FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2989082165> ?p ?o ?g. }

• W2989082165 endingPage "354" @default.
• W2989082165 startingPage "348" @default.
• W2989082165 abstract "In 2017, the American Society of Transplantation (AST) launched the Outstanding Questions in Transplantation Research forum to stimulate a community-wide discussion of how the field is evolving and to help identify areas where a better dialogue between clinicians and researchers could result in great advancements. Tolerance emerged as a topic of great interest to the AST community. This minireview provides an overview of clinical transplantation tolerance. Historical background followed by a review of the current status of attempts to establish tolerance in the clinic, highlighting the dynamic online discussion surrounding this important topic from the AST Transplantation Research forum, is provided. In 2017, the American Society of Transplantation (AST) launched the Outstanding Questions in Transplantation Research forum to stimulate a community-wide discussion of how the field is evolving and to help identify areas where a better dialogue between clinicians and researchers could result in great advancements. Tolerance emerged as a topic of great interest to the AST community. This minireview provides an overview of clinical transplantation tolerance. Historical background followed by a review of the current status of attempts to establish tolerance in the clinic, highlighting the dynamic online discussion surrounding this important topic from the AST Transplantation Research forum, is provided. There have been great advances in clinical solid organ, tissue, and cellular transplantations. Development of new immunosuppressive drugs to prevent either allograft rejection or graft-versus-host disease (GVHD) has been central to this progress. The use of these drugs has greatly improved survival of transplanted organs and patients in the short term. Yet, in the long term the use of these drugs is associated with substantial side effects, negatively impacting the quality and expectancy of life of the transplant recipients. Thus, the use of calcineurin inhibitors (CNI), that is, tacrolimus and cyclosporine, is associated with nephrotoxicity, cardiovascular and metabolic side effects, as well as increased risk of opportunistic infections and cancer.1Helderman JH Van Buren DH Amend Jr, WJ Pirsch JD. Chronic immunosuppression of the renal transplant patient.J Am Soc Nephrol. 1994; 4: S2-S9Crossref PubMed Google Scholar, 2Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an overview.Am J Kidney Dis. 2001; 38: S25-S35Abstract Full Text PDF PubMed Scopus (88) Google Scholar, 3Pirsch JD D’Alessandro AM Sollinger HW et al.Hyperlipidemia and transplantation: etiologic factors and therapy.J Am Soc Nephrol. 1992; 2: S238-S242Crossref PubMed Google Scholar, 4Shaw LM Kaplan B Kaufman D. Toxic effects of immunosuppressive drugs: mechanisms and strategies for controlling them.Clin Chem. 1996; 42: 1316-1321Crossref PubMed Scopus (62) Google Scholar Long-term CNI treatment can lead to the need for dialysis or kidney transplantation even in nonrenal transplant recipients,5O’Riordan A Wong V McCormick PA Hegarty JE Watson AJ. Chronic kidney disease post-liver transplantation.Nephrol Dial Transplant. 2006; 21: 2630-2636Crossref PubMed Scopus (88) Google Scholar thus making the demand for the already short supply of transplantable organs even more acute. Therapeutic agents that have been developed to avoid the side effects of CNIs also have not lived up to their promises. They too are associated with their own set of complications.6Wojciechowski D Vincenti F. Current status of costimulatory blockade in renal transplantation.Curr Opin Nephrol Hypertens. 2016; 25: 583-590Crossref PubMed Scopus (20) Google Scholar,7Hricik DE Formica RN Nickerson P et al.Adverse outcomes of tacrolimus withdrawal in immune-quiescent kidney transplant recipients.J Am Soc Nephrol. 