Favoring the risk-benefit balance for upper extremity transplantation--the Pittsburgh Protocol.

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. Routine applicability and widespread impact of such strategies for the upper extremity amputees with devastating limb loss could be enabled by implementation of cellular therapies that integrate and unify the concepts of transplant tolerance induction with those of reconstructive transplantation. Such therapies offer the promise of minimizing the risks, maximizing the benefits and optimizing outcomes of these innovative procedures.

[1]  B. Blomberg,et al.  Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation. , 2003, Transplant immunology.

[2]  R. Zinkernagel,et al.  Microchimerism maintains deletion of the donor cell-specific CD8+ T cell repertoire. , 2005, The Journal of clinical investigation.

[3]  C. Ricordi,et al.  Effect of living-related donor bone marrow infusion on chimerism and in vitro immunoregulatory activity in kidney transplant recipients. , 2002, Transplantation.

[4]  C. Ricordi,et al.  The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients. , 1997, The Journal of clinical investigation.

[5]  B. Griffith,et al.  Infusion of donor leukocytes to induce tolerance in organ allograft recipients , 1999, Journal of leukocyte biology.

[6]  Kimberly H. Quinn,et al.  Battlefield extremity injuries in Operation Iraqi Freedom. , 2009, Injury.

[7]  J. Woody,et al.  Harvest of human bone marrow directly from bone. , 1984, Journal of immunological methods.

[8]  C. Ricordi,et al.  The human bone marrow as an immunoregulatory organ. , 1999, Transplantation.

[9]  A. Abbas,et al.  The Roles of CD28 and CD40 Ligand in T Cell Activation and Tolerance1 , 2000, The Journal of Immunology.

[10]  A. Monaco,et al.  Possible active enhancement of a human cadaver renal allograft with antilymphocyte serum (ALS) and donor bone marrow: case report of an initial attempt. , 1976, Surgery.

[11]  P. Terasaki,et al.  Improvement of kidney-graft survival with increased numbers of blood transfusions. , 1978, The New England journal of medicine.

[12]  R. Colvin,et al.  Myeloma Responses and Tolerance Following Combined Kidney and Nonmyeloablative Marrow Transplantation: In Vivo and In Vitro Analyses , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  Paulo Fontes,et al.  Tolerogenic immunosuppression for organ transplantation , 2003, The Lancet.

[14]  S. Todo,et al.  Frequent achievement of a drug-free state after orthotopic liver transplantation. , 1993, Transplantation proceedings.

[15]  E. Engleman,et al.  Tolerance and chimerism after renal and hematopoietic-cell transplantation. , 2008, The New England journal of medicine.

[16]  R. Owen.  IMMUNOGENETIC CONSEQUENCES OF VASCULAR ANASTOMOSES BETWEEN BOVINE TWINS. , 1945, Science.

[17]  Frédéric Schuind,et al.  The International Registry on Hand and Composite Tissue Transplantation , 2010, Transplantation.

[18]  B. Portmann,et al.  Defining the outcome of immunosuppression withdrawal after liver transplantation , 1998, Hepatology.

[19]  A. Donnenberg,et al.  Development and validation of a procedure to isolate viable bone marrow cells from the vertebrae of cadaveric organ donors for composite organ grafting. , 2012, Cytotherapy.

[20]  J. Mathew,et al.  Immunoregulatory role of chimerism in clinical organ transplantation , 2001, Bone Marrow Transplantation.

[21]  A. Monaco,et al.  Studies on heterologous antilymphocyte serum in mice. VII. Optimal cellular antigen for induction of immunologic tolerance with antilymphocyte serum. , 1970, Transplantation proceedings.

[22]  T. Starzl,et al.  Cell migration and chimerism after whole‐organ transplantation: The basis of graft acceptance , 1993, Hepatology.

[23]  S. Schneeberger,et al.  Composite tissue allotransplantation: hand transplantation and beyond. , 2010, The Journal of the American Academy of Orthopaedic Surgeons.

[24]  J. Bluestone,et al.  Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance , 1985, The Journal of experimental medicine.

[25]  P. Medawar,et al.  Tolerance to homografts, twin diagnosis, and the freemartin condition in cattle , 1952, Heredity.

[26]  C. Ricordi,et al.  INVOLVEMENT OF MULTIPLE SUBPOPULATIONS OF HUMAN BONE MARROW CELLS IN THE REGULATION OF ALLOGENEIC CELLULAR IMMUNE RESPONSES1 , 2000, Transplantation.

[27]  J. Schold,et al.  The Success of Continued Steroid Avoidance After Kidney Transplantation in the US , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[28]  R. Ciubotariu,et al.  CD8+CD28− T suppressor cells and the induction of antigen‐specific, antigen‐presenting cell‐mediated suppression of Th reactivity , 2001, Immunological reviews.

[29]  C. Ricordi,et al.  In vitro immunogenicity of cadaver donor bone marrow cells used for the induction of allograft acceptance in clinical transplantation. , 1999, Transplantation.

