REVIEW URRENT C OPINION
Novel immunosuppressive strategies for composite tissue allografts Aditi Gupta a, Sean Kumer b, and Bruce Kaplan c
Purpose of review Vascularized composite tissue allografts (CTAs) provide excellent restorative options for patients with limb loss and other deformities. Acute rejection remains common with CTA and immunosuppression is used in an attempt to prevent rejection. This has created ethical debates regarding the use of intensive immunosuppression for a nonlife-saving procedure. This highlights the need for newer immunosuppressive strategies for CTA, which are described in this review. Recent findings Recent studies have looked into immunomodulation and tolerance to decrease toxicity of immunosuppression. Both strategies have had some success but have their own limitations. Although immunomodulation and decrease in immunosuppression decreases toxicity, it has been associated with higher rates of rejection. Induction of tolerance has achieved some initial success, but the initial conditioning regimens are associated with significant morbidity. Summary Although recent advancements have been made in the immunosuppressive strategies in CTA, the ideal immunosuppression strategy with low toxicity and infection risk but with the ability to prevent acute and chronic rejection is yet to be discovered. Keywords composite tissue, hand transplantation, haemopoietic stem cell transplantation, rejection, tolerance
INTRODUCTION The first documented attempt at vascularized composite tissue allografts (CTAs) was an upper limb transplant in Ecuador in 1964 [1]. The patient’s graft had a severe episode of rejection and the patient’s forearm had to be removed. The immunosuppression strategy used was azathioprine and prednisone, a regimen that was yielding approximately 40% 1-year kidney graft survival at that time. Due to experimental data implying greater antigenicity of skin than solid organs, repeated failures of CTA in animal models, and the rather nonspecific and less than optimally efficacious immunosuppressive regimens available, further clinical efforts in this area were abandoned. With improved success in transplantation after the introduction of cyclosporine A in the early 1980s followed by tacrolimus and mycophenolic acid (MPA) in 1990s, hand transplantation was revisited. The first successful hand transplant was done in Lyon, France, in 1998 [2] and in the USA in 1999 [3]. This was followed by the first bilateral hand CTA in Lyon in 2000 [1]. Transplantation of other tissues was also attempted. The first successful laryngotracheal transplant was done in www.co-transplantation.com
the USA in 1988, first knee transplant in Germany in 1994, first face transplant in France in 2005 [4] and the first full face transplant in Spain in 2010 [5]. The pace and interest in CTA have picked up in the last two decades with involvement of multiple transplant centres [6]. To date, more than 70 hand transplants have been performed across the world and more than 150 CTAs. CTA forms an excellent restorative option for patients with limb loss and other disfigurements not correctable with staged reconstructive techniques or prosthesis. It offers better quality of life, functional and aesthetic results than conventional treatments [7].
a Department of Nephrology, bDepartment of Surgery, Center for Transplantation and cUniversity of Kansas Medical Center, Kansas City, Kansas, USA
Correspondence to Aditi Gupta, MD, Division of Nephrology and Hypertension, Mail Stop 3002, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. Tel: +1 913 588 6048; fax: +1 913 588 3867; e-mail: agupta@ kumc.edu Curr Opin Organ Transplant 2014, 19:552–557 DOI:10.1097/MOT.0000000000000135 Volume 19 Number 6 December 2014
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Novel immunosuppressive strategies Gupta et al.
KEY POINTS
experiencing at least one episode of acute rejection in the first year [6], and the major affected tissue being the skin [11 ]. Animal models have demonstrated ‘split tolerance’ with simultaneous acceptance of other tissues with rejection of skin or epidermis from the same donor [12] illustrating the difficulty in surpassing skin antigenicity. In spite of the high cellular mediated rejection seen in the skin of CTAs, there is no reported graft loss secondary to it. The explanation for this may lie in the natural defense mechanism of the skin. The high antigenicity of the skin has been attributed to the large number of T cells, especially memory T cells in normal skin [13]. These memory cells do not recirculate but persist indefinitely, providing immunity, which accumulates over time with repeated infections. This adaptive mechanism carries a doubleedged sword of helping to prevent pathogens from causing damage and also creating a positive feedback loop in terms of antigenicity [14,15]. However, full thickness skin with all its underlying tissues as opposed to a simple skin graft harbours antigenpresenting cells (APCs) such as Langerhans’ cells, which regulate and maintain immune homeostasis by activating resident regulatory T cells (Tregs) [16]. Human Tregs have been shown to prevent vascular changes seen in chronic rejection and induce tolerance in human skin allografts [17]. This modulation by underlying tissue may help explain the relative success of CTA as opposed to skin alone. Corticosteroid treatment increases Tregs via increase in production of transforming growth factor-beta (TGF-b) by Langerhans cells, explaining why topical steroids may be effective in the treatment of acute rejection [18]. &
Both acute and chronic rejections are common in CTA and chronic immunosuppression is used to prevent rejection and prolong graft survival. Immunosuppression in CTA is currently based on protocols derived from other solid organ transplants. Newer immunosuppressive strategies included immunomodulation and tolerance induction. There has been some success with tolerance induction and chimerism, but morbidity associated with the initial conditioning regimen remains a concern. As current immunosuppression is associated with significant side effects, there is an ongoing search for the ideal immunosuppression strategy, one with low toxicity yet effective in preventing rejection.
Outcomes of CTA have been comparable with other transplants with a 1-year patient and graft survival of 100 and 96%, respectively [8]. However, acute rejection rates are still very high, potentially posing a risk for future chronic rejection and shortened graft survival. To overcome this risk, long-term immunosuppression must be kept adequate with the hope of maintaining CTA at an optimal functional level. The side effects of immunosuppression are well known and can range from metabolic complications to opportunistic infections. These concerns have led to ethical debates as to whether the risks of immunosuppression outweigh the benefits accrued by the procedure. CTA is not a life-saving procedure, and in fact, the immunosuppression that must accompany CTA may in fact potentially shorten longevity. Thus, there is a pressing need to develop less toxic immunosuppressive strategies in CTA.