2015; 26: 3114-3122Crossref PubMed Scopus (147) Google Scholar Moreover, even strict maintenance immunosuppressive drug therapy compliance does not avert chronic allograft injury in many recipients. Because of the limitations of prolonged drug-based immunosuppression (IS), the 10-year graft survival of deceased donor kidney transplantation remains ≈50%, and for HLA-mismatched living donor kidneys, only 60%.8Cecka JM. Kidney transplantation in the United States.in: Terasaki PI Clinical Transplantation 2008. Terasaki Research Foundation, Los Angeles, CA2008: 1-18Google Scholar Death with a functioning allograft accounts for at least half of the recipient losses, primarily due to the side effects of drug-based IS.9Schnitzler MA Skeans MA Axelrod DA et al.OPTN/SRTR 2016 annual data report: economics.Am J Transplant. 2018; 18: 464-503Crossref PubMed Scopus (23) Google Scholar Also, all of the immunosuppressive drugs currently being utilized suppress the immune system nonspecifically, even though we need to target only donor-specific alloreactive responses. This leads to increased risk of infections and malignancy. Therefore, induction of allograft tolerance has been considered the logical solution for many of these limitations associated with long-term IS as well as the best approach to reduce the risk of chronic rejection. Transplantation tolerance may be defined as the specific absence of a destructive immunologic response to a transplanted organ or tissue without ongoing exogenous IS. Alternate definitions include (1) absence of donor-specific alloantibodies, (2) no signs of destructive lymphocyte infiltration in allograft biopsies, (3) presence of possible molecular tolerance fingerprints, and (4) if systemic tolerance is sought, proof of donor-specific unresponsiveness with recovered third-party responses in functional assays in vitro, and so on. Such definitions acknowledge the important role of deletional effects to eliminate damaging alloreactive immune effectors, as well as the role that ongoing immune regulation may play in achieving, and perhaps maintaining tolerance.10Kawai T Sachs DH Sprangers B et al.Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression.Am J Transplant. 2014; 14: 1599-1611Crossref PubMed Scopus (212) Google Scholar It has been appreciated for more than 60 years that therapeutic cell transfer can allow for the establishment of donor-specific tolerance. Billingham, Brent, and Medawar11Billingham RE Brent L Medawar PB. Actively acquired tolerance of foreign cells [Reprint in J Immunol. 2010 Jan 1;184(1):5-8; PMID: 20028658].Nature. 1953; 172: 603-606Crossref PubMed Scopus (2237) Google Scholar observed in 1953 that H-2 disparate donor bone marrow–derived cells infused into fetal or newborn murine recipients could bring about lifelong specific acquired immunologic tolerance to skin allografts. Medawar ascribed chimerism to be the mechanism of this tolerance.12Anderson D Billingham RE Lampkin GH Medawar PB. The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle.Heredity. 1952; 6: 201-221Crossref Google Scholar In this he was greatly influenced by the seminal observations of Owen13Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins.Science. 1945; 102: 400-401Crossref PubMed Scopus (865) Google Scholar in dizygotic twin calves where mixing of blood cells due to cross-circulation through the common placenta in utero resulted in the freemartin effect. The use of pretransplant blood transfusions, which emerged in the 1970s and 1980s to enhance outcomes following kidney transplantation, can be viewed as an early attempt to translate the observations of Medawar and Owen from the bench to the bedside. It was observed that nonspecific and subsequently donor-specific blood transfusions (DST) improved human kidney transplant rejection-free survival.14Opelz G Terasaki PI. Improvement of kidney-graft survival with increased numbers of blood transfusions.N Engl J Med. 1978; 299: 799-803Crossref PubMed Scopus (361) Google Scholar,15Salvatierra Jr, O Vincenti F Amend W et al.Deliberate donor-specific blood transfusions prior to living related renal transplantation. A new approach.Ann Surg. 1980; 192: 543-552Crossref PubMed Scopus (305) Google Scholar More contemporary analysis of the effects of DST has highlighted its ability to augment regulatory T cells (Tregs).16Eikmans M Waanders MM Roelen DL et al.Differential effect of pretransplant blood transfusions on immune effector and regulatory compartments in HLA-sensitized and nonsensitized recipients.Transplantation. 