Long-term Tolerance Toward Haploidentical Vascularized Composite Allograft Transplantation in a Canine Model Using Bone Marrow or Mobilized Stem Cells.
2016; 100 (12): e120–e127
The development of safe and reliable protocols for the transplantation of the face and hands may be accomplished with animal modeling of transplantation of vascularized composite allografts (VCA). Previously, we demonstrated that tolerance to a VCA could be achieved after canine recipients were simultaneously given marrow from a dog leukocyte antigen-identical donor. In the present study, we extend those findings across a dog leukocyte antigen mismatched barrier.Eight recipient dogs received total body irradiation (4.5 cGy), hematopoietic cell transplantation (HCT), either marrow (n = 4) or granulocyte-colony stimulating factor mobilized peripheral blood stem cells (n = 4), and a VCA transplant from the HCT donor. Post grafting immunosuppression consisted of mycophenolate mofetil (28 days) and cyclosporine (35 days).In 4 dogs receiving bone marrow, 1 accepted both its marrow transplant and demonstrated long-term tolerance to the donor VCA (>52 weeks). Three dogs rejected both their marrow transplants and VCA at 5 to 7 weeks posttransplant. Dogs receiving mobilized stem cells all accepted their stem cell transplant and became tolerant to the VCA. However, 3 dogs developed graft-versus-host disease, whereas 1 dog rejected its stem cell graft by week 15 but exhibited long-term tolerance toward its VCA (>90 weeks).The data suggest that simultaneous transplantation of mobilized stem cells and a VCA is feasible and leads to tolerance toward the VCA in a haploidentical setting. However, there is a higher rate of donor stem cell engraftment compared with marrow HCT and an increase in the incidence of graft-versus-host disease.
View details for DOI 10.1097/TP.0000000000001496
View details for PubMedID 27861292
Simultaneous Transplantation of Hematopoietic Stem Cells and a Vascularized Composite Allograft Leads to Tolerance
2014; 98 (2): 131-138
We have previously demonstrated that tolerance to a vascularized composite allograft (VCA) can be achieved after the establishment of mixed chimerism. We test the hypothesis that tolerance to a VCA in our dog leukocyte antigen-matched canine model is not dependent on the previous establishment of mixed chimerism and can be induced coincident with hematopoietic cell transplantation (HCT).Eight dog leukocyte antigen-matched, minor antigen mismatched dogs received 200 cGy of radiation and a VCA transplant. Four dogs received donor bone marrow at the time of VCA transplantation (group 1), whereas a second group of four dogs did not (group 2). All recipients received a limited course of postgrafting immunosuppression. All dogs that received HCT and VCA were given donor, third-party, and autologous skin grafts.All group 1 recipients were tolerant to their VCA (>62 weeks). Three of the four dogs in group 2 rejected their VCA transplants after the cessation of immunosuppression. Biopsies obtained from the muscle and skin of VCA from group 1 showed few infiltrating cells compared with extensive infiltrates in biopsies of VCA from group 2. Compared with autologous skin and muscle, elevated levels of CD3+ FoxP3+ T-regulatory cells were found in the skin and muscle obtained from the VCA of HCT recipients. All group 1 animals were tolerant to their donor skin graft and promptly rejected the third-party skin grafts.These data demonstrated that donor-specific tolerance to all components of the VCA can be established through simultaneous nonmyeloablative allogeneic HCT and VCA transplantation protocol.
View details for DOI 10.1097/TP.0000000000000204
View details for Web of Science ID 000339262000009
View details for PubMedID 24918616
Implantable Cook-Swartz Doppler probe versus Synovis Flow Coupler for the post-operative monitoring of free flap breast reconstruction
JOURNAL OF PLASTIC RECONSTRUCTIVE AND AESTHETIC SURGERY
2014; 67 (7): 960-966
The Cook-Swartz Doppler has long been a trusted tool for close monitoring of blood flow after microvascular reconstruction; however, device implantation requires additional operating time. Synovis Life Technologies, Inc. received FDA approval in 2010 for the Flow Coupler, which combines an end-to-end anastomotic coupler with a removable 20 MHz Doppler, allowing both procedures to be performed simultaneously. However, its short history of widespread use necessitates further evaluation in the clinical setting. The authors studied the Synovis Flow Coupler in comparison to the more well-established Cook-Swartz Doppler for effectiveness and reliability in detection of vascular compromise.The authors reviewed 220 free flap breast reconstructions in 150 patients over a three-year period in which either the Cook-Swartz Doppler or the Synovis Flow Coupler was implanted to monitor blood flow. Outcomes measured include false-positive or false-negative rates (FPR, FNR); rates of OR take-back and salvage; and flap survival.FPR was 1.0% for the Cook-Swartz Doppler and 1.9% for the Synovis Flow Coupler (p>0.05). FNR was 0.0% for both groups. Take-back rates were 10.1% for the Cook-Swartz, and 4.5% for Synovis (p>0.05). Flap failure rates were 1.8% and 0.9% for the Cook-Swartz and Synovis devices, respectively (p>0.05).Our study reveals no statistically significant differences in outcomes for free flap breast reconstruction where either the Cook-Swartz Doppler or the Synovis Flow Coupler was used to monitor blood flow to the perforator flap.III.
View details for DOI 10.1016/j.bjps.2014.03.034
View details for Web of Science ID 000339354900017
View details for PubMedID 24767693
- Abstract 12: Achieving Tolerance in a Mismatched VCA Transplant While Reducing the Risk of GVHD: The Goal of Transient Chimerism. Plastic and reconstructive surgery 2014; 133 (3): 22-?
