Favoring the Risk–Benefit Balance for Upper Extremity Transplantation—The Pittsburgh Protocol
Section snippets
Upper extremity allotransplantation: benefit versus risk
During the past decade, upper extremity and face transplantation has become a clinical reality. In case of the human upper extremity, RT represents a superior alternative to restore the appearance, anatomy, and function in amputees who do not benefit from or decide not to choose prostheses.
In the past decade, more than 70 upper extremity transplants have been performed around the world, confirming that this procedure is not only feasible but represents a valuable option to reconstruct limb loss
Minimizing and weaning immunosuppression: premise and implications
Immunosuppressive drugs like calcineurin inhibitors such as tacrolimus have improved short-term outcomes, but failed to improve long-term outcomes after solid organ transplants.9 In addition to their adverse effects as discussed previously, immunosuppressive agents can also contribute to late allograft loss.10 Thus, several trials have attempted immunosuppression minimization months after the transplant when there is a lower risk of rejection or completely weaned patients off drugs, but have
Operational tolerance: promise and progress
Operational tolerance is defined as prolonged survival of a transplanted organ in the absence of immunosuppression, without signs of a destructive response while retaining normal reactivity to infections and tumors. Lifelong operational tolerance is difficult to achieve, especially without risk of chronic rejection. Also, complete absence of immunosuppression poses some risk of graft damage or loss as a result of low-grade chronic processes, especially as these cannot be effectively monitored
Donor bone marrow infusion/augmentation in solid organ transplantation: evolution and early insights
The early developments that served as the foundations of modern tissue transplantation are credited to the US Navy Tissue Bank, which was established in 1949 by George Hyatt, an orthopedic surgeon at the Naval Medical Center in Bethesda, Maryland. The US Navy Tissue Bank pioneered standards and criteria for tissue donation as well as procurement and processing, documentation, and clinical evaluation of a variety of tissues including DBM. Indeed, it was the US Navy Tissue Bank that was the
Donor bone marrow augmentation in solid organ transplantation: induction of chimerism and operational tolerance
Medawar established the concept of chimerism67 based on the observations of Owen68 in Freemartin calf dizygotic twins, describing a mixture of blood cells due to cross-circulation in the common placenta in utero. Such fetal chimerism is associated with lifelong unresponsiveness to donor alloantigens. Ildstad and Sachs described the phenomenon of mixed allogeneic chimerism, which was induced by inoculation of both syngeneic and allogeneic bone marrow into sublethally irradiated adult hosts, and
Nonmyeloablative depletional induction: prospects for prope tolerance
The use of lymphodepleting induction therapy to eliminate early detrimental immune signals and promote clonal deletion of effector cells has been extensively studied and was pioneered by Roy Calne.85 Studies have demonstrated the possible regulatory effects of antithymocyte globulin and the anti-CD52 antibody alemtuzumab in deleting alloreactive effector cells while preserving regulatory cells and their components.86 Limited but emerging data suggest that such induction approaches may favor or
Novel immunomodulatory therapies: the bidirectional paradigm
The pioneering studies of Medawar and Owen showed the association with donor leucocyte chimerism with acquired tolerance.31, 67, 68 However, early attempts at inducing chimerism with donor leucocyte infusions even after ablation of recipients uniformly failed ending with either lethal GVHD or rejection. Experimentally, macrochimerism was successful in inducing tolerance without GVHD under select protocols of recipient conditioning. When donor cells fell to microchimeric levels (<1%), these
Reconstructive transplantation: immunomodulation versus immunosuppression
The overarching goal of the application of the Pittsburgh Protocol in hand transplantation was to enhance the risk to benefit ratio by minimizing the number, dose, and duration of drugs used, and in turn improve the safety, efficacy, and applicability of this reconstructive modality.
When the Pittsburgh Protocol was used by Starzl and colleagues in living-related organ transplants, BM was obtained from the iliac crests of donors who were pretreated in vivo with stimulating factors to increase
Summary
Upper extremity transplantation is an innovative reconstructive strategy with potential of immediate clinical application and the most near-term pay-off for select amputees, allowing reintegration into employment and society. In this context, reducing the need and risk of immunosuppressive drugs needed for graft survival is a key and immediate goal.
Routine applicability and widespread impact of such strategies for the upper extremity amputees with devastating limb loss could be enabled
References (95)
- et al.
Estimating the prevalence of limb loss in the United States: 2005 to 2050
Arch Phys Med Rehabil
(2008) - et al.
Battlefield extremity injuries in Operation Iraqi Freedom
Injury
(2009) Concerns about human hand transplantation in the 21st century
J Hand Surg Am
(2002)- et al.
Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus
Am J Transplant
(2006) - et al.
Tolerogenic immunosuppression for organ transplantation
Lancet
(2003) - et al.
The role of donor bone marrow infusions in withdrawal of immunosuppression in adult liver allotransplantation
Am J Transplant
(2005) - et al.
Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence
J Hepatol
(2006) Withdrawal of immunosuppression in liver transplant recipients: Is this as good as it gets?
