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• W1500540667 abstract "The field of heart transplantation has seen significant progress in the past 40 years. However, the breakthroughs in long-term outcome have seen stagnation in the past decade. Through advances in genomics and transcriptomics, there is hope that an era of personalized transplant therapy lies in the future. To see where heart transplantation truly fits into the long term, searching for and understanding the alternative approaches for heart failure therapy is both important and inevitable. The application of mechanical circulatory support has contributed to the largest advancement in treatment of end stage heart failure. It has already been approved for destination therapy of heart failure, and greater portability and ease of use of the device will be the future trend. Although it is still not prime time for stem cell therapy, clinical experiences have already suggested its potential therapeutic effects. And finally, whole organ engineering is on the horizon as new techniques have opened the way for this to proceed. In the end, progress on alternative therapies largely depends on our deeper understanding of the mechanisms of heart failure and how to prevent it. The field of heart transplantation has seen significant progress in the past 40 years. However, the breakthroughs in long-term outcome have seen stagnation in the past decade. Through advances in genomics and transcriptomics, there is hope that an era of personalized transplant therapy lies in the future. To see where heart transplantation truly fits into the long term, searching for and understanding the alternative approaches for heart failure therapy is both important and inevitable. The application of mechanical circulatory support has contributed to the largest advancement in treatment of end stage heart failure. It has already been approved for destination therapy of heart failure, and greater portability and ease of use of the device will be the future trend. Although it is still not prime time for stem cell therapy, clinical experiences have already suggested its potential therapeutic effects. And finally, whole organ engineering is on the horizon as new techniques have opened the way for this to proceed. In the end, progress on alternative therapies largely depends on our deeper understanding of the mechanisms of heart failure and how to prevent it. It has been over 40 years since the first human-to-human heart transplant was performed in South Africa by Christiaan Barnard in December 1967. After early enthusiasm for the procedure subsided, decades of dedicated, steady research have ultimately led us to an era with a more encouraging outcome for heart transplantation. When approaching the topic of heart transplantation, one must take into account what translational medicine will bring to this field in the near future. The future of heart transplantation should not only entail the modalities of immunosuppressive therapy or acquired tolerance, but also alternatives to heart transplantation in the management of advanced heart failure. In this paper, because heart transplantation remains the preferred therapy for advanced heart failure, the progress and challenges of medical management after heart transplantation will be highlighted. In addition, the new advances in the mechanism of heart failure will be reviewed as this is where the future of heart failure treatment truly lies. Finally, alternative therapies for advanced heart failure in the future will be discussed. In the past decade, recipient demographics have presented some interesting trends (1Stehlik J Edwards LB Kucheryavaya AY et al.The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Report—2011.J Heart Lung Transplant. 2011; 30: 1078-1094Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar). The leading diagnosis for which heart transplant is performed has shifted from ischemic cardiomyopathy to nonischemic cardiomyopathy. Although the median age of an adult heart transplant recipient remained the same, a higher proportion of patients in their 60s and 70s have received a heart transplant during the last decade. The proportion of recipients with comorbidities and patients sensitized to HLA continue to increase. The number of patients bridged to transplant with mechanical circulatory support (MCS) devices has ascended from around 20% in the past 10 years to more than 30% in 2009. In recent years, the widening gap between the number of waiting recipients and the number of donors has resulted in a continuing trend toward transplanting urgent status recipients. In July 2006, the United Network for Organ Sharing (UNOS) made a change in organ allocation algorithm which allowed broader regional sharing of available hearts to those in more immediate need before their allocation to local, less sick candidates. This change is reported to have increased the allocation of hearts for urgent status 1A/1B from 74% in 2005 to 92% (2Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR)OPTN / SRTR 2010 Annual Data Report.. