Long-Term Results in Recipients of Combined HLA-Mismatched Kidney and Bone Marrow Transplantation Without Maintenance Immunosuppression

Kawai, Tatsuo; Sachs, David H.; Sprangers, Ben; Spitzer, Thomas R.; Saidman, Susan L.; Zorn, Emmanuel; Tolkoff-Rubin, Nina; Preffer, Frederic I.; Crisalli, Kerry; Gao, Baofeng; Wong, Waichi; Morris, Heather; LoCascio, Samuel A.; Sayre, Peter H.; Shonts, Brittany; Williams, Winfred W.; Smith, Rex Neal; Colvin, Robert B.; Sykes, Megan; Cosimi, A. Benedict

doi:10.1111/ajt.12731

Cited by 249 publications

(250 citation statements)

References 41 publications

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“…All patients developed an engraftment-related capillary leak syndrome and profound leukopenia (with an absolute neutrophil count nadir of 36/mm 3 , reaching >500/mm 3 ß14 days post-BMT). A preliminary post hoc analysis suggests that the seven "tolerant" patients from this cohort showed less hypertension and hyperlipidemia than similarly matched patients on conventional immunosuppression [77]. Regulation appears to have been involved in mediating graft acceptance in these transiently chimeric patients, but evidence for clonal deletion was also found in tolerant patients by tracking specific pretransplant defined donor-reactive recipient T cell clones using highthroughput sequencing [61].…”

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confidence: 86%

“…TCR repertoire analysis revealed a diverse T-cell repertoire [83]. Kawai [77] Scandling [80] Scandling [80] Leventhal [83] Buhler [84] Kawai [76] Scandling [79] Leventhal [88] Fudaba [85] Scandling [87] Leventhal [39] Spitzer [86] Scandling [78] nm: not mentioned; TI: thymic irradiation; TLI: total lymphoid irradiation; ATG: antithymocyte globulin; CNI: calcineurin inhibitor; MMF: mycophenolate mofetil; TAC: tacrolimus; MGH: Massachusetts General Hospital.…”

Section: Clinical Translation Of Chimerism-based Transplantation Tolementioning

confidence: 99%

“…GVHD occurred in four patients. Subsequently, a trial of simultaneous HLA-mismatched (i.e., one-haplotype mismatch) living-related kidney and BMT was conducted in patients suffering from renal failure without concomitant disease (i.e., without myeloma) [76,77]. In this study, ten patients received variations of a nonmyeloablative conditioning regimen including cyclophosphamide, anti-CD2, and thymic irradiation with or without rituximab.…”

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confidence: 99%

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Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

et al. 2015

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Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans.Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells. Keywords: Clonal deletion Mixed chimerism Nonmyeloablative conditioning Transplantation tolerance Treg cells IntroductionLong-term outcome after organ transplantation has improved little in the past few decades and remains suboptimal [1]. Grafts are still lost to immunological damage that is not prevented by current immunosuppressive drug regimens [2], which in addition cause severe adverse effects, including increased risks of malignancy and infection. Therefore, immunological tolerance -i.e., a state of specific nonresponsiveness to donor antigens -remains the "Holy Grail" in clinical organ transplantation. Among the Correspondence: Dr. Thomas Wekerle e-mail: Thomas.Wekerle@meduniwien.ac.at numerous strategies that have been tested over time, chimerismbased tolerance induction appears particularly promising [3,4]. This concept is based on the cotransplantation of donor hematopoietic stem cells (HSCs) (contained in bone marrow (BM) or mobilized peripheral blood stem cells (mPBSCs)) into the organ transplant recipient who has been sufficiently preconditioned, either with radiation or cytotoxic drugs, to permit HSC engraftment. If engraftment is achieved, multilineage chimerism ensues, which is termed "mixed" chimerism if donor representation is clearly detectable (by flow cytometry, for instance) but is less than 100% (which would constitute "full" chimerism) and can be achieved with less extensive recipient conditioning.In 1945 Ray Owen described a naturally occur...

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confidence: 86%

Section: Clinical Translation Of Chimerism-based Transplantation Tolementioning

confidence: 99%

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confidence: 99%

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Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

et al. 2015

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“…and leukemias as well as organ failure due to ESRD, liver failure or heart failure due to cardiomyopathies or other diseases [59][60][61][62]. Combined HSCT and SOT can be performed either simultaneously [59][60][61][62][63][64][65][66] or sequentially with either HSCT first followed by SOT [59,[67][68][69][70][71][72][73] or SOT first followed by HSCT [59,60,74,75].…”

Section: Journal Of Stem Cell Biology and Transplantation Issn 2575-7725mentioning

confidence: 99%

A Young Patient with Refractory Multiple Myeloma and Dialysis-Dependent Renal Failure has been Cured by Non-Cryopreserved Autologous Stem Cell Transplantation Followed by Live-Related Kidney Transplantation

Ka¹,

Bacal²,

Mokhtar³

et al. 2017

J. Stem Cell Biol. Transplant.

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“…The Immune Tolerance Network is an international clinical research consortium founded by the National Institutes of Health to assist with developing immune tolerance therapies (http://www.immunetolrance.org). This group has thus far funded one set of studies that demonstrated that an appropriate conditioning regimen can enable long-term survival and function of a transplanted kidney without requiring long-term maintenance immunosuppression [17,18].…”

Section: Immunosuppressionmentioning

confidence: 99%

Bioengineering Priorities on a Path to Ending Organ Shortage

Hunsberger

Neubert²,

Wertheim

et al. 2016

Curr Stem Cell Rep

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This perspective article covers current successes in and continuing challenges remaining in eliminating the growing organ shortage. We specifically cover data from a workshop entitled BOrgan Bioengineering and Banking Roadmap Workshop^funded by the National Science Foundation (NSF) and the Methuselah Foundation in Washington, D.C. on May 27, 2015, and a subsequent Roundtable held at the White House Office of Science and Technology Policy (OSTP) on May 28, 2015. We address four parallel and potentially cooperative approaches for bioengineering tissues and organs. The first approach is bioprinting of tissues and organs. The second approach encompasses recellularization strategies, which can involve either developing tissue scaffolds from non-transplantable human (or xenogenic) organs or tissues and then reconstituting these templates with human cells to create a functional tissue/organ or seeding synthetic biodegradable scaffolds with human cells. The third approach is optimization of cellular repair and regeneration with strategies that include shifting the balance away from maladaptive processes that lead to chronic scarring. The fourth approach is xenotransplantation, which involves developing functional tissues for human use in transgenic animals whose cells are modified to prevent immune rejection. Current challenges and limitations are addressed, which include mapping, cell sourcing and manufacturing, immunosuppression, integration, and vascularization. We identify commercialization strategies that will make these approaches economically feasible. We present solutions toward a vision to one day ending the current organ and tissue shortage, and the impact this will have on treating disease and providing indirect economic benefit by decreasing the disease burden on society and improving quality of life.

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Long-Term Results in Recipients of Combined HLA-Mismatched Kidney and Bone Marrow Transplantation Without Maintenance Immunosuppression

Cited by 249 publications

References 41 publications

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

A Young Patient with Refractory Multiple Myeloma and Dialysis-Dependent Renal Failure has been Cured by Non-Cryopreserved Autologous Stem Cell Transplantation Followed by Live-Related Kidney Transplantation

Bioengineering Priorities on a Path to Ending Organ Shortage

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