[30]  J. García-Valdecasas,et al.  ATG‐Fresenius Treatment and Low‐Dose Tacrolimus: Results of a Randomized Controlled Trial in Liver Transplantation , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[31]  B. Julian,et al.  Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients. , 1991, Transplantation.

[32]  C. Dudley,et al.  Mycophenolate Mofetil Substitution for Cyclosporine A in Renal Transplant Recipients with Chronic Progressive Allograft Dysfunction: The “Creeping Creatinine” Study1 , 2005, Transplantation.

[33]  N. Jones,et al.  Concerns about human hand transplantation in the 21st century. , 2002, The Journal of hand surgery.

[34]  J. Levitsky.  Operational tolerance: Past lessons and future prospects , 2011, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[35]  P. Medawar,et al.  ‘Actively Acquired Tolerance’ of Foreign Cells , 1953, Nature.

[36]  A. Monaco,et al.  Use of allogenic, homozygous bone marrow cells for the induction of specific immunologic tolerance in mice treated with antilymphocyte serum. , 1970, Surgical forum.

[37]  B. Griffith,et al.  Chimerism and thoracic organ transplantation. , 1996, Seminars in thoracic and cardiovascular surgery.

[38]  T. Starzl,et al.  Weaning of immunosuppression in liver transplant recipients. , 1997, Transplantation.

[39]  P. Medawar,et al.  The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle , 1951, Heredity.

[40]  P. Terasaki,et al.  Bone marrow from cadaver donors for transplantation , 1985 .

[41]  T. Starzl,et al.  Hematopoietic progenitor cell content of vertebral body marrow used for combined solid organ and bone marrow transplantation. , 1995, Transplantation.

[42]  C. Ricordi,et al.  Continuing observations on the regulatory effects of donor-specific bone marrow cell infusions and chimerism in kidney transplant recipients. , 1998, Transplantation.

[43]  S. Lederman,et al.  Induction of MHC-class I restricted human suppressor T cells by peptide priming in vitro. , 1998, Human immunology.

[44]  M. Sayegh,et al.  A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. , 2006, Journal of the American Society of Nephrology : JASN.

[45]  A. Novick,et al.  Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine1 , 2002, Transplantation.

[46]  B. Griffith,et al.  Three years of follow-up of bone marrow-augmented organ transplant recipients: the impact on donor-specific immune modulation. , 1997, Transplantation proceedings.

[47]  S. Uemoto,et al.  WEANING OF IMMUNOSUPPRESSION IN LIVING DONOR LIVER TRANSPLANT RECIPIENTS1 , 2001, Transplantation.

[48]  C. Larsen,et al.  Microchimerism and rejection in clinical transplantation , 1997, The Lancet.

[49]  S. Ildstad,et al.  Is durable macrochimerism key to achieving clinical transplantation tolerance? , 2011, Current opinion in organ transplantation.

[50]  Kathryn Ziegler-Graham,et al.  Estimating the prevalence of limb loss in the United States: 2005 to 2050. , 2008, Archives of physical medicine and rehabilitation.

[51]  B. Nashan,et al.  MULTICENTER TRIAL EXPLORING CALCINEURIN INHIBITORS AVOIDANCE IN RENAL TRANSPLANTATION , 2001, Transplantation.

[52]  T. Starzl,et al.  Transplantation Milestones Viewed With One- and Two-Way Paradigms of Tolerance , 1995 .

[53]  C. Ricordi,et al.  Cellular immune responses of human cadaver donor bone marrow cells and their susceptibility to commonly used immunosuppressive drugs in transplantation. , 1998, Transplantation.

[54]  G. Opelz,et al.  Risks of allogeneic hand transplantation , 2004, Microsurgery.

[55]  J. Moon,et al.  Donor bone marrow infusion in deceased and living donor renal transplantation. , 2004, Yonsei medical journal.

[56]  J. Thomas,et al.  Renal allograft tolerance induced with ATG and donor bone marrow in outbred rhesus monkeys. , 1983, Transplantation.

[57]  T. Starzl,et al.  WEANING OF IMMUNOSUPPRESSION IN LONG-TERM LIVER TRANSPLANT RECIPIENTS , 1995 .

[58]  C. Ricordi,et al.  Analysis of post-transplant immune status in recipients of liver/bone marrow allografts. , 1999, Human immunology.

[59]  C. Ricordi,et al.  SIX-YEAR CLINICAL EFFECT OF DONOR BONE MARROW INFUSIONS IN RENAL TRANSPLANT PATIENTS1 , 2001, Transplantation.

[60]  G. Opelz,et al.  Influence of Immunosuppressive Regimens on Graft Survival and Secondary Outcomes After Kidney Transplantation , 2009, Transplantation.

[61]  J. Lemons,et al.  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. , 1995, Transplant immunology.

[62]  J. Moon,et al.  The Role of Donor Bone Marrow Infusions in Withdrawal of Immunosuppression in Adult Liver Allotransplantation , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[63]  C. Ricordi,et al.  Regulation of alloimmune responses (GvH reactions) in vitro by autologous donor bone marrow cell preparation used in clinical organ transplantation. , 2002, Transplantation.