2010; 90: 1192-1199Crossref PubMed Scopus (17) Google Scholar Preclinical work in this era demonstrated that post- or peritransplant infusion of donor bone marrow cells (DBMC) together with T cell depletion prolonged and sometimes brought about indefinite allograft survival in adult murine and canine recipients in the absence of chronic IS.17Slavin S Fuks Z Strober S Kaplan H Howard RJ Sutherland DE. Transplantation tolerance across major histocompatibility barriers after total lymphoid irradiation.Transplantation. 1979; 28: 359-361Crossref PubMed Scopus (22) Google Scholar, 18Monaco AP Wood ML. Studies on heterologous antilymphocyte serum in mice. VII. Optimal cellular antigen for induction of immunologic tolerance with antilymphocyte serum.Transplant Proc. 1970; 2: 489-496PubMed Google Scholar, 19Caridis DT Liegeois A Barrett I Monaco AP. Enhanced survival of canine renal allografts of ALS-treated dogs given bone marrow.Transplant Proc. 1973; 5: 671-674PubMed Google Scholar In the 1970s Monaco et al20Monaco AP Clark AW Wood ML Sahyoun AI Codish SD Brown RW. Possible active enhancement of a human cadaver renal allograft with antilymphocyte serum (ALS) and donor bone marrow: case report of an initial attempt.Surgery. 1976; 79: 384-392PubMed Google Scholar attempted to induce tolerance in human kidney transplant recipients using iliac crest donor bone marrow cells (iDBMC). In a subsequent trial, Barber et al reported encouraging results initially with iDBMC infusions,21Barber WH Mankin JA Laskow DA et al.Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients.Transplantation. 1991; 51: 70-75Crossref PubMed Scopus (256) Google Scholar but later observed no significant difference with the control group.22McDaniel DO Naftilan J Hulvey K et al.Peripheral blood chimerism in renal allograft recipients transfused with donor bone marrow.Transplantation. 1994; 57: 852-856Crossref PubMed Scopus (75) Google Scholar However, Starzl et al provided renewed momentum to these protocols by their observation that microchimerism of bone marrow–derived cells was present in several transplant recipients who had stopped IS for several years without losing their grafts.23Starzl TE Demetris AJ Trucco M et al.Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance.Hepatology. 1993; 17: 1127-1152Crossref PubMed Scopus (663) Google Scholar,24Starzl TE Demetris AJ Trucco M et al.Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation.Transplantation. 1993; 55: 1272-1277Crossref PubMed Scopus (295) Google Scholar Based on this, they initiated a clinical trial using vertebral body donor bone marrow cells (vDBMC).25Fontes P Rao AS Demetris AJ et al.Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation.Lancet. 1994; 344: 151-155Abstract PubMed Scopus (275) Google Scholar Similar clinical trials with vDBMC infusions were also initiated at the University of Miami in both renal and extrarenal transplant recipients.26Mathew JM Ciancio G Burke GW et al.Immune “tolerance profiles” in donor bone marrow infused kidney transplant patients using multiple ex vivo functional assays.Hum Immunol. 2010; 71: 566-576Crossref PubMed Scopus (17) Google Scholar, 27Mathew JM Miller J. Immunoregulatory role of chimerism in clinical organ transplantation.Bone Marrow Transplant. 2001; 28: 115-119Crossref PubMed Scopus (17) Google Scholar, 28Mathew JM Garcia-Morales RO Carreno M et al.Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation.Transpl Immunol. 2003; 11: 307-321Crossref PubMed Scopus (37) Google Scholar Increased graft survival and lower chronic rejection were observed in vDBMC-infused deceased donor kidney transplant recipients compared to noninfused controls.29Ciancio G Miller J Garcia-Morales RO et al.Six-year clinical effect of donor bone marrow infusions in renal transplant patients.Transplantation. 2001; 71: 827-835Crossref PubMed Scopus (120) Google Scholar Similar observations were made by other investigators.30Gammie JS Pham SM. Simultaneous donor bone marrow and cardiac transplantation: can tolerance be induced with the development of chimerism?.Curr Opin Cardiol. 