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Out on a Limb with Composite Tissue Allografts: Expanding the Immunology Toolbox

Csete, Marie MD, PhD

doi: 10.1213/ANE.0b013e3182632bf3
Editorials: Editorial

From the Department of Anesthesiology, University of California San Diego, San Diego, California.

The author declares no conflicts of interest.

Reprints will not be available from the author.

Address correspondence to Marie Csete, MD, PhD, Department of Anesthesiology, University of California San Diego, 200 W. Arbor Dr., San Diego, CA 92103. Address e-mail to

Accepted June 4, 2012

“… And the narrowest hinge in my hand puts to scorn all machinery …”

—From Walt Whitman's Song of Myself

In this issue of the Journal, 2 papers take us to the cutting edge of medical technology, the vascularized composite tissue allotransplant (CTA), performed at only a few centers in the United States1,2 (Europe was ahead of this particular curve for both limb and face CTA, with Louisville the early adopter in the United States). Although most anesthesiologists will not be responsible for CTA patients, the advances that facilitated transplantation of upper and lower extremities and faces will affect all of organ transplantation.

Both papers point to the importance of anesthesiologist input into protocol planning and critical analysis of each patient after each CTA transplant. Inclusion of anesthesiologists upfront is gratifying to witness, as the value of anesthesiologists at the cutting edge of liver transplantation, for example, was formally acknowledged only in retrospect by our surgical colleagues. It is also great to see anesthesiologists sharing and comparing their protocols early in the history of CTA, a healthy practice, and again a contrast with liver transplantation for which collaborative, multicenter studies by transplant anesthesia groups are all too rare. Nonetheless, anesthesiologists have been a critical part of optimizing care of solid organ transplant patients, and progress in solid organ transplantation is the major foundation from which CTAs were launched.

Focus on composite tissue allografts is timely: Soldiers sent to the Iraq and Afghanistan wars suffered higher rates of amputations than in previous wars, with approximately 1500 amputees from Iraq and Afghanistan now home for rehabilitation. These wars are not the first to prompt reviews about the potential for limb transplantation. An assessment of technical hurdles for limb transplantation in 1944 was prescient in many ways but underestimated the alloimmune response.3 Many years on from this work, the absolute requirement for pharmacologic immunosuppression is the consensus major hurdle to wider application of CTA. From the dozens of CTA recipients to date, it is clear that triple drug immunosuppression facilitates long-term graft survival, but the cost is high in terms of well-known complications of infection, end-organ (particularly kidney) toxicity, and neoplasia.

Pittsburgh's approach to immunosuppression1 is new and somewhat chancy. Avoiding the “surer thing” of triple drug immunosuppression, the team opted instead for an induction regimen, donor marrow infusion after transplantation, and single-drug maintenance immunosuppression, highlighting some of the new tools in the immunosuppression toolbox. Induction therapy is directed at depleting recipient lymphocytes at the time of transplantation to prevent acute rejection, here with alemtuzumab, a monoclonal antibody (against CD52) that depletes T, B, and NK cells. Tacrolimus, a calcineurin inhibitor, was likely chosen as the single maintenance drug in part because it can promote nerve regeneration,4 which is critical to graft function.

The use of donor marrow in the setting of transplantation is a very hot area now, with a long-term goal of donor-specific tolerance. The experience with solid organ transplantation once again is the basis for confidence in this approach for CTA. A 2008 study in kidney transplant patients, under auspices of the Immune Tolerance Network, showed that in combination with induction therapy and thymus irradiation, transient chimerism after infusion of the kidney donor's marrow could lead to functional kidney graft tolerance despite human leukocyte antigen (HLA) mismatch.5 In this small study, the major upsides of the transient chimerism were no apparent graft-versus-host disease, and no requirement for myeloablative preparation for marrow transplantation. It is important to note that transient chimerism was not detected in the Pittsburgh CTA recipients, such that the potential benefit of the marrow transplant in these patients is not clear. Recently, another group reported that long-term full multilineage chimerism supporting kidney graft tolerance was achievable after marrow transplantation (marrow donated by the kidney donor). In these patients, the conditioning regimen was total body irradiation (200 Gy), fludarabine, and cyclophosphamide. The marrow-derived cells included hematopoietic stem cells and a “facilitating cell” type that was not fully disclosed by the authors.6 A surprising result in these patients was that chimerism was associated with increased numbers of T regulatory cells in the graft, suggesting that a peripheral tolerance mechanism was induced, in addition to the anticipated central deletion mechanism (elimination of cells reactive to donor antigen in the thymus). Bottom line, these 2 studies put allotransplantation tantalizingly close to the “Holy Grail” of transplant tolerance, at least for some kidney recipients.

