Chimerism-based tolerance in organ transplantation: preclinical and clinical studies

Oura, Tetsu; Cosimi, A. Benedict; Kawai, Tatsuo

doi:10.1111/cei.12969

Cited by 42 publications

(39 citation statements)

References 55 publications

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“…Of the 10 recipients enrolled in the studies, all developed transient mixed chimerism and immunosuppression was discontinued in eight patients. After a follow-up period of 7-14 years, four patients still could discontinue immunosuppression completely (62).…”

Section: Clinical Application To Kidney Transplantationmentioning

confidence: 96%

Cyclophosphamide-Induced Tolerance in Allogeneic Transplantation: From Basic Studies to Clinical Application

et al. 2020

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Immune tolerance against alloantigens plays an important role in the success of clinical organ and allogeneic hematopoietic stem cell transplantation. The mechanisms of immune tolerance to alloantigens have gradually been elucidated over time. Although there have been numerous reports to date on the induction of tolerance to alloantigens, the establishment of mixed chimerism is well-known to be crucial in the induction and maintenance of immune tolerance for either of the methods. Since the early 1980s, the murine system of cyclophosphamide (Cy)-induced tolerance has also been examined extensively. The present review focuses on studies conducted on Cy-induced immune tolerance. Clinical data of patients with allogeneic transplantation suggest that the posttransplant Cy method to induce immune tolerance has been successfully translated from basic studies into clinical practice.

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Section: Clinical Application To Kidney Transplantationmentioning

confidence: 96%

Cyclophosphamide-Induced Tolerance in Allogeneic Transplantation: From Basic Studies to Clinical Application

et al. 2020

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“…115 The notion of inducing hematopoietic chimerism for establishing immune tolerance to solid organ transplantation has been since brought to test in numerous clinical trials, and has shown great efficacy in allograft protection. [116][117][118] Hematopoietic chimerism is a form of central tolerance whose mechanisms of tolerance primarily involve clonal deletion of donor-reactive T cells and B cells in the thymus and bone marrow, respectively. 119,120 However, this tolerance approach often requires aggressive recipient bone marrow conditioning regimens and further, exposes recipients to long-term risks for graft-versus-host disease.…”

Section: A B Rief Overvie W Of Peripher Al Toler An Ce Induc Ti On mentioning

confidence: 99%

Impact of infection on transplantation tolerance

Luo

2019

Immunological Reviews

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Allograft tolerance is the ultimate goal of organ transplantation. Current strategies for tolerance induction mainly focus on inhibiting alloreactive T cells while promoting regulatory immune cells. Pathogenic infections may have direct impact on both effector and regulatory cell populations, therefore can alter host susceptibility to transplantation tolerance induction as well as impair the quality and stability of tolerance once induced. In this review, we will discuss existing data demonstrating the effect of infections on transplantation tolerance, with particular emphasis on the role of the stage of infection (acute, chronic, or latent) and the stage of tolerance (induction or maintenance) in this infection‐tolerance interaction. While the deleterious effect of acute infection on tolerance is mainly driven by proinflammatory cytokines induced shortly after the infection, chronic infection may generate exhausted T cells that could in fact facilitate transplantation tolerance. In addition to pathogenic infections, commensal intestinal microbiota also has numerous significant immunomodulatory effects that can shape the host alloimmunity following transplantation. A comprehensive understanding of these mechanisms is crucial for the development of therapeutic strategies for robustly inducing and stably maintaining transplantation tolerance while preserving host anti‐pathogen immunity in clinically relevant scenarios.

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“…Cyclosporine or Tacrolimus was slowly tapered over several months and completely discontinued at 8 months after confirming freedom from rejection by a 6-month protocol biopsy. All (10/10) patients developed transient chimerism and seven patients achieved tolerance from which four remain completely off immunosuppression (5–13 years) ( 9 , 78 , 80 ). To reduce the toxicity of the regimen and to ameliorate the engraftment syndrome cyclophosphamide has recently been substituted by TBI (2 × 150 cGy).…”

Section: Current State Of Affairsmentioning

confidence: 99%

“…So far two patients have been treated with this modified protocol, from which one remains off immunosuppression for more than 3 years. Future trials are expected to include the use of belatacept, based on murine ( 81 , 82 ) and non-human primate studies ( 79 , 80 , 83 ).…”

Section: Current State Of Affairsmentioning

confidence: 99%

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

et al. 2017

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The perception that transplantation of hematopoietic stem cells can confer tolerance to any tissue or organ from the same donor is widely accepted but it has not yet become a treatment option in clinical routine. The reasons for this are multifaceted but can generally be classified into safety and efficacy concerns that also became evident from the results of the first clinical pilot trials. In comparison to standard immunosuppressive therapies, the infection risk associated with the cytotoxic pre-conditioning necessary to allow allogeneic bone marrow engraftment and the risk of developing graft-vs.-host disease (GVHD) constitute the most prohibitive hurdles. However, several approaches have recently been developed at the experimental level to reduce or even overcome the necessity for cytoreductive conditioning, such as costimulation blockade, pro-apoptotic drugs, or Treg therapy. But even in the absence of any hazardous pretreatment, the recipients are exposed to the risk of developing GVHD as long as non-tolerant donor T cells are present. Total lymphoid irradiation and enriching the stem cell graft with facilitating cells emerged as potential strategies to reduce this peril. On the other hand, the long-lasting survival of kidney allografts, seen with transient chimerism in some clinical series, questions the need for durable chimerism for robust tolerance. From a safety point of view, loss of chimerism would indeed be favorable as it eliminates the risk of GVHD, but also complicates the assessment of tolerance. Therefore, other biomarkers are warranted to monitor tolerance and to identify those patients who can safely be weaned off immunosuppression. In addition to these safety concerns, the limited efficacy of the current pilot trials with approximately 40–60% patients becoming tolerant remains an important issue that needs to be resolved. Overall, the road ahead to clinical routine may still be rocky but the first successful long-term patients and progress in pre-clinical research provide encouraging evidence that deliberately inducing tolerance through hematopoietic chimerism might eventually make it from dream to reality.

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Chimerism-based tolerance in organ transplantation: preclinical and clinical studies

Cited by 42 publications

References 55 publications

Cyclophosphamide-Induced Tolerance in Allogeneic Transplantation: From Basic Studies to Clinical Application

Cyclophosphamide-Induced Tolerance in Allogeneic Transplantation: From Basic Studies to Clinical Application

Impact of infection on transplantation tolerance

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

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