1999; 14: 126-132Crossref PubMed Scopus (14) Google Scholar Nevertheless, none of the patients were withdrawn from IS in any of these clinical protocols, mainly due to lack of validated in vitro assays that could predict, or correlate with, operational tolerance. However, these early clinical trials provided the basis for further development of in vitro and ex vivo assay systems28Mathew JM Garcia-Morales RO Carreno M et al.Immune responses and their regulation by donor bone marrow cells in clinical organ transplantation.Transpl Immunol. 2003; 11: 307-321Crossref PubMed Scopus (37) Google Scholar as well as molecular biomarker platforms to evaluate both spontaneous and induced transplant tolerance (extensively reviewed in 31Mathew JM Leventhal JR. Clinical transplant tolerance: coming of age.Hum Immunol. 2018; 79: 255-257Crossref PubMed Scopus (3) Google Scholar). There has been considerable effort in profiling solid organ transplant recipients who develop spontaneous operational tolerance, wherein drug-based IS is deliberately withdrawn in stable transplant recipients.32Tryphonopoulos P Tzakis AG Weppler D et al.The role of donor bone marrow infusions in withdrawal of immunosuppression in adult liver allotransplantation.Am J Transplant. 2005; 5: 608-613Crossref PubMed Scopus (103) Google Scholar This phenomenon has been almost exclusively observed in liver transplantation, due to the tolerogenic properties of this organ. Even in liver transplantation, spontaneous tolerance occurs only in 20%-30% of the recipients.33Levitsky J Feng S. Tolerance in clinical liver transplantation.Hum Immunol. 2018; 79: 283-287Crossref PubMed Scopus (58) Google Scholar Studies have identified biomarkers linked with iron metabolism and homeostasis to be associated with operational tolerance in liver allograft recipients. Comparable spontaneously tolerant patients who have received a kidney transplant have been rarely identified, with IS stopped due to noncompliance or out of necessity (ie, posttransplant malignancy or severe opportunistic infection).34Roussey-Kesler G Giral M Moreau A et al.Clinical operational tolerance after kidney transplantation.Am J Transplant. 2006; 6: 736-746Crossref PubMed Scopus (154) Google Scholar Analysis of kidney transplant recipients who have developed spontaneous and sustained tolerance have revealed an association with B cells.35Chesneau M Danger R Soulillou JP Brouard S. B cells in operational tolerance.Hum Immunol. 2018; 79: 373-379Crossref PubMed Scopus (6) Google Scholar Tolerant individuals are characterized by increased numbers and frequencies of B cells in the blood and increased expression of genes associated with B cells in the blood, urine, and biopsies. Comparisons of the B cell repertoires of tolerant individuals and those receiving IS reveal that not only are the B cells more numerous but also developmental differences result in a repertoire comprising more naïve and transitional B cells in the tolerant cohort.36Newell KA Adams AB Turka LA. Biomarkers of operational tolerance following kidney transplantation – The immune tolerance network studies of spontaneously tolerant kidney transplant recipients.Hum Immunol. 2018; 79: 380-387Crossref PubMed Scopus (20) Google Scholar B cells isolated from tolerant individuals also display functional differences compared to those from individuals receiving IS. Many of these differences may serve to suppress alloimmunity. Tolerant patients have also been shown to exhibit a specific increase in blood CD4+ CD45RA− FOXP3high memory Tregs in comparison to stable kidney recipients and healthy controls.31Mathew JM Leventhal JR. Clinical transplant tolerance: coming of age.Hum Immunol. 