Favoring the Risk–Benefit Balance for Upper Extremity Transplantation—The Pittsburgh Protocol

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