Myeloma Responses and Tolerance Following Combined Kidney and Nonmyeloablative Marrow Transplantation: In Vivo and In Vitro Analyses

Fudaba, Yasuhiro; Spitzer, Thomas R.; Shaffer, Juanita; Kawai, Tatsuo; Fehr, Thomas; Delmonico, Francis L.; Preffer, Frederic I.; Tolkoff-Rubin, Nina; Dey, Bimalangshu R.; Saidman, Susan L.; Kraus, Annette B.; Bonnefoix, Thierry; McAfee, Steven L.; Power, Karen A.; Kattleman, Kristin; Colvin, Robert B.; Sachs, David H.; Cosimi, A. Benedict; Sykes, Megan

doi:10.1111/j.1600-6143.2006.01434.x

Cited by 242 publications

(210 citation statements)

References 43 publications

(48 reference statements)

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“…In addition to skin, split tolerance in chimeric canine recipients of heart transplants has also been reported, suggesting that polymorphisms in tissue-specific antigens may not be an exclusive property of the skin [52]. Most recently, clinical trials involving combined kidney transplantation and non-myeloablative BMT were conducted in human patients [53]. Surprisingly, long-term acceptance of donor kidney was not associated with maintenance of donor hematopoietic cells, which, as the authors suggested, may reflect the differential expression of donor antigens that are in fact tissue-specific.…”

Section: Discussionmentioning

confidence: 99%

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

Luo¹,

Chan²,

Shapiro³

et al. 2007

Eur J Immunol

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Stable mixed chimerism has been considered the most robust tolerance strategy. However, rejection of solid donor tissues by chimeras has been observed, a state termed split tolerance. Since new non-myeloablative mixed chimerism approaches are being actively pursued, we sought to determine whether they lead to full tolerance or split tolerance and to define the mechanisms involved. Fully mismatched mixed chimeras generated by induction with various lymphocyte-depleting antibodies along with either low-dose irradiation or busulfan and temporary sirolimus, maintained stable mixed chimerism but nevertheless rejected donor skin grafts. Generation of stable mixed chimerism using antibody targeting CD40L, but not depleting antibodies to CD4 and CD8, could prevent split tolerance when skin grafts were given together with donor bone marrow. Minor antigen matching abrogated the ability of effector T cells to reject donor skin grafts. A CFSE killing assay indicated that chimeras were both directly and indirectly tolerant of donor hematopoietic cell antigens, suggesting that minor mismatches triggered a tissue-specific response. Thus, split tolerance due to tissuerestricted polymorphic antigens prevents full tolerance in a number of nonmyeloablative mixed chimerism protocols and a 'tolerizing' agent is required to overcome split tolerance. A model of the requirements for split tolerance is presented.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/36938_s.pdf IntroductionMuch of the effort to develop donor-specific transplantation tolerance has been focused on inducing peripheral tolerance through costimulation blockade. While initially promising, with more extensive tests of this approach the success has been somewhat limited, particularly when translated to larger animal models and to the clinic [1]. In hindsight this may not be surprising given that tolerance naturally occurs primarily in the thymus and only secondarily in the periphery [2]. In contrast, the approach of generating hematopoietic chimerism via bone marrow transplantation (BMT) takes advantage of the thymic central tolerance mechanisms, and is considered the most robust method of inducing donor-specific tolerance [3][4][5][6]. The chimer- ism approach is limited clinically by the harsh recipient conditioning needed to establish chimerism and the possibility of graft-vs.-host disease [7]. More recently less toxic strategies have been developed that establish mixed allogeneic chimerism, where substantial levels of donor and recipient hematopoietic cells co-exist in the recipient, and have raised hope that robust transplantation tolerance will soon be routine clinically [6]. Mixed chimerism has been considered to induce tolerance to all other donor tissues. If true, mixed chimerism could be a solution for both solid organ transplantation and cellular transplants, such as allogeneic islets used to treat type-1 diabetes. However, studies in full chimeras, where virtually all hematopoietic cells in the recipien...

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Section: Discussionmentioning

confidence: 99%

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

Luo¹,

Chan²,

Shapiro³

et al. 2007

Eur J Immunol

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“…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%

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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“…The group from Massachusetts General Hospital (MGH) showed tolerance in six patients undergoing simultaneous bone marrow and kidney transplants from human leukocyte antigen (HLA)-identical donors for the treatment of multiple myeloma in patients with renal failure (Fudaba et al 2006). Three patients showed transient donor chimerism, but were successfully weaned off immunosuppression.…”

Section: Mixed Chimerismmentioning

confidence: 99%

Tolerance--Is It Worth It?

Finger

Strom

Matas

2013

Cold Spring Harbor Perspectives in Medicine

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We are entering an exciting time in the study of immunologic tolerance. Several cellular and molecular strategies have been developed that show promise in nonhuman transplant models and these approaches are just now appearing in clinical trials. Tolerance strategies that prevent immune rejection and obviate the need for immunosuppressive medications (with inherent risk of cancer, infection, and organ toxicity) would improve both graft and patient survival. Each tolerance protocol brings its own set of associated risks. As the results of these trials become available, we must continue to evaluate their successes and failures. The balance of these outcomes will help us answer the question: "Tolerance-Is it worth it?"WHAT IS TOLERANCE?

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Myeloma Responses and Tolerance Following Combined Kidney and Nonmyeloablative Marrow Transplantation: In Vivo and In Vitro Analyses

Cited by 242 publications

References 43 publications

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

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

Tolerance--Is It Worth It?

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