- About this Journal
- Abstracting and Indexing
- Aims and Scope
- Annual Issues
- Article Processing Charges
- Articles in Press
- Author Guidelines
- Bibliographic Information
- Citations to this Journal
- Contact Information
- Editorial Board
- Editorial Workflow
- Free eTOC Alerts
- Publication Ethics
- Reviewers Acknowledgment
- Submit a Manuscript
- Subscription Information
- Table of Contents
Clinical and Developmental Immunology
Volume 2012 (2012), Article ID 863264, 8 pages
Tolerance Induction Strategies in Vascularized Composite Allotransplantation: Mixed Chimerism and Novel Developments
1Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA
2Department of Plastic and Reconstructive Surgery Research, University of Manchester, Manchester, UK
3Biology Department, Emmanuel College, Boston, MA, USA
Received 1 July 2012; Revised 6 November 2012; Accepted 3 December 2012
Academic Editor: Gerald Brandacher
Copyright © 2012 David A. Leonard et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
- T. Gibson and P. B. Medawar, “The fate of skin homografts in man,” Journal of Anatomy, vol. 77, pp. 299–310, 1943.
- M. Siemionow and A. Klimczak, “Advances in the development of experimental composite tissue transplantation models,” Transplant International, vol. 23, no. 1, pp. 2–13, 2010.
- E. Morelon, J. Kanitakis, and P. Petruzzo, “Immunological issues in clinical composite tissue allotransplantation: where do we stand today?” Transplantation, vol. 93, no. 9, pp. 855–859, 2012.
- E. A. Kouwenhoven, J. N. M. IJzermans, and R. W. F. de Bruin, “Etiology and pathophysiology of chronic transplant dysfunction,” Transplant International, vol. 13, no. 6, pp. 385–401, 2000.
- P. Petruzzo, J. Kanitakis, L. Badet et al., “Long-term follow-up in composite tissue allotransplantation: in-depth study of five (hand and face) recipients,” American Journal of Transplantation, vol. 11, no. 4, pp. 808–816, 2011.
- V. S. Gorantla and A. J. Demetris, “Acute and chronic rejection in upper extremity transplantation: what have we learned?” Hand Clinics, vol. 27, no. 4, pp. 481–493, 2011.
- D. H. Sachs, “Tolerance: of mice and men,” Journal of Clinical Investigation, vol. 111, no. 12, pp. 1819–1821, 2003.
- N. Pilat, K. Hock, and T. Wekerle, “Mixed chimerism through donor bone marrow transplantation: a tolerogenic cell therapy for application in organ transplantation,” Current Opinion in Organ Transplantation, vol. 17, no. 1, pp. 63–70, 2012.
- R. D. Owen, “Immunogenetic consequences of vascular anastomoses between bovine twins,” Science, vol. 102, no. 2651, pp. 400–401, 1945.
- M. Sykes and D. H. Sachs, “Mixed chimerism,” Philosophical Transactions of the Royal Society of London. Series B, vol. 356, no. 1409, pp. 707–726, 2001.
- S. T. Ildstad, S. M. Wren, and J. A. Bluestone, “Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance,” Journal of Experimental Medicine, vol. 162, no. 1, pp. 231–244, 1985.
- M. Sykes, “Mixed chimerism and transplant tolerance,” Immunity, vol. 14, no. 4, pp. 417–424, 2001.
- N. Pilat and T. Wekerle, “Transplantation tolerance through mixed chimerism,” Nature Reviews Nephrology, vol. 6, no. 10, pp. 594–605, 2010.
- S. T. Ildstad and D. H. Sachs, “Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of alllografts or xenografts,” Nature, vol. 307, no. 5947, pp. 168–170, 1984.
- Y. Sharabi and D. H. Sachs, “Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen,” Journal of Experimental Medicine, vol. 169, no. 2, pp. 493–502, 1989.
- C. A. Huang, Y. Fuchimoto, R. Scheier-Dolberg, M. C. Murphy, D. M. Neville, and D. H. Sachs, “Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large-animal model,” Journal of Clinical Investigation, vol. 105, no. 2, pp. 173–181, 2000.
- T. R. Spitzer, F. Delmonico, N. Tolkoff-Rubin et al., “Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism,” Transplantation, vol. 68, no. 4, pp. 480–484, 1999.
- T. Wekerle, J. Kurtz, M. H. Sayegh et al., “Peripheral deletion after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death,” Journal of Immunology, vol. 166, no. 4, pp. 2311–2316, 2001.