IMMUNOLOGIC BARRIERS Over the years, our understanding of immunologic barriers to CTA has advanced significantly. Unlike solid organ transplants, CTA involves grafting of heterogeneous tissue types with different antigenicity with each tissue evoking a distinct immune response. Skin and vessels seem to be the major immunologic challenges [7] and elicit both cellular and humoral responses. There seems to be a lower rate of antibody-mediated rejection (AMR) in CTAs. In over 150 CTAs completed spanning 15 years, there are only two reports of AMR [9 ,10 ] and these rejection episodes did not result in loss of the graft. In contrast, cellular rejection is a common occurrence in CTA with 85–90% of all hand allografts &
&
REJECTION Three mechanisms have been described for triggering allorecognition and T-cell activation needed for skin rejection: first, direct interaction of recipient T-cell receptors with intact major histocompatibility complex (MHC) presented by APCs; second, indirect allorecognition of recipient T cells with recipient APCs presenting processed donor MHC; and third, semi-direct interaction of recipient T cells with recipient APCs carrying intact donor MHC peptide complexes. Other factors such as ischemia reperfusion injury, immunosuppression and infectious complications also modify immunologic mechanisms. Rejection is diagnosed with punch skin biopsies, as it is expected that skin would be the first and most common tissue to reject. The grading of histological rejection is done with the Banff Criteria [19,20]. It is difficult to predict the stage and prognosis of
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rejection with biopsies alone as shown in a recent study [21], and the treatment of rejection is largely based on the clinical presentation and the current level of immunosuppression. Usually, rejection is treated with various combinations of steroid boluses, increase in maintenance immunosuppression, antithymocyte globulin and topical tacrolimus and corticosteroids [22–25]. Extracorporeal photopheresis was also tried in acute rejection in CTA with concomitant cytomegalovirus infection [26]. Successful treatment of AMR in the first presensitized recipient of a full face transplant was recently reported [10 ]. Chronic rejection, thought to be less common than acute rejection and less frequent than in solid organ transplant [27], is now being recognized in more CTAs [28]. Chronic rejection presents with transplant vasculopathy manifested by neointimal proliferation of arterioles, vessel wall fibrosis, progressive luminal occlusion, tertiary lymphoid follicles along with skin and muscular atrophy, nail changes and fibrosis of deeper tissue [29 ]. Immunosuppression with mammalian target of rapamycin (mTOR) inhibitors has also been tried with CTA in hope of preventing chronic rejection. Rapamycin has shown to facilitate selective expansion of Tregs and inhibiting clonal proliferation of effector cells [30]. Management of chronic rejection is still in its infancy, and overall, low total numbers in CTA has limited the research in this area. &
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STRATEGIES IN IMMUNOSUPPRESSION Immunosuppression concepts and protocols in CTAs have essentially been derived from experience in solid organ transplants with overall immunosuppression similar or slightly greater than that used in renal transplantation [31]. Similar to other organ transplantation, there are centre-to-centre variations [6]. Typical immunosuppression protocols include induction immunosuppression with antithymocyte globulin (thymoglobulin), anti-interleukin 2 (IL-2) receptor mAbs (daclizumab and basiliximab) or anti-CD52 mAbs (campath-1H). Thymoglobulin is a polyclonal antibody against multiple T-cell antigens. For induction, typically 5–6 mg/kg body weight of thymoglobulin is administered in three to five divided doses. Thymoglobulin results in depletion of lymphocytes by complement-mediated cell lysis and uptake of opsonized cells. Its administration can be complicated with a cytokine release syndrome with fever, chills, rash, anaemia, thrombocytopenia and serum sickness. Basiliximab and daclizumab are chimeric murine/human mAb preparations that bind specifically to the alpha subunit of the IL-2 receptor on activated T cells and 554
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inhibit IL-2-mediated proliferation and differentiation of T cells, without depleting them. Basiliximab is infused intraoperatively and on the fourth posttransplant day at the dose of 20 mg. Daclizumab is no longer being manufactured in Europe or the USA. Being humanized, these are generally better tolerated and do not cause the cytokine release syndrome seen with thymoglobulin or alemtuzumab. Alemtuzumab (Campath-1H) is a humanized antiCD52 panlymphocytic (against both B and T cells) mAb approved for treatment of chronic lymphocytic leukaemia, but used off label in transplant as a single dose of 30 mg. Due to associated side effects including cytokine release syndrome and infectious complications, it is slowly being replaced by thymoglobulin. Maintenance immunotherapy in CTA is usually with triple therapy, including tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. Tacrolimus (Prograf, Astella Pharma USA, Inc.) is a macrolide compound originally isolated from Streptomyces tsukubaensis. Calcineurin inhibitors (tacrolimus and cyclosporine) inhibit IL-2 and interferon-gamma production. They are metabolized in the liver via CYP 3A4 and thus have several drug interactions. MPA is produced by the fungus Penicillium. Commonly used MPA compounds are the 2-morpholinoethyl ester, MMF (CellCept, Genentech, Inc.) and mycophenolate sodium (Myfortic, Novartis AG, Inc.). MPA inhibits inosine monophosphate dehydrogenase, preventing the formation of GMP, thus blocking the synthesis of guanine triphosphate or deoxyguanine triphosphate and therefore replication. Unlike most mammalian cells that are able to maintain GMP levels through the purine salvage pathway, lymphocytes lack this capacity. As a result, MPA selectively inhibits the proliferation of both B and T lymphocytes. Reduction in the above immunosuppression or immunomodulation has been attempted and shows limited success with an increase in acute rejection that may require additional rescue immunosuppression. Immunosuppression minimization is also being studied with immunomodulatory properties of donor bone marrow [32 ] and extracorporeal photopheresis [33,34], which has had some success in heart and lung transplantation [35,36]. Use of newer agents such as Belatacept has not been reported yet in CTA. &
TOLERANCE INDUCTION The need for chronic immunosuppression and risk for rejection can be eliminated by achieving donorspecific tolerance, that is the absence of destructive immune response to the allograft without the need for long-term immunosuppression. Tolerance has Volume 19 Number 6 December 2014
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been successfully induced in small animal models using different protocols. However, transition to larger animals has not been as successful. Amongst the different methods used to induce tolerance, haemopoietic stem cell (HSC) chimerism is currently one of the best studied approaches [37 ]. &
Donor dentritic cells Dentritic cells are potent APCs with an ability to induce tolerance via immune deviation, T cell anergy/apoptosis or Treg generation [46–48]. They interact with T cells and suppress CD4þ and CD8þ T cell proliferation [49] and control CD4þCD25þ FoxP3þ Tregs [50].
HAEMOPOIETIC STEM CELL CHIMERISM HSC refers to a state in which host and donorderived haematopoietic cells coexist within an individual. Chimerism could be either macro-chimerism or micro-chimerism. Macro-chimerism consists of bone marrow transplant in conditioned recipient and micro-chimerism refers to migration of passenger leukocytes from a transplanted allograft into an unconditioned recipient. Ildstad and Sachs [38] provided proof of concept for tolerance induction by mixed chimerism, wherein lethally irradiated mice were reconstituted with synergic mixture of bone marrow from both the donor and the recipient strains and developed donor-specific tolerance of skin grafts. Although chimerism may lower the amount of chronic immunosuppression needed, important considerations in chimerism are the morbidity associated with the conditioning regimens, risk of graft-versus-host disease and feasibility in CTA. Evaluation of the risk versus benefit ratio should be started from beginning of the therapy rather than beginning of the transplant.
