Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants

Strober, Samuel

doi:10.1182/blood-2015-12-685107

Cited by 31 publications

(25 citation statements)

References 67 publications

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“…Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppression in 16 of 22 matched patients without rejection episodes or recurrence of primary renal disease in 5 year follow up [36][37][38][39]. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34 + cells infused as compared to matched recipients in a dose escalation study.…”

Section: Total Lymphoid Elimination Protocolsmentioning

confidence: 96%

Current State of Tolerance: The Holy Grail

Rathore¹

2017

Arch Clin Nephrol

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Research in Tolerance and Chimerism by Transplant immunologists for over half a century is akin to the pursuit of the Holy Grail. Animal experiments for inducing tolerance may not have been successful initially but in that process, our knowledge of the fascinating immune system has been greatly enriched. Understanding of innate and adaptive immune systems has paved the way for development of potent immunosuppression. However, achieving clinical or operational tolerance long term in renal transplant recipients in the absence of immunosuppression is the ultimate goal for clinicians. Reduction in immunosuppression will lower morbidity and mortality associated with heavy burden of immunosuppression. This review article will be of particular interest to clinicians involved in delivering care to renal transplant recipients. We have elucidated mechanisms of self-tolerance through central and peripheral tolerance, evolution of tolerogenic strategies, difference between macro and micro-chimerism, overview of successful protocols for inducing tolerance and recent work in the development of expanding regulatory cell lines. It is most encouraging to note progress using cellular therapies as reported by Immune Tolerance Network and by Transplant Research & Immunology group at Oxford. We may not be far from achieving clinical tolerance albeit with minimal if not completely immunosuppression free regimens in the longer term. Review Article Tolerance in TransplantationThe highest result of education is toleranceHelen Keller [1], Tolerance is derived from 'tolero' in Latin, which means to endure. Achieving transplant tolerance has been the subject of research for over half a century and our current understanding of tolerance has evolved during that time. It is by no means complete and the search for true tolerance continues.Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression. It can be described as donor specifi c non-reactivity in experimental models [2]. "Clinical operational tolerance" is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections [3,4].In contrast, "Immunological tolerance" is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specifi c immunological acceptance of the allograft by the host immune system in the absence of immunosuppression. Self-toleranceThe concept of tolerance towards transplanted organs is best understood through learning about self-tolerance. The lymphoid system, which consists of T and B-lymphocytes, controls the immune system protecting the host from foreign pathogens. In the developmental pathway of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between s...

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Section: Total Lymphoid Elimination Protocolsmentioning

confidence: 96%

Current State of Tolerance: The Holy Grail

Rathore¹

2017

Arch Clin Nephrol

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“…Previous work has focused on combining solid organ and hematopoietic stem cell transplants. [8][9][10][11][12][13] However, with this approach only a minimal intensity conditioning regimen can be applied, most patients develop transient chimerism, and a proportion of patients need to be maintained on long-term immunosuppression.…”

Section: Sequential Kidney and Allogeneic Hematopoietic Stem Cell Tramentioning

confidence: 99%

“…17 In this setting, a more intense conditioning cannot be applied and most patients will reject the hematopoietic graft. 9,10,13 Although some patients may remain tolerant to the donor graft, rejection of hematopoietic cells might predispose to late chronic rejection of the solid organ, while administration of donor lymphocyte infusion (DLI) early after HSCT to convert to full donor chimerism is usually associated with a high incidence of GVHD. 17 Moreover, while mixed chimerism can be more likely obtained after HLA matched HSCT, in HLA mismatched transplantation there is a higher tendency to reject the donor cells.…”

Section: Sequential Kidney and Allogeneic Hematopoietic Stem Cell Tramentioning

confidence: 99%

Sequential kidney and allogeneic hematopoietic stem cell transplantation

et al. 2019

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“…None of the patients enrolled had kidney graft loss or GVHD with up to 14 years of observation (Scandling et al 2015). Strober (2016) reviewed a total of 41 HLA-matched and mismatched patients who were treated in three medical centers (MGH, Stanford University and Northwestern University) and who could be completely withdrawn from immunosuppressive drugs after combined kidney and HSCT transplantation and concluded that HSCT is a feasible approach leading to the complete withdrawal of immunosuppressive drugs from kidney transplant patients with follow-up periods of up to 10 years (median: 20 to 62 months). A prospective single-center study (Vanikar et al 2013) also reported that kidney transplantation by using HSCT in thymus, bone marrow and the portal and peripheral circulation safely and effectively prevents recurrent FSGS in patients with biopsy-proven primary FSGS.…”

Section: Therapeutic Potential Of Bmt For Recurrent Fsgsmentioning

confidence: 99%

Extrarenal determinants of kidney filter function

2017

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The kidney is an organ involved in cross talk with many human organs. The link between the immune system and the kidney has been studied in some detail, although data precisely elucidating their interaction are sparse, in particular with regard to the function of the kidney filter apparatus. Current research suggests that an understanding of the impairment of this cross talk between the bone marrow, as a fundament of the immune system and the kidney will provide meaningful insights into the pathophysiological mechanisms of impaired kidney filter function. Circulating factors have long been implicated in the pathogenesis of idiopathic nephrotic syndrome, particularly focal segmental glomerulosclerosis (FSGS) and its recurrence. Soluble urokinase receptor (suPAR) has emerged as a circulating factor responsible for FSGS and also as an early predictive marker for the development of various renal diseases. The bone marrow has recently been revealed as a predominant source of suPAR with deleterious effects on the kidney filter. These new findings have led to bone marrow or hematopoietic stem cell transplants being considered as potential therapeutic options for preventing the post-transplantation recurrence of FSGS or even as a treatment for the original disease associated with high suPAR levels. Whereas bone marrow transplantation for patients with preexisting chronic kidney disease is challenging, recent clinical trials have demonstrated the promising outcome of combined bone marrow and kidney transplantation in patients with kidney failure. In this review, with its brief update on suPAR, we describe the critical new role of the bone marrow in the pathogenesis of the kidney disease process and the functional connection between these two organs through the soluble mediator, suPAR. We also comment on the feasibility of bone marrow transplants for the treatment of patients with chronic renal failure arising from recurrent FSGS.

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Use of hematopoietic cell transplants to achieve tolerance in patients with solid organ transplants

Cited by 31 publications

References 67 publications

Current State of Tolerance: The Holy Grail

Current State of Tolerance: The Holy Grail

Sequential kidney and allogeneic hematopoietic stem cell transplantation

Extrarenal determinants of kidney filter function

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