Liver Transpl
(2002)- et al.
The success of continued steroid avoidance after kidney transplantation in the US
Am J Transplant
(2009) - et al.
Chimerism and transplantation tolerance: cause and effect
Immunol Today
(1996)
Harvest of human bone marrow directly from bone
J Immunol Methods
Bone marrow from cadaver donors for transplantation
Blood
Three years of follow-up of bone marrow-augmented organ transplant recipients: the impact on donor-specific immune modulation
Transplant Proc
Analysis of post-transplant immune status in recipients of liver/bone marrow allografts
Hum Immunol
Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation
Transpl Immunol
Donor-specific bone marrow cells suppress lymphocyte reactivity to donor antigens and differentially modulate TH1 and TH2 cytokine gene expression in the responder cell population
Transpl Immunol
Microchimerism and rejection in clinical transplantation
Lancet
Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses
Am J Transplant
Induction of MHC-class I restricted human suppressor T cells by peptide priming in vitro
Hum Immunol
ATG-fresenius treatment and low-dose tacrolimus: results of a randomized controlled trial in liver transplantation
Am J Transplant
Limb amputation and limb deficiency: epidemiology and recent trends in the United States
South Med J
Composite tissue allotransplantation: hand transplantation and beyond
J Am Acad Orthop Surg
The International Registry on Hand and Composite Tissue Transplantation
Transplantation
Immunosuppressive agents in transplantation: mechanisms of action and current antirejection strategies
Microsurgery
Risks of allogeneic hand transplantation
Microsurgery
Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation
Transplantation
The natural history of chronic allograft nephropathy
N Engl J Med
Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen: results of a five-year, prospective, randomized study
J Am Soc Nephrol
Mycophenolate mofetil substitution for cyclosporine a in renal transplant recipients with chronic progressive allograft dysfunction: The creeping creatinine study
Transplantation
Reduced exposure to calcineurin inhibitors in renal transplantation
N Engl J Med
Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial
Transplantation
Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation
Transplantation
Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine
Transplantation
Frequent achievement of a drug-free state after orthotopic liver-transplantation
Transplant Proc
Weaning of immunosuppression in long-term liver transplant recipients
Transplantation
Weaning of immunosuppression in liver transplant recipients
Transplantation
Defining the outcome of immunosuppression withdrawal after liver transplantation
Hepatology
Weaning of immunosuppression in living donor liver transplant recipients
Transplantation
Tolerance: Is it worth the risk?
Transplantation
A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy
Ann Surg
Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis
Transplantation
Actively acquired tolerance of foreign cells
Nature
Improvement of kidney graft survival with increased numbers of blood transfusions
N Engl J Med
Deliberate donor-specific blood transfusions prior to living-related renal transplantation
Ann Surg
Transplantation tolerance across major histocompatibility barriers after total lymphoid irradiation
Transplantation
Studies on heterologous antilymphocyte serum in mice: VII. Optimal cellular antigen for induction of immunologic tolerance with ALS
Transplant Proc
Enhanced survival of canine renal allografts of ALS-treated dogs given bone marrow
Transplant Proc
Cited by (37)
The Ethics of Hand Transplantation: A Systematic Review
2018, Journal of Hand SurgeryCitation Excerpt :Instead, we hope that by highlighting the work and discussions that have taken place during the past 25 years, we may further advance the discussion. Indeed, the field has survived many changes: from the early days when bilateral, distal forearm amputees were considered the only ethical candidates for transplantation1,28,57 to current, encouraging results demonstrated by proximal, above-elbow unilateral amputees67,71; from initial views on immunosuppression, which considered it impossible to manage VCA on regimens equivalent to those of kidney transplant patients7,10,29,68 to the implementation of immunosuppression minimization protocols that have made it possible to maintain allograft survival up to 7 years or more without evidence of long-term renal or other toxicity.53,72,73 Such advancements have shifted the risk-benefit ratio.
Anesthesia and Perioperative Care in Reconstructive Transplantation
2017, Anesthesiology ClinicsCitation Excerpt :This remains the longest surviving VCA in the world at 19 years after surgery.29 The Pittsburgh Protocol using donor bone marrow (DBM) cell infusion, was the world’s first successful implementation of an immunomodulatory therapy in clinical RT.30 The premise of the Pittsburgh Protocol is to use nonmyeloablative depletional conditioning with induction agents (eg, alemtuzumab) to eliminate alloreactive effector cells while preserving regulatory cells and creating a permissive window. Additionally, the non-T-cell–depleted DBM infusion (along with bone marrow stem cells) is aimed to accomplish clonal exhaustion-deletion of effector cells (coincident with the burst of donor antigen) and help in immunomodulation of the hyporesponsive recipient immune system under lower doses of maintenance therapy.
Novel cell-based strategies for immunomodulation in vascularized composite allotransplantation
2023, Current Opinion in Organ TransplantationNoninvasive evaluation of intragraft immune responses in upper extremity transplantation
2021, Transplant InternationalThe past the present and the future of face transplantation
2020, Current Opinion in Organ Transplantation