CELL-BASED THERAPIES TO INDUCE TOLERANCE Various cell-based therapies to induce tolerance have shown promise but confirmatory trials are awaited. These are discussed below.
T-cell costimulatory blockade Antigen recognition by MHC complexes of APCs has to be accompanied by further costimulatory signals to exert an immune response. Blocking these signals leads alloreactive T and B cells to become anergic/ apoptotic. The role of CD4þCD25þFoxP3þ Tregs has been extensively studied [39] in CTA. Blocking CD28/B7 costimulation has shown to improve graft survival [40,41]. Anti-CD154 also delayed rejection but was associated with prothrombotic properties [42,43]. Combined blockade of CD40/CD154 and B7/CD28 pathways has shown effective results too [44]. Recipient Tregs in conjunction with anti-CD40L mAb and CTLA4Ig costimulatory blockade with Rapamycin achieved skin tolerance after bone marrow transplantation in a murine model [45].
Mesenchymal stem cells Mesenchymal stem cells (MSCs) are derived from the bone marrow stroma and are involved in synthesis of various cytokines and growth factors thus affecting the immune system. They have successfully achieved tolerance in CTA in animal models [51]. Recently, adipose tissue-derived MSCs, similar to HSC, have shown some success in hind limb allotransplantation in rats [52 ]. This novel strategy has advantages over HSC chimerism due to relative ease of harvesting adipose tissue-derived stem cells, lower donor morbidity and the larger number of cells that can be obtained. MSCs accelerate wound healing and closure with more rapid epithelialization, granulation tissue formation and angiogenesis [53]. They have the capacity to differentiate in the wound and also to release soluble factors that regulate cellular responses to injury. MSCs attract macrophages, endothelial cells, keratinocytes and dermal fibroblasts to the wounds aiding in decreasing inflammation, promotion of phagocytosis of debris and approximation of matrix deposition, which is important in repair and regeneration in CTA. &&
GENE TARGETING OF TRANSPLANTED ORGANS Transferring donor-specific genes to recipient via donor-specific transfusions induces micro-chimerism, wherein recipient’s bone marrow expresses donor protein. The vector genome enters the nucleus of the cell and the host expresses the therapeutic transgene in long term. There has been some reported success in rodent models [54].
CONCLUSION AND FUTURE DIRECTIONS The cosmetic, functional and psychological benefits of CTAs have to be balanced with the morbidity of the surgery and risks of long-term immunosuppression. Different tissues in CTA have different antigenic properties. Acute rejection is common with CTA and chronic rejection is now being more recognized as an important cause for shortened graft survival, such as in other solid organ transplants. Both acute and chronic rejections need to be
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prevented effectively to improve functionality and survival of the graft. Newer strategies aimed at limiting side effects of immunosuppression are being studied. Both immunomodulation and tolerance induction have some initial success, but our understanding of immune regulation in transplant and ideal immunosuppression in CTA has yet to be optimized. Future options must utilize effective regimens with lower toxicity and risk of infectious morbidities. Acknowledgements None. Conflicts of interest None of the authors have any conflicts of interest or financial disclosures relevant to this article.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Tobin GR, Breidenbach WC 3rd, Ildstad ST, et al. The history of human composite tissue allotransplantation. Transplant Proc 2009; 41:466–471. 2. Dubernard JM, Owen E, Herzberg G, et al. Human hand allograft: report on first 6 months. Lancet 1999; 353:1315–1320. 3. Jones JW, Gruber SA, Barker JH, Breidenbach WC. Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team. N Engl J Med 2000; 343:468–473. 4. Dubernard JM, Lengele B, Morelon E, et al. Outcomes 18 months after the first human partial face transplantation. N Engl J Med 2007; 357:2451–2460. 5. Barret JP, Gavalda J, Bueno J, et al. Full face transplant: the first case report. Ann Surg 2011; 254:252–256. 6. Petruzzo P, Lanzetta M, Dubernard JM, et al. The International Registry on Hand and Composite Tissue Transplantation. Transplantation 2010; 90:1590– 1594. 7. Kaufman CL, Blair B, Murphy E, Breidenbach WB. A new option for amputees: transplantation of the hand. J Rehabil Res Dev 2009; 46:395–404. 8. Schneeberger S, Landin L, Jableki J, et al. Achievements and challenges in composite tissue allotransplantation. Transpl Int 2011; 24:760–769. 9. Weissenbacher A, Hautz T, Zelger B, et al. Antibody-mediated rejection in & hand transplantation. Transpl Int 2014; 27:e13–e17. This is the first study of antibody-mediated rejection in a composite tissue allotransplantation. 10. Chandraker A, Arscott R, Murphy GF, et al. The management of antibody& mediated rejection in the first presensitized recipient of a full-face allotransplant. Am J Transplant 2014; 14:1446–1452. This is a recent study of successful management of acute antibody-mediated rejection in a presensitized recipient of a full face transplant. 11. Hautz T, Zelger BG, Weissenbacher A, et al. Standardizing skin biopsy & sampling to assess rejection in vascularized composite allotransplantation. Clin Transplant 2013; 27:E81–E90. This article summarizes important signs of rejection in the skin component of a vascularized composite allograft. 12. Hettiaratchy S, Melendy E, Randolph MA, et al. Tolerance to composite tissue allografts across a major histocompatibility barrier in miniature swine. Transplantation 2004; 77:514–521. 13. Clark RA, Chong B, Mirchandani N, et al. The vast majority of CLAþ T cells are resident in normal skin. J Immunol 2006; 176:4431–4439. 14. Clark RA, Watanabe R, Teague JE, et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci Transl Med 2012; 4:117ra117. 15. Jiang X, Clark RA, Liu L, et al. Skin infection generates nonmigratory memory CD8þ T(RM) cells providing global skin immunity. Nature 2012; 483:227– 231. 16. Seneschal J, Clark RA, Gehad A, et al. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 2012; 36:873–884. 17. Issa F, Hester J, Goto R, et al. Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model. Transplantation 2010; 90:1321–1327.