[64]  T. Starzl,et al.  CHIMERISM AND DONOR‐SPECIFIC NONREACTIVITY 27 TO 29 YEARS AFTER KIDNEY ALLOTRANSPLANTATION , 1993, Transplantation.

[65]  D. Strong.  The US Navy Tissue Bank: 50 Years on the Cutting Edge , 2004, Cell and Tissue Banking.

[66]  M. Sayegh,et al.  Clinical Transplantation Tolerance: Many Rivers to Cross , 2007, The Journal of Immunology.

[67]  P. Halloran,et al.  Reduced exposure to calcineurin inhibitors in renal transplantation. , 2007, The New England journal of medicine.

[68]  G. McCaughan.  Withdrawal of immunosuppression in liver transplant recipients: Is this as good as it gets? , 2002, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[69]  D. Abramowicz,et al.  Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen: results of a five-year, prospective, randomized study. , 2005, Journal of the American Society of Nephrology : JASN.

[70]  T. Starzl,et al.  Transplantation tolerance from a historical perspective , 2001, Nature Reviews Immunology.

[71]  B. Blomberg,et al.  FoxP3 mRNA Transcripts and Regulatory Cells in Renal Transplant Recipients 10 Years After Donor Marrow Infusion , 2007, Transplantation.

[72]  V. Gorantla,et al.  Immunosuppressive agents in transplantation: Mechanisms of action and current anti‐rejection strategies , 2000, Microsurgery.

[73]  E. Schiff,et al.  Multiple Bone Marrow Infusions to Enhance Acceptance of Allografts from the Same Donor , 1995, Annals of the New York Academy of Sciences.

[74]  L. Turka,et al.  Lymphocyte depletion as a barrier to immunological tolerance. , 2005, Contributions to nephrology.

[75]  T. Larson,et al.  Complete Avoidance of Calcineurin Inhibitors in Renal Transplantation: A Randomized Trial Comparing Sirolimus and Tacrolimus , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[76]  S. Knight,et al.  Steroid Avoidance or Withdrawal After Renal Transplantation Increases the Risk of Acute Rejection but Decreases Cardiovascular Risk. A Meta-Analysis , 2010, Transplantation.

[77]  D. Sachs,et al.  Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen , 1989, The Journal of experimental medicine.

[78]  G. Loss,et al.  Tolerance: Is It Worth the Risk? , 2005, Transplantation.

[79]  A. Berrebi,et al.  Tolerance induction by "megadose" hematopoietic transplants: donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. , 1998, Transplantation.

[80]  R. Calne.  "Prope" tolerance: induction, lymphocyte depletion with minimal maintenance. , 2005, Transplantation.

[81]  R. Stoney,et al.  Deliberate Donor‐specific Blood Transfusions Prior to Living Related Renal Transplantation: A New Approach , 1980, Annals of surgery.

[82]  T. Starzl,et al.  Tolerance for organ recipients: A clash of paradigms , 2006, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[83]  C. Ricordi,et al.  Modulatory effects of human donor bone marrow cells on allogeneic cellular immune responses. , 1997, Transplantation.

[84]  J. Chapman,et al.  The natural history of chronic allograft nephropathy. , 2003, The New England journal of medicine.

[85]  G. Tisone,et al.  Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence. , 2006, Journal of hepatology.

[86]  D. Sachs,et al.  Chimerism and transplantation tolerance: cause and effect. , 1996, Immunology today.

[87]  E. Mackenzie,et al.  Limb Amputation and Limb Deficiency: Epidemiology and Recent Trends in the United States , 2002, Southern medical journal.

[88]  T. Starzl,et al.  Antigen localization and migration in immunity and tolerance. , 1998, The New England journal of medicine.

[89]  Z. Fuks,et al.  Transplantation tolerance across major histocompatibility barriers after total lymphoid irradiation. , 1979, Transplantation.

[90]  M. Kocova,et al.  MICROCHIMERISM LINKED TO CYTOTOXIC T LYMPHOCYTE FUNCTIONAL UNRESPONSIVENESS (CLONAL ANERGY) IN A TOLERANT RENAL TRANSPLANT RECIPIENT , 1995, Transplantation.

[91]  E. Woodle,et al.  A Prospective, Randomized, Double-Blind, Placebo-Controlled Multicenter Trial Comparing Early (7 Day) Corticosteroid Cessation Versus Long-Term, Low-Dose Corticosteroid Therapy , 2008, Annals of surgery.

[92]  F. Schena,et al.  Conversion From Calcineurin Inhibitors to Sirolimus Maintenance Therapy in Renal Allograft Recipients: 24-Month Efficacy and Safety Results From the CONVERT Trial , 2009, Transplantation.

[93]  A. Monaco,et al.  Enhanced survival of canine renal allografts of ALS- treated dogs given bone marrow. , 1973, Transplantation proceedings.

[94]  S. Pham,et al.  Simultaneous donor bone marrow and cardiac transplantation: can tolerance be induced with the development of chimerism? , 1999, Current opinion in cardiology.