocols for tolerance induction in composite tissue allograft would eliminate the need for lifelong immunosuppression. The major goal of transplantation immunology is to develop immunologic nonresponsiveness (tolerance) to allograft transplants and long-term drug-free survival. A number of protocols have been designed to develop tolerance in experimental systems; however, none of them has been translated to clinical transplantation. In this review, the authors discuss current knowledge and strategies used for tolerance induction and the role of passenger leukocytes for allograft acceptance and rejection. Tolerogenic properties of dendritic cells and immunotherapy with regulatory T cells are introduced as having future potential for tolerance induction in solid organ and composite tissue allograft transplants. The induction of donor-specific tolerance would generate new options for the application of composite tissue allograft transplants and may be considered as a future direction in plastic and reconstructive surgery.