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18. Egawa G, Kabashima K. Skin as a peripheral lymphoid organ: revisiting the concept of skin-associated lymphoid tissues. J Invest Dermatol 2011; 131:2178–2185. 19. Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff 2007 working classification of skin-containing composite tissue allograft pathology. Am J Transplant 2008; 8:1396–1400. 20. Cendales LC, Kirk AD, Moresi JM, et al. Composite tissue allotransplantation: classification of clinical acute skin rejection. Transplantation 2006; 81:418– 422. 21. Hautz T, Zelger B, Brandacher G, et al. Histopathologic characterization of mild rejection (grade I) in skin biopsies of human hand allografts. Transpl Int 2012; 25:56–63. 22. Breidenbach WC, Gonzales NR, Kaufman CL, et al. Outcomes of the first 2 American hand transplants at 8 and 6 years posttransplant. J Hand Surg Am 2008; 33:1039–1047. 23. Pomahac B, Pribaz J, Eriksson E, et al. Restoration of facial form and function after severe disfigurement from burn injury by a composite facial allograft. Am J Transplant 2011; 11:386–393. 24. Guo S, Han Y, Zhang X, et al. Human facial allotransplantation: a 2-year follow-up study. Lancet 2008; 372:631–638. 25. Petruzzo P, Kanitakis J, Badet L, et al. Long-term follow-up in composite tissue allotransplantation: in-depth study of five (hand and face) recipients. Am J Transplant 2011; 11:808–816. 26. Lantieri L, Meningaud JP, Grimbert P, et al. Repair of the lower and middle parts of the face by composite tissue allotransplantation in a patient with massive plexiform neurofibroma: a 1-year follow-up study. Lancet 2008; 372:639–645. 27. Kaufman CL, Ouseph R, Blair B, et al. Graft vasculopathy in clinical hand transplantation. Am J Transplant 2012; 12:1004–1016. 28. Kaufman CL, Breidenbach W. World experience after more than a decade of clinical hand transplantation: update from the Louisville hand transplant program. Hand Clin 2011; 27:417–421. 29. Mundinger GS, Munivenkatappa R, Drachenberg CB, et al. Histopathology of && chronic rejection in a nonhuman primate model of vascularized composite allotransplantation. Transplantation 2013; 95:1204–1210. This study described chronic rejection in vascularized composite grafts in nonhuman primate model with serial biopsies and immunochemical studies. 30. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4þCD25þFoxP3þ regulatory T cells. Blood 2005; 105:4743–4748. 31. Chang J, Davis CL, Mathes DW. The impact of current immunosuppression strategies in renal transplantation on the field of reconstructive transplantation. J Reconstr Microsurg 2012; 28:7–19. 32. Schneeberger S, Gorantla VS, Brandacher G, et al. Upper-extremity trans& plantation using a cell-based protocol to minimize immunosuppression. Ann Surg 2013; 257:345–351. This is a case series of five patients who received donor bone marrow cells and were maintained with tacrolimus monotherapy with infrequent rejection episodes. 33. Barr ML, Meiser BM, Eisen HJ, et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 1998; 339:1744–1751. 34. Morrell MR, Despotis GJ, Lublin DM, et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2010; 29:424–431. 35. Lantieri L, Hivelin M, Audard V, et al. Feasibility, reproducibility, risks and benefits of face transplantation: a prospective study of outcomes. Am J Transplant 2011; 11:367–378. 36. Hivelin M, Siemionow M, Grimbert P, Lantieri L. Extracorporeal photopheresis: from solid organs to face transplantation. Transpl Immunol 2009; 21:117– 128. 37. Leonard DA, Cetrulo CL Jr, McGrouther DA, Sachs DH. Induction of tolerance & of vascularized composite allografts. Transplantation 2013; 95:403–409. This is a good review on development of tolerance in composite tissue allografts. 38. Ildstad ST, Sachs DH. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 1984; 307:168–170. 39. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3þ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10:490–500. 40. Haspot F, Seveno C, Dugast AS, et al. Anti-CD28 antibody-induced kidney allograft tolerance related to tryptophan degradation and TCR class II B7 regulatory cells. Am J Transplant 2005; 5:2339–2348. 41. Siemionow M, Ortak T, Izycki D, et al. Induction of tolerance in compositetissue allografts. Transplantation 2002; 74:1211–1217. 42. Elster EA, Xu H, Tadaki DK, et al. Treatment with the humanized CD154specific monoclonal antibody, hu5C8, prevents acute rejection of primary skin allografts in nonhuman primates. Transplantation 2001; 72:1473–1478. 43. Koyama I, Kawai T, Andrews D, et al. Thrombophilia associated with antiCD154 monoclonal antibody treatment and its prophylaxis in nonhuman primates. Transplantation 2004; 77:460–462. 44. Larsen CP, Elwood ET, Alexander DZ, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996; 381:434–438. 45. Pilat N, Baranyi U, Klaus C, et al. Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning. Am J Transplant 2010; 10:751–762.
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Novel immunosuppressive strategies Gupta et al. 46. Morelli AE, Thomson AW. Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction. Immunol Rev 2003; 196:125–146. 47. Fugier-Vivier IJ, Rezzoug F, Huang Y, et al. Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment. J Exp Med 2005; 201:373–383. 48. Lutz MB, Suri RM, Niimi M, et al. Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. Eur J Immunol 2000; 30:1813–1822. 49. Munn DH, Sharma MD, Mellor AL. Ligation of B7-1/B7-2 by human CD4þ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J Immunol 2004; 172:4100–4110. 50. Fehervari Z, Sakaguchi S. Control of Foxp3þ CD25þCD4þ regulatory cell activation and function by dendritic cells. Int Immunol 2004; 16:1769– 1780.
51. Pan H, Zhao K, Wang L, et al. Mesenchymal stem cells enhance the induction of mixed chimerism and tolerance to rat hind-limb allografts after bone marrow transplantation. J Surg Res 2010; 160:315–324. 52. Jeong SH, Ji YH, Yoon ES. Immunosuppressive activity of adipose tissue&& derived mesenchymal stem cells in a rat model of hind limb allotransplantation. Transplant Proc 2014; 46:1606–1614. This study shows how adipose tissue derived mesenchymal stem cells from donor rats exhibit in-vitro immunosuppressive properties by inhibiting T cell proliferation and prolonged hind limb graft survival in rats. 53. Hocking AM, Gibran NS. Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res 2010; 316: 2213–2219. 54. Bagley J, Tian C, Sachs DH, Iacomini J. Induction of T-cell tolerance to an MHC class I alloantigen by gene therapy. Blood 2002; 99:4394–4399.