2018; 79: 255-257Crossref PubMed Scopus (3) Google Scholar Even though the participation of immunoregulatory cells has been reported, the various mechanisms operating in these rare patients are elusive or at best inconclusive. Prospective validation of biomarkers, importantly with confirmation of immunologic quiescence on allograft histology, is an important ongoing area of investigation. Several clinical trials in kidney transplantation over the past 2 decades have highlighted the ability of therapeutic cell transfer using donor-derived hematopoietic stem cells (HSC) to establish donor-specific tolerance and allow for IS withdrawal (Table 1). At Massachusetts General Hospital, the effort has been directed to induce mixed chimerism with unmodified donor bone marrow–infused peritransplant in haplo-identical living donor kidney transplant recipients using conditioning with thymic irradiation combined with antibody-based T cell depletion (the anti-CD2 mAb MEDI-507), rituximab, and cyclophosphamide.37Spitzer TR Delmonico F Tolkoff-Rubin N 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. 1999; 68: 480-484Crossref PubMed Scopus (352) Google Scholar, 38Kawai T Cosimi AB Spitzer TR et al.HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2008; 358: 353-361Crossref PubMed Scopus (850) Google Scholar, 39Kawai T Sachs DH Sykes M Cosimi AB Immune Tolerance NetworkHLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2013; 368: 1850-1852Crossref PubMed Scopus (140) Google Scholar Chimerism was only transient and occurred at very low levels. Operational tolerance was induced in 7 of 10 subjects, 4 of whom remain off IS. Most patients developed “engraftment syndrome” characterized by severe but transient renal dysfunction in the first week posttransplant. A modified version of the protocol with total body irradiation (TBI) replacing cyclophosphamide has demonstrated the ability to avoid engraftment syndrome.40Sasaki H Oura T Spitzer TR et al.Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach.Hum Immunol. 2018; 79: 258-265Crossref PubMed Scopus (28) Google Scholar Disease recurrence has also been observed in certain operationally tolerance subjects requiring reinitiation of IS. Mechanistic studies from the Massachusetts General Hospital cohort indicate that both clonal deletion and immune regulation by Tregs play a role in the establishment and maintenance of tolerance.41Sykes M. Immune monitoring of transplant patients in transient mixed chimerism tolerance trials.Hum Immunol. 2018; 79: 334-342Crossref PubMed Scopus (9) Google ScholarTABLE 1Clinical transplantation tolerance trails from around the worldaThere may be other clinical trials that we are not aware of.Center/entityOrganHLAProtocolsNReferences (if any)MGHKidneyMatchbCompleted.Full/mixed chimerism (myeloma/kidney)1042Spitzer TR Sykes M Tolkoff-Rubin N et al.Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease.Transplantation. 2011; 91: 672-676Crossref PubMed Scopus (121) Google ScholarKidneyMismatchbCompleted.Mixed (transient) chimerism1240Sasaki H Oura T Spitzer TR et al.Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach.Hum Immunol. 2018; 79: 258-265Crossref PubMed Scopus (28) Google ScholarStanfordKidneyMatchcOngoing (“n” from latest report).Mixed chimerism2943Scandling JD Busque S Lowsky R et al.Macrochimerism and clinical transplant tolerance.Hum Immunol. 2018; 79: 266-271Crossref PubMed Scopus (21) Google ScholarKidneyMismatch bCompleted.Mixed chimerism1943Scandling JD Busque S Lowsky R et al.Macrochimerism and clinical transplant tolerance.Hum Immunol. 2018; 79: 266-271Crossref PubMed Scopus (21) Google ScholarCIRM (Stanford & Northwestern)KidneyMismatchdTo be initiated soon.DHSC & recipient regulatory T cells (mixed chimerism)22dTo be initiated soon.NorthwesternKidneyMatchbCompleted.Alemtuzumab and donor HSC infusion2044Leventhal JR Mathew JM Salomon DR et al.Nonchimeric HLA-identical renal transplant tolerance: regulatory immunophenotypic/genomic biomarkers.Am J Transplant. 2016; 16: 221-234Crossref PubMed Scopus (39) Google ScholarKidneyMismatchbCompleted.Durable chimerism (FCRx)3745Leventhal JR Ildstad ST. Tolerance induction in HLA disparate living donor kidney transplantation by facilitating cell-enriched donor stem cell Infusion: the importance of durable chimerism.Hum Immunol. 2018; 79: 272-276Crossref PubMed Scopus (33) Google ScholarKidneyMismatchbCompleted.Regulatory T cells (TRACT therapeutics)946Mathew JM H-Voss J LeFever A et al.A phase I clinical trial with ex vivo expanded recipient regulatory T cells in living donor kidney transplants.Sci Rep. 2018; 8: 7428Crossref PubMed Scopus (135) Google ScholarLiverMismatchbCompleted.TAC to SRL monotherapy, then withdrawalManuscript accepted in HepatologyKidneyMismatchdTo be initiated soon.Regulatory T cells (TRACT therapeutics)120dTo be initiated soon.Johns HopkinsKidneyMismatchFull chimerism (FCRx)1UCSFKidneyMismatchcOngoing (“n” from latest report).Regulatory T cells347Chandran S Tang Q Sarwal M et al.Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants.Am J Transplant. 2017; 17: 2945-2954Crossref PubMed Scopus (128) Google ScholarLiverMismatchcOngoing (“n” from latest report).Alloantigen-specific Tregs (ARTEMIS)18https://clinicaltrials.gov/ct2/show/NCT02474199?term=NCT02474199&rank=1The One StudyKidneyMismatchDonor-alloantigen-reactive regulatory T cells (UCSF)6https://clinicaltrials.gov/ct2/show/NCT02244801?term=NCT02244801&rank=1KidneyMismatchAutologous tolerogenic dendritic cells11https://clinicaltrials.gov/ct2/show/NCT02252055?term=NCT02252055&rank=1KidneyMismatchDonor-derived regulatory macrophage8https://clinicaltrials.gov/ct2/show/NCT02085629?term=NCT02085629&rank=1KidneyMismatchcOngoing (“n” from latest report).Regulatory T cells (UK)15https://clinicaltrials.gov/ct2/show/NCT02129881?term=NCT02129881&rank=1KidneyMismatchcOngoing (“n” from latest report).Regulatory T cells (Germany)9https://clinicaltrials.gov/ct2/show/NCT02371434?term=NCT02371434&rank=1KidneyMismatchcOngoing (“n” from latest report).Regulatory T cells With Belatacept (Boston)8https://clinicaltrials.gov/ct2/show/NCT02091232?term=NCT02091232&rank=1Kings College (UK)LiverMismatchRegulatory T cells (ThRIL)9https://clinicaltrials.gov/ct2/show/NCT02166177?term=NCT02166177&rank=1IRCCS; ItalyKidneyMismatchcOngoing (“n” from latest report).Mesenchymal stromal cells4+48Casiraghi F Perico N Remuzzi G. Mesenchymal stromal cells for tolerance induction in organ transplantation.Hum Immunol. 2018; 79: 304-313Crossref PubMed Scopus (36) Google ScholarPittsburghLiverMismatchRegulatory dendritic cells1249Thomson AW Humar A Lakkis FG Metes DM. Regulatory dendritic cells for promotion of liver transplant operational tolerance: rationale for a clinical trial and accompanying mechanistic studies.Hum Immunol. 2018; 79: 314-321Crossref PubMed Scopus (45) Google ScholarTalarisKidneyMismatchdTo be initiated soon.Full chimerism (FCRx) - multicenter120dTo be initiated soon.Sam Sang University, (South Korea)KidneyMismatchcOngoing (“n” from latest report).Mixed chimerism950Lee K Park J Chung Y Kim S. Tolerance induction with hematopoietic stem cells in kidney transplantations [abstract].Am J Transplant. 2019; 19: 349-350Google ScholarHokkaido University, JapanLiverMismatchcOngoing (“n” from latest report).Regulatory T cells (Tregs)1051Todo S Yamashita K. Anti-donor regulatory T cell therapy in liver transplantation.Hum Immunol. 2018; 79: 288-293Crossref PubMed Scopus (23) Google ScholarUHN, Toronto, CanadaLiverMismatchAutologous hematopoietic stem cells552Chruscinski A Atkins H Clement A et al.Proof-of-principle phase 2A study to evaluate autologous hematopoietic stem cell transplantation for allogeneic organ transplant tolerance (ASCOTT) [abstract].Am J Transplant. 2019; 19PubMed Google ScholarCIRM, California Institute of Regenerative Medicine; DHSC, donor hematopoietic stem cells; FCRx, DHSC plus facilitating cells; HSC, hematopoietic stem cells; IRCCS, Istituto di Ricovero e Cura a Carattere Scientifico; SRL, sirolimus; TAC, tacrolimus; UCSF, University of California at San Francisco; UHN, University Health Network.a There may be other clinical trials that we are not aware of.b Completed.c Ongoing (“n” from latest report).d To be initiated soon. Open table in a new tab CIRM, California Institute of Regenerative Medicine; DHSC, donor hematopoietic stem cells; FCRx, DHSC plus facilitating cells; HSC, hematopoietic stem cells; IRCCS, Istituto di Ricovero e Cura a Carattere Scientifico; SRL, sirolimus; TAC, tacrolimus; UCSF, University of California at San Francisco; UHN, University Health Network. The Stanford University protocol uses posttransplant anti-thymocyte globulin and total lymphoid irradiation (TLI).53Scandling JD Busque S Dejbakhsh-Jones S et al.Tolerance and chimerism after renal and hematopoietic-cell transplantation.N Engl J Med. 2008; 358: 362-368Crossref PubMed Scopus (409) Google Scholar, 54Scandling JD Busque S Dejbakhsh-Jones S et al.Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants.Am J Transplant. 2012; 12: 1133-1145Crossref PubMed Scopus (161) Google Scholar, 55Scandling JD Busque S Shizuru JA et al.Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation.Am J Transplant. 2015; 15: 695-704Crossref PubMed Scopus (137) Google Scholar This is followed by the administration of a manipulated donor hematopoietic cell product controlling for the dose of CD34+ and CD3+ cells with weaning of IS based upon the presence of durable mixed chimerism. Overall, 24/29 HLA identical living donor kidney subjects have been taken off immunosuppressive agents. Establishment of durable donor chimerism for at least 6 months was associated with successful immunosuppressive drug withdrawal in HLA identical renal allograft recipients. Tolerance was maintained despite the loss of chimerism in the majority of these patients following cessation of IS. Interestingly, persistent allograft tolerance did afford protection from recurrence of the original cause of renal failure in certain subjects who lost chimerism. Attempts to achieve persistent IS-independent mixed chimerism and tolerance in mismatched donor/recipient pairs using the Stanford TLI approach have not been successful, despite escalating doses of donor CD3+ T cells in the stem cell graft. No subjects have lost a graft.43Scandling JD Busque S Lowsky R et al.Macrochimerism and clinical transplant tolerance.Hum Immunol. 2018; 79: 266-271Crossref PubMed Scopus (21) Google Scholar A Phase 3 trial of the Stanford approach in HLA identical patients has been initiated by Medeor Therapeutics. Two trials have been conducted at Northwestern University. In 1, a total of 37 patients (36 at Northwestern, 1 at Duke) have been transplanted in a Phase 2 trial including HLA-mismatched, unrelated and related living donor kidney transplant recipients using nonmyeloablative conditioning (fludarabine, cyclophosphamide, and low-dose TBI) combined with a manipulated stem cell product enriched for a CD8+/TCR- population of cells termed facilitating cells (the total product denoted as FCRx).56Leventhal 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 (321) Google Scholar Withdrawal of IS is conducted over a 1-year period and is based upon the presence of durable donor chimerism. Twenty-six subjects have achieved durable chimerism (T cell chimerism >50%) as determined by short tandem repeat polymerase chain reaction analysis, and were taken off IS. Twenty-three of these subjects developed “full” peripheral blood chimerism, with >98% donor cells.45Leventhal JR Ildstad ST. Tolerance induction in HLA disparate living donor kidney transplantation by facilitating cell-enriched donor stem cell Infusion: the importance of durable chimerism.Hum Immunol. 2018; 79: 272-276Crossref PubMed Scopus (33) Google Scholar Follow-up after IS withdrawal ranges from 12 to 100 months. None of the subjects successfully withdrawn from IS have experienced rejection episodes and none have had to resume IS. Disease recurrence has not been seen in at-risk patients with persistent donor chimerism off of all immunosuppression. Two subjects had allograft loss related to early posttransplant infections. Two subjects developed GVHD. Patient and graft survival are similar to a comparison cohort treated with standard of care. Efforts are under way to launch a Phase 3 trial to assess the “FCRx” approach in the near future. A second trial at Northwestern has focused upon therapeutic donor s" @default.
• W2989082165 created "2019-11-22" @default.
• W2989082165 creator A5010856093 @default.
• W2989082165 creator A5019264917 @default.
• W2989082165 date "2020-02-01" @default.
• W2989082165 modified "2023-09-27" @default.
• W2989082165 title "Outstanding questions in transplantation: Tolerance" @default.
• W2989082165 cites W1580156494 @default.
• W2989082165 cites W1648718288 @default.
• W2989082165 cites W1914417236 @default.
• W2989082165 cites W1941682190 @default.
• W2989082165 cites W1945663257 @default.
• W2989082165 cites W1951315012 @default.
• W2989082165 cites W1967702267 @default.
• W2989082165 cites W1981631137 @default.
• W2989082165 cites W1983215753 @default.
• W2989082165 cites W1993215234 @default.