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD2011: 89-106Google Scholar) currently, while decreasing mortality on the wait list by 17% (3Singh TP Almond CS Taylor DO Graham DA Decline in heart transplant wait list mortality in the United States following broader regional sharing of donor hearts.Circ Heart Fail. 2012; 5: 249-258Crossref PubMed Scopus (79) Google Scholar). With improvement in device technology, more patients on the wait list have received left ventricular assist devices (LVADs). It is notable that the current UNOS policy, which grants 30 days of Status 1A time to patients on LVADs, seems to have lagged behind clinical results obtained with the current generation of LVADs, and resulted in a marked decline in transplantation of patients listed using a nondevice strategy. Recently, the incidence of multiorgan transplantation, including heart–lung, heart–kidney and heart–liver, has risen steadily over the years (1Stehlik J Edwards LB Kucheryavaya AY et al.The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Report—2011.J Heart Lung Transplant. 2011; 30: 1078-1094Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar). On the basis of the data from Organ Procurement and Transplantation Network (OPTN), survival of multiorgan transplant recipient is comparable with heart transplant alone. The fact that multiorgan transplant recipients are observed to have less episodes of acute rejection as well as decreased incidence of chronic rejection (cardiac allograft vasculopathy), has implicated the possible protective immune modulation occurring in multiorgan transplant (4Pinderski LJ Kirklin JK McGiffin D et al.Multi-organ transplantation: Is there a protective effect against acute and chronic rejection?.J Heart Lung Transplant. 2005; 24: 1828-1833Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). In the future, novel approaches are needed to expand and optimize both the donor and recipient population. Institution based liberalization of marginal donor acceptance criteria needs to be evaluated. The role of LVAD versus heart transplantation in a subgroup of heart failure patients is to be determined by clinical trials that directly compare the effectiveness of destination therapy and heart transplantation. For sensitized patients, the utilization of the virtual cross-match could expand the available donor pool (5Pei R Lee JH Shih NJ Chen M Terasaki PI Single human leukocyte antigen flow cytometry beads for accurate identification of human leukocyte antigen antibody specificities.Transplantation. 2003; 75: 43-49Crossref PubMed Scopus (330) Google Scholar). Primary experience of using virtual cross-match in heart transplantation has shown to shorten waiting time without increasing subsequent occurrence of rejection and mortality (6Yanagida R Czer LS Reinsmoen NL et al.Impact of virtual cross match on waiting times for heart transplantation.Ann Thorac Surg. 2011; 92: 2104-2111Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). In renal transplantation, the virtual cross-match has already been adopted in the United States for organ allocation. It is reported that this implementation has increased efficiency in organ allocation and is helping to facilitate transplantation of broadly sensitized candidates (7Bingaman AW Murphey CL Palma-Vargas J Wright F A virtual crossmatch protocol significantly increases access of highly sensitized patients to deceased donor kidney transplantation.Transplantation. 2008; 86: 1864-1868Crossref PubMed Scopus (59) Google Scholar). A recent novel C1q assay to detect the ability of immunoglobulin G antibodies to fix complement is now available which can assess the functional significance of posttransplant alloantibodies. This may significantly alter the approach to sensitized patients in the future (8Chin C Chen G Sequeria F et al.Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients.J Heart Lung Transplant. 2011; 30: 158-163Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). The advances of transplantation largely rely on the contemporary use of immunosuppressants. Unfortunately, the success of immunosuppression comes at a cost of indefinite complicated regimen of medications and high risk of treatment-related complications. Besides this, the mortality beyond 1 year after heart transplantation is constantly decreasing by approximately three–four percentage points per year, which is higher than that of a general population, and there has been no statistically significant improvement in the past two decades (1Stehlik J Edwards LB Kucheryavaya AY et al.The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Report—2011.J Heart Lung Transplant. 