- C. Domenig, A. Sanchez-Fueyo, J. Kurtz et al., “Roles of deletion and regulation in creating mixed chimerism and allograft tolerance using a nonlymphoablative irradiation-free protocol,” Journal of Immunology, vol. 175, no. 1, pp. 51–60, 2005.
- J. Kurtz, H. Ito, T. Wekerle, J. Shaffer, and M. Sykes, “Mechanisms involved in the establishment of tolerance through costimulatory blockade and BMT: lack of requirement for CD40L-mediated signaling for tolerance or deletion of donor-reactive CD4+ cells,” American Journal of Transplantation, vol. 1, no. 4, pp. 339–349, 2001.
- J. Kurtz, T. Wekerle, and M. Sykes, “Tolerance in mixed chimerism: a role for regulatory cells?” Trends in Immunology, vol. 25, no. 10, pp. 518–523, 2004.
- T. Wekerle, J. Kurtz, H. Ito et al., “Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment,” Nature Medicine, vol. 6, no. 4, pp. 464–469, 2000.
- T. Wekerle, M. H. Sayegh, J. Hill et al., “Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance,” Journal of Experimental Medicine, vol. 187, no. 12, pp. 2037–2044, 1998.
- T. Kawai, A. B. Cosimi, R. B. Colvin et al., “Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys,” Transplantation, vol. 59, no. 2, pp. 256–262, 1995.
- T. Kawai, A. B. Cosimi, T. R. Spitzer et al., “HLA-mismatched renal transplantation without maintenance immunosuppression,” The New England Journal of Medicine, vol. 358, no. 4, pp. 353–361, 2008.
- J. Leventhal, M. Abecassis, J. Miller et al., “Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation,” Science Translational Medicine, vol. 4, no. 124, Article ID 124ra28, 2012.
- D. W. Mathes, M. A. Randolph, M. G. Solari et al., “Split tolerance to a composite tissue allograft in a swine model,” Transplantation, vol. 75, no. 1, pp. 25–31, 2003.
- S. Hettiaratchy, E. Melendy, M. A. Randolph et al., “Tolerance to composite tissue allografts across a major histocompatibility barrier in miniature swine,” Transplantation, vol. 77, no. 4, pp. 514–521, 2004.
- B. M. Horner, M. A. Randolph, R. Duran-Struuck et al., “Induction of tolerance to an allogeneic skin flap transplant in a preclinical large animal model,” Transplantation Proceedings, vol. 41, no. 2, pp. 539–541, 2009.
- J. E. Murray, “Organ transplantation (skin, kidney, heart) and the plastic surgeon,” Plastic and Reconstructive Surgery, vol. 47, no. 5, pp. 425–431, 1971.
- W. P. A. Lee, J. P. Rubin, J. L. Bourget et al., “Tolerance to limb tissue allografts between swine matched for major histocompatibility complex antigens,” Plastic and Reconstructive Surgery, vol. 107, no. 6, pp. 1482–1490, 2001.
- R. E. Billingham and W. K. Silvers, “The induction of tolerance of skin homografts in rats with pooled cells from multiple donors,” Journal of Immunology, vol. 83, pp. 667–679, 1959.
- B. M. Horner, M. A. Randolph, C. A. Huang, and P. E. M. Butler, “Skin tolerance: in search of the Holy Grail,” Transplant International, vol. 21, no. 2, pp. 101–112, 2008.
- D. Steinmuller, “The enigma of skin allograft rejection,” Transplantation Reviews, vol. 12, no. 1, pp. 42–57, 1998.
- L. J. Perloff and C. F. Barker, “The immediately vascularized skin allograft,” Transplantation, vol. 28, no. 2, pp. 125–130, 1979.
- K. Wood and D. H. Sachs, “Chimerism and transplantation tolerance: cause and effect,” Immunology Today, vol. 17, no. 12, pp. 584–587, 1996.
- E. T. Elwood, C. P. Larsen, D. H. Maurer et al., “Microchimerism and rejection in clinical transplantation,” The Lancet, vol. 349, no. 9062, pp. 1358–1360, 1997.
- D. W. Mathes, B. Hwang, S. S. Graves et al., “Tolerance to vascularized composite allografts in canine mixed hematopoietic chimeras,” Transplantation, vol. 92, no. 12, pp. 1301–1308, 2011.