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Novel immunosuppressive strategies for composite tissue allografts Aditi Gupta a, Sean Kumer b, and Bruce Kaplan c
Purpose of review Vascularized composite tissue allografts (CTAs) provide excellent restorative options for patients with limb loss and other deformities. Acute rejection remains common with CTA and immunosuppression is used in an attempt to prevent rejection. This has created ethical debates regarding the use of intensive immunosuppression for a nonlife-saving procedure. This highlights the need for newer immunosuppressive strategies for CTA, which are described in this review. Recent findings Recent studies have looked into immunomodulation and tolerance to decrease toxicity of immunosuppression. Both strategies have had some success but have their own limitations. Although immunomodulation and decrease in immunosuppression decreases toxicity, it has been associated with higher rates of rejection. Induction of tolerance has achieved some initial success, but the initial conditioning regimens are associated with significant morbidity. Summary Although recent advancements have been made in the immunosuppressive strategies in CTA, the ideal immunosuppression strategy with low toxicity and infection risk but with the ability to prevent acute and chronic rejection is yet to be discovered. Keywords composite tissue, hand transplantation, haemopoietic stem cell transplantation, rejection, tolerance
INTRODUCTION The first documented attempt at vascularized composite tissue allografts (CTAs) was an upper limb transplant in Ecuador in 1964 [1]. The patient’s graft had a severe episode of rejection and the patient’s forearm had to be removed. The immunosuppression strategy used was azathioprine and prednisone, a regimen that was yielding approximately 40% 1-year kidney graft survival at that time. Due to experimental data implying greater antigenicity of skin than solid organs, repeated failures of CTA in animal models, and the rather nonspecific and less than optimally efficacious immunosuppressive regimens available, further clinical efforts in this area were abandoned. With improved success in transplantation after the introduction of cyclosporine A in the early 1980s followed by tacrolimus and mycophenolic acid (MPA) in 1990s, hand transplantation was revisited. The first successful hand transplant was done in Lyon, France, in 1998 [2] and in the USA in 1999 [3]. This was followed by the first bilateral hand CTA in Lyon in 2000 [1]. Transplantation of other tissues was also attempted. The first successful laryngotracheal transplant was done in www.co-transplantation.com
the USA in 1988, first knee transplant in Germany in 1994, first face transplant in France in 2005 [4] and the first full face transplant in Spain in 2010 [5]. The pace and interest in CTA have picked up in the last two decades with involvement of multiple transplant centres [6]. To date, more than 70 hand transplants have been performed across the world and more than 150 CTAs. CTA forms an excellent restorative option for patients with limb loss and other disfigurements not correctable with staged reconstructive techniques or prosthesis. It offers better quality of life, functional and aesthetic results than conventional treatments [7].
a Department of Nephrology, bDepartment of Surgery, Center for Transplantation and cUniversity of Kansas Medical Center, Kansas City, Kansas, USA
Correspondence to Aditi Gupta, MD, Division of Nephrology and Hypertension, Mail Stop 3002, 3901 Rainbow Blvd, Kansas City, KS 66160, USA. Tel: +1 913 588 6048; fax: +1 913 588 3867; e-mail: agupta@ kumc.edu Curr Opin Organ Transplant 2014, 19:552–557 DOI:10.1097/MOT.0000000000000135 Volume 19 Number 6 December 2014
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Novel immunosuppressive strategies Gupta et al.
KEY POINTS
experiencing at least one episode of acute rejection in the first year [6], and the major affected tissue being the skin [11 ]. Animal models have demonstrated ‘split tolerance’ with simultaneous acceptance of other tissues with rejection of skin or epidermis from the same donor [12] illustrating the difficulty in surpassing skin antigenicity. In spite of the high cellular mediated rejection seen in the skin of CTAs, there is no reported graft loss secondary to it. The explanation for this may lie in the natural defense mechanism of the skin. The high antigenicity of the skin has been attributed to the large number of T cells, especially memory T cells in normal skin [13]. These memory cells do not recirculate but persist indefinitely, providing immunity, which accumulates over time with repeated infections. This adaptive mechanism carries a doubleedged sword of helping to prevent pathogens from causing damage and also creating a positive feedback loop in terms of antigenicity [14,15]. However, full thickness skin with all its underlying tissues as opposed to a simple skin graft harbours antigenpresenting cells (APCs) such as Langerhans’ cells, which regulate and maintain immune homeostasis by activating resident regulatory T cells (Tregs) [16]. Human Tregs have been shown to prevent vascular changes seen in chronic rejection and induce tolerance in human skin allografts [17]. This modulation by underlying tissue may help explain the relative success of CTA as opposed to skin alone. Corticosteroid treatment increases Tregs via increase in production of transforming growth factor-beta (TGF-b) by Langerhans cells, explaining why topical steroids may be effective in the treatment of acute rejection [18]. &
Both acute and chronic rejections are common in CTA and chronic immunosuppression is used to prevent rejection and prolong graft survival. Immunosuppression in CTA is currently based on protocols derived from other solid organ transplants. Newer immunosuppressive strategies included immunomodulation and tolerance induction. There has been some success with tolerance induction and chimerism, but morbidity associated with the initial conditioning regimen remains a concern. As current immunosuppression is associated with significant side effects, there is an ongoing search for the ideal immunosuppression strategy, one with low toxicity yet effective in preventing rejection.
Outcomes of CTA have been comparable with other transplants with a 1-year patient and graft survival of 100 and 96%, respectively [8]. However, acute rejection rates are still very high, potentially posing a risk for future chronic rejection and shortened graft survival. To overcome this risk, long-term immunosuppression must be kept adequate with the hope of maintaining CTA at an optimal functional level. The side effects of immunosuppression are well known and can range from metabolic complications to opportunistic infections. These concerns have led to ethical debates as to whether the risks of immunosuppression outweigh the benefits accrued by the procedure. CTA is not a life-saving procedure, and in fact, the immunosuppression that must accompany CTA may in fact potentially shorten longevity. Thus, there is a pressing need to develop less toxic immunosuppressive strategies in CTA.