2011; 30: 1078-1094Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar). Therefore, the future improvement of posttransplantation survival is likely to result from interventions aimed at the processes responsible for the long-term mortality, such as cardiac allograft vasculopathy, which extensively depends on our understanding of chronic rejection and transplantation tolerance. By far, tremendous progress in our understanding of cell-mediated rejection was centered on activation of T cells and developing new immunosuppressive agents targeting crucial signal pathways (9Halloran PF Immunosuppressive drugs for kidney transplantation.N Engl J Med. 2004; 351: 2715-2729Crossref PubMed Scopus (1177) Google Scholar). More and more interests have been drawn to regulatory T cells (Treg). Naturally occurring CD25+CD4+ Treg that develops in the thymus under the control of the transcription factor Foxp3 has a critical role in peripheral immune homeostasis (10Fontenot JD Gavin MA Rudensky AY Foxp3 programs the development and function of CD41CD251regulatory T cells..Nat Immunol. 2003; 4: 330-336Crossref PubMed Scopus (0) Google Scholar). In addition, Treg has also been shown to suppress immune responses to foreign antigens in the context of transplantation (11Wood KJ Sakaguchi S Regulatory T cells in transplantation tolerance.Nat Rev Immunol. 2003; 3: 199-210Crossref PubMed Scopus (1174) Google Scholar). Alloantigen induced Treg cells can prevent acute, as well as delayed or chronic graft rejection. Although Treg can be generated and induced by alloantigen pretreatment (12Kingsley CI Karim M Bushell AR Wood KJ CD25+CD4+Regulatory T cells prevent graft rejection: CTLA-4- and IL-10- dependent immunoregulation of alloresponses.J Immunol. 2002; 168: 1080-1086Crossref PubMed Scopus (0) Google Scholar,13Bushell A Morris P Wood K Transplantation tolerance induced by antigen pretreatment and depleting anti-CD4 antibody depends on CD4+ T cell regulation during the induction phase of the response.Eur J Immunol. 1995; 25: 2643-2649Crossref PubMed Scopus (0) Google Scholar), as seen in animal models, the presence of the allograft as the source of donor alloantigen was essential for maintaining the unresponsive state (14Hamano K Rawsthorne M Bushell A Morris PJ Wood KJ Evidence that the continued presence of the organ graft and not peripheral donor microchimerism is essential for the maintenance of tolerance to alloantigen in anti-CD4 treated recipients.Transplantation. 1996; 62: 856-860Crossref PubMed Google Scholar). In this light, the ability to generate specific alloantigen reactive Treg offers the possibility of preventing transplant rejection without indefinite global immunosuppression in the future. The role of antibodies in the pathogenesis of chronic rejection is increasingly acknowledged. Traditionally, B cells are considered as antibody secreting cells, but in fact, they contribute to antibody-mediated rejection as antibody presenting cells interacting with T cells (15Tarlinton DM Batista F Smith KGC The B-cell response to protein antigens in immunity and transplantation.Transplantation. 2008; 85: 1698-1704Crossref PubMed Scopus (0) Google Scholar), and expressing complement receptors, thus regulating adaptive immunity (16Carroll MC The complement system in regulation of adaptive immunity.Nat Immunol. 2004; 5: 981-986Crossref PubMed Scopus (797) Google Scholar). Recent studies of operational tolerant human renal transplant recipients reported increased numbers of B cells compared to recipients with stable function receiving immunosuppression (17Newell KA Asare A Kirk AD et al.Identification of a B cell signature associated with renal transplant tolerance in humans.J Clin Invest. 2010; 120: 1836-1847Crossref PubMed Scopus (552) Google Scholar,18Sagoo P Perucha E Sawitzki B et al.Development of a crossplatform biomarker signature to detect renal transplant tolerance in humans.J Clin Invest. 2010; 120: 1848-1861Crossref PubMed Scopus (0) Google Scholar). Some findings even suggest that B cells in tertiary lymphoid tissue could also regulate immune responses and thus slow down the destruction process (19Le Texier L Thebault P Lavault A et al.Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile.Am J Transplant. 2011; 11: 429-438Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). Not until recent, is there evidence that the B cell compartment may be a source of regulatory B cells (Breg). Breg is currently defined by their ability to secrete IL-10 upon stimulation. The involvement of Breg has been found to play a role in other autoimmune diseases (20Mauri C Blair PA Regulatory B cells in autoimmunity: Developments and controversies.Nat Rev Rheumatol. 