- P. J. Kilshaw, L. Brent, and M. Pinto, “Suppressor T cells in mice made unresponsive to skin allografts,” Nature, vol. 255, no. 5508, pp. 489–491, 1975.
- R. K. Gershon, S. Liebhaber, and S. Ryu, “T cell regulation of T cell responses to antigen,” Immunology, vol. 26, no. 5, pp. 909–923, 1974.
- S. Sakaguchi, M. Miyara, C. M. Costantino, and D. A. Hafler, “FOXP3+ regulatory T cells in the human immune system,” Nature Reviews Immunology, vol. 10, no. 7, pp. 490–500, 2010.
- O. Joffre, T. Santolaria, D. Calise et al., “Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes,” Nature Medicine, vol. 14, no. 1, pp. 88–92, 2008.
- O. Joffre, N. Gorsse, P. Romagnoli, D. Hudrisier, and J. P. M. Van Meerwijk, “Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes,” Blood, vol. 103, no. 11, pp. 4216–4221, 2004.
- S. Bigenzahn, P. Blaha, Z. Koporc et al., “The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade,” American Journal of Transplantation, vol. 5, no. 6, pp. 1237–1247, 2005.
- N. Pilat, U. Baranyi, C. Klaus et al., “Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning,” American Journal of Transplantation, vol. 10, no. 4, pp. 751–762, 2010.
- M. Battaglia, A. Stabilini, and M. G. Roncarolo, “Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells,” Blood, vol. 105, no. 12, pp. 4743–4748, 2005.
- F. Issa, J. Hester, R. Goto, S. N. Nadig, T. E. Goodacre, and K. Wood, “Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model,” Transplantation, vol. 90, no. 12, pp. 1321–1327, 2010.
- P. Hoffmann, J. Ermann, M. Edinger, C. Garrison Fathman, and S. Strober, “Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation,” Journal of Experimental Medicine, vol. 196, no. 3, pp. 389–399, 2002.
- P. A. Taylor, C. J. Lees, and B. R. Blazar, “The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality,” Blood, vol. 99, no. 10, pp. 3493–3499, 2002.
- R. M. Steinman, “The control of immunity and tolerance by dendritic cells,” Pathologie Biologie, vol. 51, no. 2, pp. 59–60, 2003.
- A. E. Morelli and A. W. Thomson, “Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction,” Immunological Reviews, vol. 196, pp. 125–146, 2003.
- D. H. Munn, M. D. Sharma, and A. L. Mellor, “Ligation of B7-1/B7-2 by human CD4+ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells,” Journal of Immunology, vol. 172, no. 7, pp. 4100–4110, 2004.
- Z. Fehérvári and S. Sakaguchi, “Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells,” International Immunology, vol. 16, no. 12, pp. 1769–1780, 2004.
- S. M. Barratt-Boyes and A. W. Thomson, “Dendritic cells: tools and targets for transplant tolerance,” American Journal of Transplantation, vol. 5, no. 12, pp. 2807–2813, 2005.
- U. Grohmann, R. Bianchi, C. Orabona et al., “Functional plasticity of dendritic cell subsets as mediated by CD40 versus B7 activation,” Journal of Immunology, vol. 171, no. 5, pp. 2581–2587, 2003.
- G. T. Belz, W. R. Heath, and F. R. Carbone, “The role of dendritic cell subsets in selection between tolerance and immunity,” Immunology and Cell Biology, vol. 80, no. 5, pp. 463–468, 2002.
- M. Garrovillo, A. Ali, H. A. Depaz et al., “Induction of transplant tolerance with immunodominant allopeptide-pulsed host lymphoid and myeloid dendritic cells,” American Journal of Transplantation, vol. 1, no. 2, pp. 129–137, 2001.
- Y. R. Kuo, C. W. Huang, S. Goto et al., “Alloantigen-pulsed host dendritic cells induce T-cell regulation and prolong allograft survival in a rat model of hindlimb allotransplantation,” Journal of Surgical Research, vol. 153, no. 2, pp. 317–325, 2009.
- J. M. Sacks, Y. R. Kuo, A. Taieb et al., “Prolongation of composite tissue allograft survival by immature recipient dendritic cells pulsed with donor antigen and transient low-dose immunosuppression,” Plastic and Reconstructive Surgery, vol. 121, no. 1, pp. 37–49, 2008.