IMMUNOLOGIC BARRIERS Over the years, our understanding of immunologic barriers to CTA has advanced significantly. Unlike solid organ transplants, CTA involves grafting of heterogeneous tissue types with different antigenicity with each tissue evoking a distinct immune response. Skin and vessels seem to be the major immunologic challenges [7] and elicit both cellular and humoral responses. There seems to be a lower rate of antibody-mediated rejection (AMR) in CTAs. In over 150 CTAs completed spanning 15 years, there are only two reports of AMR [9 ,10 ] and these rejection episodes did not result in loss of the graft. In contrast, cellular rejection is a common occurrence in CTA with 85–90% of all hand allografts &
&
REJECTION Three mechanisms have been described for triggering allorecognition and T-cell activation needed for skin rejection: first, direct interaction of recipient T-cell receptors with intact major histocompatibility complex (MHC) presented by APCs; second, indirect allorecognition of recipient T cells with recipient APCs presenting processed donor MHC; and third, semi-direct interaction of recipient T cells with recipient APCs carrying intact donor MHC peptide complexes. Other factors such as ischemia reperfusion injury, immunosuppression and infectious complications also modify immunologic mechanisms. Rejection is diagnosed with punch skin biopsies, as it is expected that skin would be the first and most common tissue to reject. The grading of histological rejection is done with the Banff Criteria [19,20]. It is difficult to predict the stage and prognosis of
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rejection with biopsies alone as shown in a recent study [21], and the treatment of rejection is largely based on the clinical presentation and the current level of immunosuppression. Usually, rejection is treated with various combinations of steroid boluses, increase in maintenance immunosuppression, antithymocyte globulin and topical tacrolimus and corticosteroids [22–25]. Extracorporeal photopheresis was also tried in acute rejection in CTA with concomitant cytomegalovirus infection [26]. Successful treatment of AMR in the first presensitized recipient of a full face transplant was recently reported [10 ]. Chronic rejection, thought to be less common than acute rejection and less frequent than in solid organ transplant [27], is now being recognized in more CTAs [28]. Chronic rejection presents with transplant vasculopathy manifested by neointimal proliferation of arterioles, vessel wall fibrosis, progressive luminal occlusion, tertiary lymphoid follicles along with skin and muscular atrophy, nail changes and fibrosis of deeper tissue [29 ]. Immunosuppression with mammalian target of rapamycin (mTOR) inhibitors has also been tried with CTA in hope of preventing chronic rejection. Rapamycin has shown to facilitate selective expansion of Tregs and inhibiting clonal proliferation of effector cells [30]. Management of chronic rejection is still in its infancy, and overall, low total numbers in CTA has limited the research in this area. &
&&
STRATEGIES IN IMMUNOSUPPRESSION Immunosuppression concepts and protocols in CTAs have essentially been derived from experience in solid organ transplants with overall immunosuppression similar or slightly greater than that used in renal transplantation [31]. Similar to other organ transplantation, there are centre-to-centre variations [6]. Typical immunosuppression protocols include induction immunosuppression with antithymocyte globulin (thymoglobulin), anti-interleukin 2 (IL-2) receptor mAbs (daclizumab and basiliximab) or anti-CD52 mAbs (campath-1H). Thymoglobulin is a polyclonal antibody against multiple T-cell antigens. For induction, typically 5–6 mg/kg body weight of thymoglobulin is administered in three to five divided doses. Thymoglobulin results in depletion of lymphocytes by complement-mediated cell lysis and uptake of opsonized cells. Its administration can be complicated with a cytokine release syndrome with fever, chills, rash, anaemia, thrombocytopenia and serum sickness. Basiliximab and daclizumab are chimeric murine/human mAb preparations that bind specifically to the alpha subunit of the IL-2 receptor on activated T cells and 554
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inhibit IL-2-mediated proliferation and differentiation of T cells, without depleting them. Basiliximab is infused intraoperatively and on the fourth posttransplant day at the dose of 20 mg. Daclizumab is no longer being manufactured in Europe or the USA. Being humanized, these are generally better tolerated and do not cause the cytokine release syndrome seen with thymoglobulin or alemtuzumab. Alemtuzumab (Campath-1H) is a humanized antiCD52 panlymphocytic (against both B and T cells) mAb approved for treatment of chronic lymphocytic leukaemia, but used off label in transplant as a single dose of 30 mg. Due to associated side effects including cytokine release syndrome and infectious complications, it is slowly being replaced by thymoglobulin. Maintenance immunotherapy in CTA is usually with triple therapy, including tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. Tacrolimus (Prograf, Astella Pharma USA, Inc.) is a macrolide compound originally isolated from Streptomyces tsukubaensis. Calcineurin inhibitors (tacrolimus and cyclosporine) inhibit IL-2 and interferon-gamma production. They are metabolized in the liver via CYP 3A4 and thus have several drug interactions. MPA is produced by the fungus Penicillium. Commonly used MPA compounds are the 2-morpholinoethyl ester, MMF (CellCept, Genentech, Inc.) and mycophenolate sodium (Myfortic, Novartis AG, Inc.). MPA inhibits inosine monophosphate dehydrogenase, preventing the formation of GMP, thus blocking the synthesis of guanine triphosphate or deoxyguanine triphosphate and therefore replication. Unlike most mammalian cells that are able to maintain GMP levels through the purine salvage pathway, lymphocytes lack this capacity. As a result, MPA selectively inhibits the proliferation of both B and T lymphocytes. Reduction in the above immunosuppression or immunomodulation has been attempted and shows limited success with an increase in acute rejection that may require additional rescue immunosuppression. Immunosuppression minimization is also being studied with immunomodulatory properties of donor bone marrow [32 ] and extracorporeal photopheresis [33,34], which has had some success in heart and lung transplantation [35,36]. Use of newer agents such as Belatacept has not been reported yet in CTA. &
TOLERANCE INDUCTION The need for chronic immunosuppression and risk for rejection can be eliminated by achieving donorspecific tolerance, that is the absence of destructive immune response to the allograft without the need for long-term immunosuppression. Tolerance has Volume 19 Number 6 December 2014
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been successfully induced in small animal models using different protocols. However, transition to larger animals has not been as successful. Amongst the different methods used to induce tolerance, haemopoietic stem cell (HSC) chimerism is currently one of the best studied approaches [37 ]. &
Donor dentritic cells Dentritic cells are potent APCs with an ability to induce tolerance via immune deviation, T cell anergy/apoptosis or Treg generation [46–48]. They interact with T cells and suppress CD4þ and CD8þ T cell proliferation [49] and control CD4þCD25þ FoxP3þ Tregs [50].
HAEMOPOIETIC STEM CELL CHIMERISM HSC refers to a state in which host and donorderived haematopoietic cells coexist within an individual. Chimerism could be either macro-chimerism or micro-chimerism. Macro-chimerism consists of bone marrow transplant in conditioned recipient and micro-chimerism refers to migration of passenger leukocytes from a transplanted allograft into an unconditioned recipient. Ildstad and Sachs [38] provided proof of concept for tolerance induction by mixed chimerism, wherein lethally irradiated mice were reconstituted with synergic mixture of bone marrow from both the donor and the recipient strains and developed donor-specific tolerance of skin grafts. Although chimerism may lower the amount of chronic immunosuppression needed, important considerations in chimerism are the morbidity associated with the conditioning regimens, risk of graft-versus-host disease and feasibility in CTA. Evaluation of the risk versus benefit ratio should be started from beginning of the therapy rather than beginning of the transplant.