Antiinflammatory stem cells (mesenchymal stem cells [MSCs] and multipotent adult progenitor cells) are also in clinical trials as adjuncts to kidney, islet, and liver transplantation and for treatment of graft-versus-host disease. MSCs are adult stem cells, activated in inflammatory environments to produce a variety of antiinflammatory mediators as well as a variety of growth factors.7 The advantage of allogeneic MSCs is that they do not elicit cytotoxic alloreactivity, and they have been administered to thousands of patients without major side effects. So third-party MSCs (not donor, not recipient) can be used off-the-shelf and their use in many inflammatory disease processes is spreading quickly, although often in unregulated settings. For clinical trials in transplant recipients, the use of MSCs is targeted at reducing the amount of pharmacologic immunosuppression needed in the immediate posttransplant period, because the cells do not permanently engraft.

One amazing feature of the Pittsburgh success is the age of the CTA recipients. Aging is an inflammatory state, and nerve regeneration capacity diminishes dramatically with age, 2 important strikes against older CTA recipients. The young immune system with less complement and antibody production, less cytokine production after mitogen stimulation, with phenotypically immature thymocytes and fewer NK cells, is more conducive to tolerance induction than the adult immune system.8 Patients who receive liver transplants at a very young age can often be weaned from immunosuppression without a marrow transplant. Of 20 selected stable liver transplant recipients who received living related grafts at a mean age of 7 months, 12 had functional graft tolerance after weaning from immunosuppressive drugs.9 In this study, sensitization status, donor-specific antibodies, and HLA mismatch were not factors in tolerance induction, but prolonged stable graft function preceding immunosuppression withdrawal was considered important, implying that many years of immunosuppression would have to be endured before withdrawal of immunosuppression should be attempted. International clinical experience confirms that the potential for adults to achieve tolerance of their liver grafts after immunosuppression withdrawal is significantly less than that for pediatric populations.

Will tolerance ever be achievable for vascularized composite tissue allografts? The Pittsburgh paper describes skin as the most antigenic tissue, as noted by the Nobel laureate Joseph Murray,10 raising the bar for functional tolerance of CTA grafts. However, this assumption has been challenged by the small experience with CTA. Skin may not be the major fuel for the immunogenic fire when it is part of a composite graft, and vascular rejection may predominate in at least some CTA recipients.11

All of this talk of immunology, tolerance, and stem cells is foreign territory to most anesthesiologists. (Frankly, I think that immunology is foreign territory to most biologists, and immunologists seem to speak an untranslatable language.) But anesthesiologists have surprising territorial overlap with immunologists, and so, the potential to enter a dialog at this pivotal time in the history of transplantation. Our care of transplant patients starts with donor management. Many prominent anesthesiology labs are devoted to the study of ischemia-reperfusion injury and how anesthetics can be used to manipulate the injury. The ischemia-reperfusion injury of organ donation is associated with upregulation of HLA antigen in the retrieved grafts,12 potentially an important target for anesthetic or other drug interventions. MSCs are now being investigated by several anesthesiology researchers for analgesic effects of the cells in the setting of chronic pain. Characterization of the contribution of the immune system to chronic pain in a variety of models and the mechanisms by which MSCs turn down the immune response in pain states could also provide important insights into the utility of MSCs in the setting of organ transplantation.

The importance of the anesthesiologist as perioperative physician is exemplified by the authors of the CTA reports in this issue of Anesthesia & Analgesia. They deserve resounding congratulations for their care of complex patients built on long experience in solid organ transplantation, and for reminding us of exciting new challenges to our specialty.

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Dr. Marie Csete is the Section Editor for Book, Multimedia, and Meeting Reviews for the Journal. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Csete was not involved in any way with the editorial process or decision.

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Name: Marie Csete, MD, PhD.

Contribution: This author conceived and wrote the manuscript.

Attestation: Marie Csete approved the final manuscript.

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© 2012 International Anesthesia Research Society