- E. K. Horibe, J. Sacks, J. Unadkat et al., “Rapamycin-conditioned, alloantigen-pulsed dendritic cells promote indefinite survival of vascularized skin allografts in association with T regulatory cell expansion,” Transplant Immunology, vol. 18, no. 4, pp. 307–318, 2008.
- R. Ikeguchi, J. M. Sacks, J. V. Unadkat et al., “Long-term survival of limb allografts induced by pharmacologically conditioned, donor alloantigen-pulsed dendritic cells without maintenance immunosuppression,” Transplantation, vol. 85, no. 2, pp. 237–246, 2008.
- H. R. Turnquist, G. Raimondi, A. F. Zahorchak, R. T. Fischer, Z. Wang, and A. W. Thomson, “Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance,” Journal of Immunology, vol. 178, no. 11, pp. 7018–7031, 2007.
- P. Yu, S. Xiong, Q. He et al., “Induction of allogeneic mixed chimerism by immature dendritic cells and bone marrow transplantation leads to prolonged tolerance to major histocompatibility complex disparate allografts,” Immunology, vol. 127, no. 4, pp. 500–511, 2009.
- A. F. Zahorchak, L. S. Kean, D. Tokita et al., “Infusion of stably immature monocyte-derived dendritic cells plus CTLA4Ig modulates alloimmune reactivity in rhesus macaques,” Transplantation, vol. 84, no. 2, pp. 196–206, 2007.
- M. V. Dhodapkar and R. M. Steinman, “Antigen-bearing immature dendritic cells induce peptide-specific CD8+ regulatory T cells in vivo in humans,” Blood, vol. 100, no. 1, pp. 174–177, 2002.
- M. V. Dhodapkar, R. M. Steinman, J. Krasovsky, C. Munz, and N. Bhardwaj, “Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells,” Journal of Experimental Medicine, vol. 193, no. 2, pp. 233–238, 2001.
- A. W. Thomson, J. M. Sacks, Y. R. Kuo et al., “Dendritic cell therapy in composite tissue allotransplantation,” Transplantation Proceedings, vol. 41, no. 2, pp. 537–538, 2009.
- R. J. Deans and A. B. Moseley, “Mesenchymal stem cells: biology and potential clinical uses,” Experimental Hematology, vol. 28, no. 8, pp. 875–884, 2000.
- F. Dazzi, R. Ramasamy, S. Glennie, S. P. Jones, and I. Roberts, “The role of mesenchymal stem cells in haemopoiesis,” Blood Reviews, vol. 20, no. 3, pp. 161–171, 2006.
- M. K. Majumdar, M. Keane-Moore, D. Buyaner et al., “Characterization and functionality of cell surface molecules on human mesenchymal stem cells,” Journal of Biomedical Science, vol. 10, no. 2, pp. 228–241, 2003.
- S. Glennie, I. Soeiro, P. J. Dyson, E. W. F. Lam, and F. Dazzi, “Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells,” Blood, vol. 105, no. 7, pp. 2821–2827, 2005.
- M. Krampera, S. Glennie, J. Dyson et al., “Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide,” Blood, vol. 101, no. 9, pp. 3722–3729, 2003.
- P. Sbano, A. Cuccia, B. Mazzanti et al., “Use of donor bone marrow mesenchymal stem cells for treatment of skin allograft rejection in a preclinical rat model,” Archives of Dermatological Research, vol. 300, no. 3, pp. 115–124, 2008.
- A. Bartholomew, C. Sturgeon, M. Siatskas et al., “Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo,” Experimental Hematology, vol. 30, no. 1, pp. 42–48, 2002.
- O. Ringdén, M. Uzunel, I. Rasmusson et al., “Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease,” Transplantation, vol. 81, no. 10, pp. 1390–1397, 2006.
- H. Pan, K. Zhao, L. Wang et al., “Mesenchymal stem cells enhance the induction of mixed chimerism and tolerance to rat hind-limb allografts after bone marrow transplantation,” Journal of Surgical Research, vol. 160, no. 2, pp. 315–324, 2010.
- Y. R. Kuo, S. Goto, H. S. Shih et al., “Mesenchymal stem cells prolong composite tissue allotransplant survival in a swine model,” Transplantation, vol. 87, no. 12, pp. 1769–1777, 2009.
- S. Schneeberger, V. S. Gorantla, G. Brandacher et al., “Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression,” Annals of Surgery, 2012.
- J. Bolaños-Meade, E. J. Fuchs, L. Luznik et al., “HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease,” Blood, vol. 120, no. 22, pp. 4285–4291, 2012.