2010; 6: 636-643Crossref PubMed Scopus (148) Google Scholar). In murine models, there is evidence that Breg increase the number of Treg (21Carter NA Vasconcellos R Rosser EC et al.Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells.J Immunol. 2011; 186: 5569-5579Crossref PubMed Scopus (344) Google Scholar). In humans, the B cell subset CD19+CD24hiCD38hi has been found to secrete the highest amount of IL-10 in response to CD40 stimulation, compared to other peripheral blood B cell subsets (22Blair PA Norena LY Flores-Borja F et al.CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients.Immunity. 2010; 32: 129-140Abstract Full Text Full Text PDF PubMed Scopus (1176) Google Scholar). However, much remains to be done to define the role of B cells in transplant tolerance. Although innate immune response is not able to reject an allograft on its own, it can mediate graft damage, leading to the development of cardiac allograft vasculopathy (23Li XC The significance of non-T-cell pathways in graft rejection: Implications for transplant tolerance.Transplantation. 2010; 90: 1043-1047Crossref PubMed Scopus (30) Google Scholar). Recent recognition of nonspecific activation of innate immune response to tissue damage (24Kim IK Bedi DS Denecke C Ge X Tullius SG Impact of innate and adaptive immunity on rejection and tolerance.Transplantation. 2008; 86: 889-894Crossref PubMed Scopus (63) Google Scholar) has indicated that the physical process of organ removing, reimplanting and reperfusing have already started the cascade of rejection through initiating stress responses which result in changes in gene and protein expression within the donor tissue (24Kim IK Bedi DS Denecke C Ge X Tullius SG Impact of innate and adaptive immunity on rejection and tolerance.Transplantation. 2008; 86: 889-894Crossref PubMed Scopus (63) Google Scholar, 25Pallet N Fougeray S Beaune P Legendre C Thervet E Anglicheau D Endoplasmic reticulum stress: An unrecognized actor in solid organ transplantation.Transplantation. 2009; 88: 605-613Crossref PubMed Scopus (37) Google Scholar, 26Famulski KS Broderick G Einecke G et al.Transcriptome analysis reveals heterogeneity in the injury response of kidney transplants.Am J Transplant. 2007; 7: 2483-2495Crossref PubMed Scopus (66) Google Scholar). Advances in normothermic organ preservation hopefully could help decrease the rejection process as well as allow greater utilization of available organs (27Jamieson RW Friend PJ Organ reperfusion and preservation.Front Biosci. 2008; 13: 221-235Crossref PubMed Scopus (0) Google Scholar). Currently, a multicenter randomized clinical trial using the Organ Care System (Transmedics), which preserves the hearts in a warm blood perfused beating state, is under recruiting phase in the United States (28TransMedics. Randomized Study of Organ Care System Cardiac for Preservation of Donated Hearts for Eventual Transplantation (PROCEEDII). Available at: http://clinicaltrials.gov/ct2/show/NCT00855712. Accessed 2011.Google Scholar). In the past decade, the induction of specific tolerance to donor antigens while retaining the ability to combat infection and prevent tumor formation has remained a desirable yet elusive goal of transplant immunology. Deliberately establishing central tolerance through transplantation of donor bone marrow into recipients who are appropriately conditioned to allow development of either full or mixed chimerism has long been recognized to be able to effectively induce donor-specific tolerance. However, allogeneic bone marrow transplantation requires precondition of myelo-depletion. Over the past few years, nonmyeloablative induction employing 3 Gy total body irradiation and adding irradiation of the thymic/mediastinal area or treatment with T cell-depleting antibodies resulting in mixed chimerism to induce organ allograft tolerance has arisen as a novel and investigational therapy (29Fudaba Y Spitzer TR Shaffer J et al.Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: In vivo and in vitro analyses.Am J Transplant. 2006; 6: 2121-2133Crossref PubMed Scopus (219) Google Scholar). Unfortunately, when reviewing our current experiences of tolerance induction with reduced intensity hematopoietic cell transplantation for achievement of kidney allograft tolerance, it is noticed that almost all mixed chimerism would be lost within months (30Fehr T Sykes M Clinical experience with mixed chimerism to induce transplantation tolerance.Transpl Int. 2008; 21: 1118-1135Crossref PubMed Scopus (0) Google Scholar). The reason for unstable tolerance is not fully understood, but it is suggested to be related to inflammatory responses (7Bingaman AW Murphey CL Palma-Vargas J Wright F A virtual crossmatch protocol significantly increases access of highly sensitized patients to deceased donor kidney transplantation.Transplantation. 