Long-Term Tolerance to Kidney Allografts After Induced Rejection of Donor Hematopoietic Chimerism in a Preclinical Canine Model
2012; 94 (6): 562-568
Allogeneic hematopoietic cell transplantation provides a reliable method for inducing tolerance toward solid organ grafts. However, this procedure can result in graft-versus-host disease, thereby limiting its application. Here, we test the hypothesis that mixed chimerism can be intentionally reverted to host hematopoiesis without rejection of a kidney graft.Recipient dogs were given 2-Gy total-body irradiation (TBI) before and a short course of immunosuppression after marrow infusion from dog leukocyte antigen-identical littermates. All dogs achieved stable mixed chimerism. After a mean of 20 weeks, one cohort of dogs received kidney transplants from their respective marrow donors. Subsequently, recipients were reconditioned with 2-Gy TBI and given autologous granulocyte colony-stimulating factor-mobilized leukocytes (recipient leukocyte infusion [RLI]) that had been collected before marrow transplantation.Dogs receiving a second TBI and RLI without a kidney transplant rejected their donor hematopoietic graft within 3 weeks. Dogs that received kidney grafts, followed by a second TBI and RLI, rejected their marrow graft without rejecting their transplanted kidneys for periods greater than 1 year.Mixed chimerism may be clinically reverted to 100% recipient without rejection of a kidney allograft. This finding may have application toward minimizing the risk of graft-versus-host disease in solid organ transplantation patients given hematopoietic cell transplantation from human leukocyte antigen-identical donors.
View details for DOI 10.1097/TP.0b013e3182646bf1
View details for Web of Science ID 000309223100008
View details for PubMedID 22929594
The Impact of Current Immunosuppression Strategies in Renal Transplantation on the Field of Reconstructive Transplantation
JOURNAL OF RECONSTRUCTIVE MICROSURGERY
2012; 28 (1): 7-19
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.
View details for DOI 10.1055/s-0031-1285988
View details for Web of Science ID 000299598500003
View details for PubMedID 21842460
Tolerance to Vascularized Composite Allografts in Canine Mixed Hematopoietic Chimeras
2011; 92 (12): 1301-1308
Mixed donor-host chimerism, established through hematopoietic cell transplantation (HCT), is a reproducible strategy for the induction of tolerance toward solid organs. Here, we ask whether a nonmyeloablative conditioning regimen establishing mixed donor-host chimerism leads to tolerance of antigenic vascularized composite allografts.Stable mixed chimerism was established in dogs given a sublethal dose (1-2 Gy) total body irradiation before and a short course of immunosuppression after dog leukocyte antigen-identical marrow transplantation. Vascularized composite allografts from marrow donors were performed after a median of 36 months (range, 4-54 months) after HCT.All marrow recipients maintained mixed donor-host hematopoietic chimerism and accepted vascularized composite allografts for periods ranging between 52 and 90 weeks; in turn, marrow donors rejected vascularized composite allografts from their respective marrow recipients within 18 to 29 days. Biopsies of muscle and skin of vascularized composite allografts from mixed chimeras showed few infiltrating cells compared with extensive infiltrates in biopsies of vascularized composite allografts from marrow donors. Elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle of vascularized composite allografts of mixed chimeras compared with normal tissues. In mixed chimeras, increased numbers of T-regulatory cells were found in draining compared with nondraining lymph nodes of vascularized composite allografts.These data suggest that nonmyeloablative HCT may form the basis for future clinical applications of solid organ transplantation and that T-regulatory cells may function toward maintenance of the vascularized composite allograft.
View details for DOI 10.1097/TP.0b013e318237d6d4
View details for Web of Science ID 000298149200007
View details for PubMedID 22082819
Ethical, Financial, and Policy Considerations in Hand Transplantation
2011; 27 (4): 553-?
Currently, more than 65 hand transplants have been performed with studies demonstrating favorable cosmetic and functional outcomes and cortical reintegration of the transplanted hand. Due to such favorable outcomes, many view hand transplant as a potential gold standard for treatment of a double amputee. However, ethical debate continues regarding risks and benefits of this nonlifesaving procedure. Clinicians, patients, and society must agree on whether hand transplantation is ethical and affordable. If a decision is made to transplant a hand, this must be performed in a dedicated center that facilitates integration of multiple specialists, ethicists, pharmacists, and rehabilitationists.
View details for DOI 10.1016/j.hcl.2011.07.006
View details for Web of Science ID 000297823800017
View details for PubMedID 22051396
Multiple receptors coupled to phospholipase C gate long-term depression in visual cortex
JOURNAL OF NEUROSCIENCE
2005; 25 (49): 11433-11443
Long-term depression (LTD) in sensory cortices depends on the activation of NMDA receptors. Here, we report that in visual cortical slices, the induction of LTD (but not long-term potentiation) also requires the activation of receptors coupled to the phospholipase C (PLC) pathway. Using immunolesions in combination with agonists and antagonists, we selectively manipulated the activation of alpha1 adrenergic, M1 muscarinic, and mGluR5 glutamatergic receptors. Inactivation of these PLC-coupled receptors prevents the induction of LTD, but only when the three receptors were inactivated together. LTD is fully restored by activating any one of them or by supplying intracellular D-myo-inositol-1,4,5-triphosphate (IP3). LTD was also impaired by intracellular application of PLC or IP3 receptor blockers, and it was absent in mice lacking PLCbeta1, the predominant PLC isoform in the forebrain. We propose that visual cortical LTD requires a minimum of PLC activity that can be supplied independently by at least three neurotransmitter systems. This essential requirement places PLC-linked receptors in a unique position to control the induction of LTD and provides a mechanism for gating visual cortical plasticity via extra-retinal inputs in the intact organism.
View details for DOI 10.1523/JNEUROSCI.4084-05.2005
View details for Web of Science ID 000233941900021
View details for PubMedID 16339037