• W2989082165 cites W1998039712 @default.
• W2989082165 cites W2003176999 @default.
• W2989082165 cites W2011835709 @default.
• W2989082165 cites W2014751151 @default.
• W2989082165 cites W2039239630 @default.
• W2989082165 cites W2039801541 @default.
• W2989082165 cites W2041687279 @default.
• W2989082165 cites W2054436378 @default.
• W2989082165 cites W2080795998 @default.
• W2989082165 cites W2087519572 @default.
• W2989082165 cites W2090640038 @default.
• W2989082165 cites W2094686114 @default.
• W2989082165 cites W2103073605 @default.
• W2989082165 cites W2107841942 @default.
• W2989082165 cites W2119322191 @default.
• W2989082165 cites W2123252570 @default.
• W2989082165 cites W2128379299 @default.
• W2989082165 cites W2132243512 @default.
• W2989082165 cites W2138734371 @default.
• W2989082165 cites W2154455036 @default.
• W2989082165 cites W2161957114 @default.
• W2989082165 cites W2164736972 @default.
• W2989082165 cites W2165336179 @default.
• W2989082165 cites W2170268782 @default.
• W2989082165 cites W2284630235 @default.
• W2989082165 cites W2315718309 @default.
• W2989082165 cites W2320423786 @default.
• W2989082165 cites W2328257317 @default.
• W2989082165 cites W2337139679 @default.
• W2989082165 cites W2510762251 @default.
• W2989082165 cites W2571885609 @default.
• W2989082165 cites W2726575235 @default.
• W2989082165 cites W2740089916 @default.
• W2989082165 cites W2765413797 @default.
• W2989082165 cites W2765511912 @default.
• W2989082165 cites W2766101332 @default.
• W2989082165 cites W2768501299 @default.
• W2989082165 cites W2777246413 @default.
• W2989082165 cites W2778341848 @default.
• W2989082165 cites W2781372458 @default.
• W2989082165 cites W2783476856 @default.
• W2989082165 cites W2790341443 @default.
• W2989082165 cites W2791950869 @default.
• W2989082165 cites W2792266728 @default.
• W2989082165 cites W2792395829 @default.
• W2989082165 cites W2792985650 @default.
• W2989082165 cites W2792986947 @default.
• W2989082165 cites W2794037394 @default.
• W2989082165 cites W2801024566 @default.
• W2989082165 cites W2917338207 @default.
• W2989082165 cites W2938403968 @default.
• W2989082165 cites W4233084236 @default.
• W2989082165 cites W4294349031 @default.
• W2989082165 doi "https://doi.org/10.1111/ajt.15680" @default.
• W2989082165 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31675469" @default.
• W2989082165 hasPublicationYear "2020" @default.
• W2989082165 type Work @default.
• W2989082165 sameAs 2989082165 @default.
• W2989082165 citedByCount "18" @default.
• W2989082165 countsByYear W29890821652020 @default.
• W2989082165 countsByYear W29890821652021 @default.
• W2989082165 countsByYear W29890821652022 @default.
• W2989082165 countsByYear W29890821652023 @default.
• W2989082165 crossrefType "journal-article" @default.
• W2989082165 hasAuthorship W2989082165A5010856093 @default.
• W2989082165 hasAuthorship W2989082165A5019264917 @default.
• W2989082165 hasBestOaLocation W29890821651 @default.
• W2989082165 hasConcept C141071460 @default.
• W2989082165 hasConcept C177713679 @default.
• W2989082165 hasConcept C2911091166 @default.
• W2989082165 hasConcept C71924100 @default.
• W2989082165 hasConceptScore W2989082165C141071460 @default.
• W2989082165 hasConceptScore W2989082165C177713679 @default.
• W2989082165 hasConceptScore W2989082165C2911091166 @default.
• W2989082165 hasConceptScore W2989082165C71924100 @default.
• W2989082165 hasIssue "2" @default.
• W2989082165 hasLocation W29890821651 @default.
• W2989082165 hasLocation W29890821652 @default.
• W2989082165 hasOpenAccess W2989082165 @default.
• W2989082165 hasPrimaryLocation W29890821651 @default.
• W2989082165 hasRelatedWork W2058866009 @default.

• next