2008; 86: 1864-1868Crossref PubMed Scopus (59) Google Scholar). Recently, a new approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells and tolerogenic graft facilitating cells combined with nonmyeloablative conditioning has resulted in engraftment, durable chimerism and more stable tolerance in eight kidney transplant recipients with highly mismatched related and unrelated donors (31Leventhal J Abecassis M Miller J et al.Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.Sci Transl Med. 2012; 4: 124ra28Crossref PubMed Scopus (320) Google Scholar). This achievement has implicated the possibility to induce stable mixed chimerism even across HLA barriers in regular clinical practice. In heart transplantation, tolerance induction seems to be less justified than kidney and liver, maybe due to a more immunogenic phenotype, either intrinsically, or in the context of ischemia/reperfusion injury, or the metabolically active contractile environment. Excitingly, the University of Louisville has recently completed a clinical trial entitled “Bone Marrow Transplant to Induce Tolerance in Heart Transplant Recipients” (32National Institute of Health. Bone marrow transplant to induce tolerance in heart transplant recipients. Available at: http://clinicaltrials.gov/ct2/show/NCT00497757. Accessed 2011.Google Scholar). This study result (pending) might provide a breakthrough in the approach to heart transplantation. In the meantime, other approaches involving peripheral tolerance induction (donor specific lymphocytes fail to respond to donor antigen or fail to cause graft injury because of low level/masking of donor antigen) using newer immunosuppressant agents can serve as an adjuvant option for tolerance induction in solid organ transplant, including heart transplant. The direction for further tolerance induction research is to keep explicating the mechanism of tolerance, increase safety and broaden the applicability of this protocol. The term “accommodation” was invoked to describe endothelial cell resistance to antibody-mediated rejection after ABO-incompatible kidney or experimental xenograft transplant. In both cases, the endothelial antigens that are the targets of the antibody response are mainly carbohydrates. Currently, evidence that accommodation occurs clinically are the success of ABO incompatible renal graft transplantation (33Montgomery RA Locke JE King KE et al.ABO incompatible renal transplantation: A paradigm ready for broad implementation.Transplantation. 2009; 87: 1246-1255Crossref PubMed Scopus (194) Google Scholar) and ABO incompatible infant heart transplantation (34Roche SL Burch M O’Sullivan J et al.Multicenter experience of ABO-incompatible pediatric cardiac transplantation.Am J Transplant. 2008; 8: 208-215Crossref PubMed Scopus (65) Google Scholar). As the pre- and posttransplantation protocols develop, the overall mortality, morbidity and graft survival in both these two fields are currently comparable with outcomes from the United Network for Organ Sharing (UNOS) registry (35Shin M Kim SJ ABO incompatible kidney transplantation-current status and uncertainties.J Transplant. 2011; 2011: 970421Crossref PubMed Google Scholar,36Saczkowski R Dacey C Bernier PL Does ABO-incompatible and ABO-compatible neonatal heart transplant have equivalent survival?.Interact Cardiovasc Thorac Surg. 2010; 10: 1026-1033Crossref PubMed Scopus (22) Google Scholar). It is suggested that unregulated expression of protective genes such as A20, B cell lymphoma 2 (Bcl-2), B cell lymphoma-extra large (Bcl-xL) and heme oxygenase-1 is one of the possible mechanisms of endothelial cells’ resistance to antibody- and complement-mediated damage (37Stussi G West L Cooper DK Seebach JD ABO-incompatible allotransplantation as a basis for clinical xenotransplantation.Xenotransplantation. 2006; 13: 390-399Crossref PubMed Scopus (28) Google Scholar). However, accommodation in infant heart transplantation involves donor-specific B cell tolerance, because the majority of infants have not yet developed normal production of isohemagglutinins before transplant and most make minimal or no antibodies to donor A or B antigens or both after transplant. There is much interest in how to achieve successful HLA-incompatible allograft transplantation in HLA-sensitized patients and how to treat antibody-mediated rejection after ABO-incompatible allograft transplantation. Unfortunately, it is known that there are important differences between immune responses to blood group and xenoantigens compared with HLAs, which elicit far more complicated T cell-dependent immune responses. Further work toward elucidating the biology of accommodation and antibody-mediated injury is needed. Assuming that induced tolerance in organ transplantation cannot be achieved in the near future, the use of immunosuppression medicine and immune monitoring will still be required. Minimizing immunosuppression and