CELL-BASED THERAPIES TO INDUCE TOLERANCE Various cell-based therapies to induce tolerance have shown promise but confirmatory trials are awaited. These are discussed below.
T-cell costimulatory blockade Antigen recognition by MHC complexes of APCs has to be accompanied by further costimulatory signals to exert an immune response. Blocking these signals leads alloreactive T and B cells to become anergic/ apoptotic. The role of CD4þCD25þFoxP3þ Tregs has been extensively studied [39] in CTA. Blocking CD28/B7 costimulation has shown to improve graft survival [40,41]. Anti-CD154 also delayed rejection but was associated with prothrombotic properties [42,43]. Combined blockade of CD40/CD154 and B7/CD28 pathways has shown effective results too [44]. Recipient Tregs in conjunction with anti-CD40L mAb and CTLA4Ig costimulatory blockade with Rapamycin achieved skin tolerance after bone marrow transplantation in a murine model [45].
Mesenchymal stem cells Mesenchymal stem cells (MSCs) are derived from the bone marrow stroma and are involved in synthesis of various cytokines and growth factors thus affecting the immune system. They have successfully achieved tolerance in CTA in animal models [51]. Recently, adipose tissue-derived MSCs, similar to HSC, have shown some success in hind limb allotransplantation in rats [52 ]. This novel strategy has advantages over HSC chimerism due to relative ease of harvesting adipose tissue-derived stem cells, lower donor morbidity and the larger number of cells that can be obtained. MSCs accelerate wound healing and closure with more rapid epithelialization, granulation tissue formation and angiogenesis [53]. They have the capacity to differentiate in the wound and also to release soluble factors that regulate cellular responses to injury. MSCs attract macrophages, endothelial cells, keratinocytes and dermal fibroblasts to the wounds aiding in decreasing inflammation, promotion of phagocytosis of debris and approximation of matrix deposition, which is important in repair and regeneration in CTA. &&
GENE TARGETING OF TRANSPLANTED ORGANS Transferring donor-specific genes to recipient via donor-specific transfusions induces micro-chimerism, wherein recipient’s bone marrow expresses donor protein. The vector genome enters the nucleus of the cell and the host expresses the therapeutic transgene in long term. There has been some reported success in rodent models [54].
CONCLUSION AND FUTURE DIRECTIONS The cosmetic, functional and psychological benefits of CTAs have to be balanced with the morbidity of the surgery and risks of long-term immunosuppression. Different tissues in CTA have different antigenic properties. Acute rejection is common with CTA and chronic rejection is now being more recognized as an important cause for shortened graft survival, such as in other solid organ transplants. Both acute and chronic rejections need to be
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prevented effectively to improve functionality and survival of the graft. Newer strategies aimed at limiting side effects of immunosuppression are being studied. Both immunomodulation and tolerance induction have some initial success, but our understanding of immune regulation in transplant and ideal immunosuppression in CTA has yet to be optimized. Future options must utilize effective regimens with lower toxicity and risk of infectious morbidities. Acknowledgements None. Conflicts of interest None of the authors have any conflicts of interest or financial disclosures relevant to this article.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Tobin GR, Breidenbach WC 3rd, Ildstad ST, et al. The history of human composite tissue allotransplantation. Transplant Proc 2009; 41:466–471. 2. Dubernard JM, Owen E, Herzberg G, et al. Human hand allograft: report on first 6 months. Lancet 1999; 353:1315–1320. 3. Jones JW, Gruber SA, Barker JH, Breidenbach WC. Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team. N Engl J Med 2000; 343:468–473. 4. Dubernard JM, Lengele B, Morelon E, et al. Outcomes 18 months after the first human partial face transplantation. N Engl J Med 2007; 357:2451–2460. 5. Barret JP, Gavalda J, Bueno J, et al. Full face transplant: the first case report. Ann Surg 2011; 254:252–256. 6. Petruzzo P, Lanzetta M, Dubernard JM, et al. The International Registry on Hand and Composite Tissue Transplantation. Transplantation 2010; 90:1590– 1594. 7. Kaufman CL, Blair B, Murphy E, Breidenbach WB. A new option for amputees: transplantation of the hand. J Rehabil Res Dev 2009; 46:395–404. 8. Schneeberger S, Landin L, Jableki J, et al. Achievements and challenges in composite tissue allotransplantation. Transpl Int 2011; 24:760–769. 9. Weissenbacher A, Hautz T, Zelger B, et al. Antibody-mediated rejection in & hand transplantation. Transpl Int 2014; 27:e13–e17. This is the first study of antibody-mediated rejection in a composite tissue allotransplantation. 10. Chandraker A, Arscott R, Murphy GF, et al. The management of antibody& mediated rejection in the first presensitized recipient of a full-face allotransplant. Am J Transplant 2014; 14:1446–1452. This is a recent study of successful management of acute antibody-mediated rejection in a presensitized recipient of a full face transplant. 11. Hautz T, Zelger BG, Weissenbacher A, et al. Standardizing skin biopsy & sampling to assess rejection in vascularized composite allotransplantation. Clin Transplant 2013; 27:E81–E90. This article summarizes important signs of rejection in the skin component of a vascularized composite allograft. 12. Hettiaratchy S, Melendy E, Randolph MA, et al. Tolerance to composite tissue allografts across a major histocompatibility barrier in miniature swine. Transplantation 2004; 77:514–521. 13. Clark RA, Chong B, Mirchandani N, et al. The vast majority of CLAþ T cells are resident in normal skin. J Immunol 2006; 176:4431–4439. 14. Clark RA, Watanabe R, Teague JE, et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci Transl Med 2012; 4:117ra117. 15. Jiang X, Clark RA, Liu L, et al. Skin infection generates nonmigratory memory CD8þ T(RM) cells providing global skin immunity. Nature 2012; 483:227– 231. 16. Seneschal J, Clark RA, Gehad A, et al. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 2012; 36:873–884. 17. Issa F, Hester J, Goto R, et al. Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model. Transplantation 2010; 90:1321–1327.
