Mixed chimerism established by hematopoietic stem cell transplantation is maintained by host and donor T regulatory cells

Kinsella, Francesca; Zuo, Jianmin; Inman, Charlotte; Pearce, Hayden; Maggs, Luke; Eldershaw, Suzy; Chan, Y L Tracey; Nunnick, Jane; Nagra, Sandeep; Griffiths, Mike; Craddock, Charles; Malladi, Ram; Moss, Paul

doi:10.1182/bloodadvances.2018025502

Cited by 24 publications

(29 citation statements)

References 56 publications

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“…However, considering these results it would seem plausible that IMC several months prior to relapse does not reflect circulating leukemic cells but rather a reduced alloreactivity of the graft gradually paving the way for recurrence of the malignant clone. This is supported by a recent study showing an increased proportion of T regulatory cells in patients with mixed compared to full donor chimerism . Thus, highly sensitive, sequential measurements of chimerism could provide information on the potency of the graft‐versus‐leukemia effect, with the potential of guiding interventions aimed at strengthening this effect …”

Section: Discussionsupporting

confidence: 88%

“…This is supported by a recent study showing an increased proportion of T regulatory cells in patients with mixed compared to full donor chimerism. 56 Thus, highly sensitive, sequential measurements of chimerism could provide information on the potency of the graftversus-leukemia effect, with the potential of guiding interventions aimed at strengthening this effect. 33 We next tested whether RQ-PCR chimerism status during the first 90 days post-HCT was associated with relapse risk.…”

Section: Discussionmentioning

confidence: 99%

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Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia

Haugaard

Madsen

Marquart

et al. 2019

Pediatric Transplantation

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Analysis of chimerism in blood post‐HCT using STR‐PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. RQ‐PCR chimerism is 10‐ to 100‐fold more sensitive, but clinical studies in children are sparse. We analyzed IMC in blood samples following transplantation for acute lymphoblastic or myeloid leukemia in 56 children. IMC was defined as a minimum increase of (a) 0.1% or (b) 0.05% recipient DNA between two samples. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (HR 12.8 [95% CI: 3.9‐41.4; P < .0001] and 7.6 [95% CI: 2.2‐26.9; P < .01], respectively). The first IMC was detected at a median of 208 days prior to relapse. The 5‐year cumulative incidence of relapse for children with a single IMC was 45.5% (CI 12.3‐74.4) and 41.0% (14.2‐66.6) for IMC above 0.1% and 0.05%, respectively. However, in 47 and 38 children never attaining IMC > 0.1% and >0.05%, 10 and 8 children relapsed, respectively. In a landmark analysis, no association was found between IMC prior to 90 days post‐HCT and subsequent relapse by either classification of IMC and AUC for RQ‐PCR chimerism was 54.2% (95 CI 27.7‐ 84.8). Although limited by a retrospective design, these results indicate that monitoring of RQ‐PCR chimerism in peripheral blood may have a role in early detection of relapse in acute childhood leukemia.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia

Haugaard

Madsen

Marquart

et al. 2019

Pediatric Transplantation

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“…Multiple studies have demonstrated that developing mixed chimerism post-HCT in non-malignant disease is associated with a lower incidence of aGvHD and cGvHD and among patients with mixed chimerism, cGvHD is associated with a more frequent evolution toward complete chimerism ( 72 ). The proportion of Treg cells is increased in patients with mixed chimerism after SCT and acts to suppress the alloreactive immune response ( 73 ). In non-malignant diseases, especially those undergoing reduced intensity conditioning resulting in dynamic chimera states, interventions to increase Tregs may stabilize mixed chimerism and lead to lower rates of cGvHD.…”

Section: T Cell Immune Dysregulationmentioning

confidence: 99%

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease

Rozmus

2021

Front. Immunol.

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Chronic graft-versus-host disease (GvHD) has become a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) and can burden patients with devastating and lifelong health effects. Our understanding of the pathogenic mechanisms underlying chronic GvHD remains incomplete and this lack of understanding is reflected by lack of clear therapeutic approaches to steroid refractory disease. Observations predominantly from mouse models and human correlative studies currently support a three phase model for the initiation and development of chronic GvHD: 1) early inflammation and tissue damage triggers the innate immune system. This leads to inflammatory cytokine/chemokine patterns that recruit effector immune cell populations; 2) chronic inflammation causes the loss of central and peripheral tolerance mechanisms leading to emergence of pathogenic B and T cell populations that promote autoimmune and alloimmune reactions; 3) the dysregulated immunity causes altered macrophage polarization, aberrant tissue repair leading to scarring and end organ fibrosis. This model has led to the evaluation of many new therapies aimed at limiting inflammation, targeting dysregulated signaling pathways and restoring tolerance mechanisms. However, chronic GvHD is a multisystem disease with complex clinical phenotypes and it remains unclear as to which cluster of patients will respond best to specific therapeutic strategies. However, it is possible to gain novel insights from immune-related monogenic diseases. These diseases either share common clinical manifestations, replicate steps from the three phase chronic GvHD model or serve as surrogates for perfectly targeted drugs being investigated in chronic GvHD therapy. In this review, we will summarize the evidence from these monogenic immune related diseases that provide insight into pathogenic pathways in chronic GvHD, rationales for current therapies and novel directions for future drug discovery.

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“…These findings suggest that the long-term graft survival might be due to the ability of the transferred T regs to induce infectious tolerance. Recent studies show that both the donor and recipient T regs contribute to suppress the alloreactive responses after HCT ( 105 , 117 , 118 ). The integration of T reg therapy into combined organ or islet transplantation is therefore a potentially non-toxic method for improving tolerance induction and establishing mixed hematopoietic chimerism.…”

Section: Critical Role Of Tregs In Mixed Chimerism and Graft Tolerancmentioning

confidence: 99%

Tregs and Mixed Chimerism as Approaches for Tolerance Induction in Islet Transplantation

Pathak

Meyer

2021

Front. Immunol.

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Pancreatic islet transplantation is a promising method for the treatment of type 1 and type 3 diabetes whereby replacement of islets may be curative. However, long-term treatment with immunosuppressive drugs (ISDs) remains essential for islet graft survival. Current ISD regimens carry significant side-effects for transplant recipients, and are also toxic to the transplanted islets. Pre-clinical efforts to induce immune tolerance to islet allografts identify ways in which the recipient immune system may be reeducated to induce a sustained transplant tolerance and even overcome autoimmune islet destruction. The goal of these efforts is to induce tolerance to transplanted islets with minimal to no long-term immunosuppression. Two most promising cell-based therapeutic strategies for inducing immune tolerance include T regulatory cells (Tregs) and donor and recipient hematopoietic mixed chimerism. Here, we review preclinical studies which utilize Tregs for tolerance induction in islet transplantation. We also review myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT) strategies in preclinical and clinical studies to induce sustained mixed chimerism and allograft tolerance, in particular in islet transplantation. Since Tregs play a critical role in the establishment of mixed chimerism, it follows that the combination of Treg and HSCT may be synergistic. Since the success of the Edmonton protocol, the feasibility of clinical islet transplantation has been established and nascent clinical trials testing immune tolerance strategies using Tregs and/or hematopoietic mixed chimerism are underway or being formulated.

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Mixed chimerism established by hematopoietic stem cell transplantation is maintained by host and donor T regulatory cells

Cited by 24 publications

References 56 publications

Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia

Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia

Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease

Tregs and Mixed Chimerism as Approaches for Tolerance Induction in Islet Transplantation

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