immunosuppression-associated complications without sacrificing the efficacy will still be the goal of posttransplantation management. During the past decades, various new drugs have been added into posttransplantation clinical practice. From the development of more powerful and specific immunosuppressants, especially beneficial for sensitized patients, to new treatments for cardiac allograft vasculopathy, advances in the science of immunology seem to hold the key to expanding the success of heart transplantation in our treatment of end-stage cardiac disease. The mammalian target of rapamycin (mTOR) plays an important role in growth factor-driven proliferation of a number of cell types, including vascular smooth muscle cells and lymphocytes. Several clinical trials of cardiac transplantation demonstrate that inhibitors of mTOR, such as sirolimus (38Keogh A Richardson RM Rugyrok P et al.Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: A randomized clinical trial.Circulation. 2004; 110: 2694-2700Crossref PubMed Scopus (385) Google Scholar) and everolimus (39Eisen HJ Tuzcu EM Dorent R et al.Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients.N Engl J Med. 2003; 349: 847-858Crossref PubMed Scopus (1005) Google Scholar), are highly effective in preventing acute cellular rejection and in ameliorating cardiac allograft vasculopathy. In patients with established cardiac allograft vasculopathy (40Mancini D Pinney S Burkhoff D et al.Use of rapamycin slows progression of cardiac transplantation vasculopathy.Circulation. 2003; 108: 48-53Crossref PubMed Scopus (368) Google Scholar) or malignancy (41Majewski M Korecka M Joergensen J et al.Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from post-transplant lymphoproliferative disorder at allograft protecting doses.Transplantation. 2003; 75: 1710-1717Crossref PubMed Scopus (0) Google Scholar, 42Rubio-Viqueira B Hidalgo M Targeting mTOR for cancer treatment.Adv Exp Med Biol. 2006; 587: 309-327Crossref PubMed Scopus (27) Google Scholar, 43Stallone G Schena A Infante B Di Paolo S Loverre A Maggio G Sirolimus for Kaposi’s sarcoma in renal-transplant recipients.N Engl J Med. 2005; 352: 1317-1323Crossref PubMed Scopus (820) Google Scholar, 44Kauffman HM Cherikh WS Cheng Y Hanto DW Kahan BD Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies.Transplantation. 2005; 80: 883-889Crossref PubMed Scopus (550) Google Scholar), switching immunosuppressants to mTOR was proven to improve clinical outcome. Another novel use of mTOR is to develop calcineurin inhibitor (CNI)-free immunosuppressive regimens. Several studies indicate that weaning of CNIs after initiation of sirolimus therapy may improve renal function, but this weaning should be attempted more than 6 months posttransplantation in patients who do not have excessive longstanding renal insufficiency (45Kushwaha SS Khalpey Z Frantz RP et al.Sirolimus in cardiac transplantation: Use as a primary immunosuppressant in calcineurin inhibitor-induced nephrotoxicity.J Heart Lung Transplant. 2005; 24: 2129-2136Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,46Moloney ED O’Mahony U Kirwan M et al.Pharmacokinetics of sirolimus in heart transplant recipients with chronic renal impairment.Transplant Proc. 2004; 36: 1547-1550Crossref PubMed Scopus (0) Google Scholar). Recent advances in immunosuppression have mostly involved the development and expanded use of polyclonal and monoclonal antibodies to reduce antibody levels in candidates for transplantation with high titers. Rituximab, a chimeric anti-CD20 (anti-B cell) monoclonal antibody, has been proven to be effective as a desensitization regimen in combination with intravenous immune globulin for kidney transplant patients awaiting a transplant from either a living donor or a deceased donor (47Vo AA Lukovsky M Toyoda M et al.Rituximab and intravenous immune globulin for desensitization during renal transplantation.N Engl J Med. 2008; 359: 242-251Crossref PubMed Scopus (545) Google Scholar). Rituximab has been shown to expand the transitional B cell compartment upon reconstitution (48Kopchaliiska D Zachary AA Montgomery RA Leffell MS Reconstitution of peripheral allospecific CD19 + B-cell subsets after B-lymphocyte depletion therapy in renal transplant patients.Transplantation. 2009; 87: 1394-1401Crossref PubMed Scopus (0) Google Scholar). A clinical trial applying rituximab in heart transplant patient is currently undergoing (49National Institute of Allergy and Infectious Diseases. Prevention of cardiac allograft vasculopathy using rit" @default.
• W1500540667 created "2016-06-24" @default.
• W1500540667 creator A5087709436 @default.
• W1500540667 date "2012-11-01" @default.
• W1500540667 modified "2023-10-04" @default.
• W1500540667 title "The Future of Heart Transplantation" @default.
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