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18. Egawa G, Kabashima K. Skin as a peripheral lymphoid organ: revisiting the concept of skin-associated lymphoid tissues. J Invest Dermatol 2011; 131:2178–2185. 19. Cendales LC, Kanitakis J, Schneeberger S, et al. The Banff 2007 working classification of skin-containing composite tissue allograft pathology. Am J Transplant 2008; 8:1396–1400. 20. Cendales LC, Kirk AD, Moresi JM, et al. Composite tissue allotransplantation: classification of clinical acute skin rejection. Transplantation 2006; 81:418– 422. 21. Hautz T, Zelger B, Brandacher G, et al. Histopathologic characterization of mild rejection (grade I) in skin biopsies of human hand allografts. Transpl Int 2012; 25:56–63. 22. Breidenbach WC, Gonzales NR, Kaufman CL, et al. Outcomes of the first 2 American hand transplants at 8 and 6 years posttransplant. J Hand Surg Am 2008; 33:1039–1047. 23. Pomahac B, Pribaz J, Eriksson E, et al. Restoration of facial form and function after severe disfigurement from burn injury by a composite facial allograft. Am J Transplant 2011; 11:386–393. 24. Guo S, Han Y, Zhang X, et al. Human facial allotransplantation: a 2-year follow-up study. Lancet 2008; 372:631–638. 25. Petruzzo P, Kanitakis J, Badet L, et al. Long-term follow-up in composite tissue allotransplantation: in-depth study of five (hand and face) recipients. Am J Transplant 2011; 11:808–816. 26. Lantieri L, Meningaud JP, Grimbert P, et al. Repair of the lower and middle parts of the face by composite tissue allotransplantation in a patient with massive plexiform neurofibroma: a 1-year follow-up study. Lancet 2008; 372:639–645. 27. Kaufman CL, Ouseph R, Blair B, et al. Graft vasculopathy in clinical hand transplantation. Am J Transplant 2012; 12:1004–1016. 28. Kaufman CL, Breidenbach W. World experience after more than a decade of clinical hand transplantation: update from the Louisville hand transplant program. Hand Clin 2011; 27:417–421. 29. Mundinger GS, Munivenkatappa R, Drachenberg CB, et al. Histopathology of && chronic rejection in a nonhuman primate model of vascularized composite allotransplantation. Transplantation 2013; 95:1204–1210. This study described chronic rejection in vascularized composite grafts in nonhuman primate model with serial biopsies and immunochemical studies. 30. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4þCD25þFoxP3þ regulatory T cells. Blood 2005; 105:4743–4748. 31. Chang J, Davis CL, Mathes DW. The impact of current immunosuppression strategies in renal transplantation on the field of reconstructive transplantation. J Reconstr Microsurg 2012; 28:7–19. 32. Schneeberger S, Gorantla VS, Brandacher G, et al. Upper-extremity trans& plantation using a cell-based protocol to minimize immunosuppression. Ann Surg 2013; 257:345–351. This is a case series of five patients who received donor bone marrow cells and were maintained with tacrolimus monotherapy with infrequent rejection episodes. 33. Barr ML, Meiser BM, Eisen HJ, et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 1998; 339:1744–1751. 34. Morrell MR, Despotis GJ, Lublin DM, et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2010; 29:424–431. 35. Lantieri L, Hivelin M, Audard V, et al. Feasibility, reproducibility, risks and benefits of face transplantation: a prospective study of outcomes. Am J Transplant 2011; 11:367–378. 36. Hivelin M, Siemionow M, Grimbert P, Lantieri L. Extracorporeal photopheresis: from solid organs to face transplantation. Transpl Immunol 2009; 21:117– 128. 37. Leonard DA, Cetrulo CL Jr, McGrouther DA, Sachs DH. Induction of tolerance & of vascularized composite allografts. Transplantation 2013; 95:403–409. This is a good review on development of tolerance in composite tissue allografts. 38. Ildstad ST, Sachs DH. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 1984; 307:168–170. 39. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3þ regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10:490–500. 40. Haspot F, Seveno C, Dugast AS, et al. Anti-CD28 antibody-induced kidney allograft tolerance related to tryptophan degradation and TCR class II B7 regulatory cells. Am J Transplant 2005; 5:2339–2348. 41. Siemionow M, Ortak T, Izycki D, et al. Induction of tolerance in compositetissue allografts. Transplantation 2002; 74:1211–1217. 42. Elster EA, Xu H, Tadaki DK, et al. Treatment with the humanized CD154specific monoclonal antibody, hu5C8, prevents acute rejection of primary skin allografts in nonhuman primates. Transplantation 2001; 72:1473–1478. 43. Koyama I, Kawai T, Andrews D, et al. Thrombophilia associated with antiCD154 monoclonal antibody treatment and its prophylaxis in nonhuman primates. Transplantation 2004; 77:460–462. 44. Larsen CP, Elwood ET, Alexander DZ, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996; 381:434–438. 45. Pilat N, Baranyi U, Klaus C, et al. Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning. Am J Transplant 2010; 10:751–762.
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Novel immunosuppressive strategies Gupta et al. 46. Morelli AE, Thomson AW. Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction. Immunol Rev 2003; 196:125–146. 47. Fugier-Vivier IJ, Rezzoug F, Huang Y, et al. Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment. J Exp Med 2005; 201:373–383. 48. Lutz MB, Suri RM, Niimi M, et al. Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. Eur J Immunol 2000; 30:1813–1822. 49. Munn DH, Sharma MD, Mellor AL. Ligation of B7-1/B7-2 by human CD4þ T cells triggers indoleamine 2,3-dioxygenase activity in dendritic cells. J Immunol 2004; 172:4100–4110. 50. Fehervari Z, Sakaguchi S. Control of Foxp3þ CD25þCD4þ regulatory cell activation and function by dendritic cells. Int Immunol 2004; 16:1769– 1780.
51. Pan H, Zhao K, Wang L, et al. Mesenchymal stem cells enhance the induction of mixed chimerism and tolerance to rat hind-limb allografts after bone marrow transplantation. J Surg Res 2010; 160:315–324. 52. Jeong SH, Ji YH, Yoon ES. Immunosuppressive activity of adipose tissue&& derived mesenchymal stem cells in a rat model of hind limb allotransplantation. Transplant Proc 2014; 46:1606–1614. This study shows how adipose tissue derived mesenchymal stem cells from donor rats exhibit in-vitro immunosuppressive properties by inhibiting T cell proliferation and prolonged hind limb graft survival in rats. 53. Hocking AM, Gibran NS. Mesenchymal stem cells: paracrine signaling and differentiation during cutaneous wound repair. Exp Cell Res 2010; 316: 2213–2219. 54. Bagley J, Tian C, Sachs DH, Iacomini J. Induction of T-cell tolerance to an MHC class I alloantigen by gene therapy. Blood 2002; 99:4394–4399.
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