Treatment of the Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome (IPEX) by Allogeneic Bone Marrow Transplantation

Baud., Olivier; Goulet, Olivier; Canioni, Danielle; Deist, Françoise Le; Radford, Isabelle; Rieu, D; Dupuis‐Girod, Sophie; Cerf‐Bensussan, Nadine; Cavazzana‐Calvo, Marina; Brousse, Nicole; Fischer, Alain; Rivet, Christine; Bodemer, Christine; Wildin, Robert S.; Casanova, Jean‐Laurent

doi:10.1056/nejm200106073442304

Cited by 245 publications

(163 citation statements)

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“…This SNP is in high linkage disequilibrium (LD) with the SNPs rs1051677 and rs6941 reported in the Johnson study (D' ϭ 1; Figure 1), thus we suggest that both of these studies are potentially identifying a locus for disease susceptibility. 1,2 The other SNP rs2440 reported by Johnson et al was also associated with disease susceptibility in our study albeit with a Figure 1. D' LD plot for the XRCC5 gene was calculated using CEU genotype data for the markers genotyped across this region.…”

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confidence: 45%

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Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation

Seidel¹,

Fritsch²,

Lion³

et al. 2009

Blood

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Mutations of FoxP3 result in the disturbance of FoxP3 expression and lack of functional CD4 ϩ CD25 high regulatory T cells in humans, causing immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The only curative approach for IPEX syndrome, which is fatal within the first year of life in many cases, is allogeneic hematopoietic stem cell transplantation (HSCT). We monitored lineage-specific chimerism in a FoxP3-deficient patient after nonmyeloablative HSCT and graft rejection over 6 years. The patient lost donor chimerism in T cells, B cells, NK cells, monocytes, and granulocytes 1 year after transplantation, but remained clinically healthy without immunosuppression. To elucidate the immunologic basis of his continuing remission, we performed detailed lymphocyte subset analyses and detected FoxP3-expressing CD4 ϩ CD25 high T cells, comprising 1% to 2% of the CD4 ϩ T cells (ϳ 10/ L), which were more than 90% donor-derived. The patient is disease-free and shows no signs of autoimmunity, suggesting that stable, selective engraftment of regulatory T cells is possible and associated with cure from IPEX syndrome.HSCT may be a curative approach for IPEX syndrome. 1-3 However, the required levels of donor chimerism and conditioning intensity are unknown. Myeloablative conditioning is associated with substantial transplantation-related mortality, 2-5 whereas nonmyeloablative conditioning carries an increased risk of rejection because of dysregulated effector T-cell function. 6 Here we report a boy with IPEX syndrome who underwent peripheral blood HSCT at the age of 11 months from an unrelated 10/10-matched donor (2 ϫ 10 7 /kg CD34 ϩ , 10 9 /kg CD3 ϩ cells) after nonmyeloablative conditioning according to the local protocol (fludarabine 6 ϫ 30 mg/m 2 ; melphalan 140 mg/ m 2 ; alemtuzumab 5 ϫ 0.2 mg/kg). The post-HSCT course was uncomplicated with complete engraftment on day ϩ12. All IPEX-linked symptoms resolved until day ϩ30. Acute graftversus-host disease (skin, II°) was treated with steroids until day ϩ56; cyclosporin A was tapered 1 year after transplantation. At this time, in vitro responses to vaccine antigens and phytohemagglutinin were normal. Six years posttransplantation the patient remains insulin-dependent due to irreversible islet cell damage but has no active autoimmunity. The clinically healthy boy shows no increased frequency or severity of infections (Table S1; available on the Blood website; see the Supplemental Materials link at the top of the online article). Chimerism was determined in peripheral blood cell subsets regularly (described elsewhere 6 ). Approval was obtained from the St Anna Children's Hospital (Vienna, Austria) Institutional Review Board for these studies. Informed consent was obtained in accordance with the Declaration of Helsinki.After 100% donor cell engraftment, there was a continuous decline throughout the first year to an overall and subset-specific donor chimerism of 5% to 10% (Ϯ 6%; Figure 1A) without any clinical symptoms of relapse. Five-, 5.5-, and ...

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confidence: 45%

“…1 The authors used a comprehensive selection strategy for identifying single nucleotide polymorphisms (SNPs) and have reported an association between the high risk of VTE and genetic variants located in XRCC5.…”

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confidence: 99%

Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation

Seidel¹,

Fritsch²,

Lion³

et al. 2009

Blood

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“…We also note that the first patient with Treg cell-deficient IPEX syndrome to undergo bone marrow transplantation had low donor chimerism and later died of HLH. 26 Together, these data indicate that transient Treg cell deficiency warrants further investigation as a potential contributor to the proinflammatory environment during clinical FHL/MAS. Such an effect might be driven by the compounding effects of altered CD25 expression and reduced IL-2 production and sCD25 levels, as we observe here in mice, or in the patient context it might be primarily driven by the high sCD25 level, which is already known to define FHL/MAS.…”

Section: Patients With Fhl/mas Experience Low Treg Cell Numbers Durinmentioning

confidence: 78%

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

Humblet-Baron

Franckaert

Dooley

et al. 2016

Journal of Allergy and Clinical Immunology

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Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8 1 T-cell activation. HLH occurs as both acquired and familial hemophagocytic lymphohistiocytosis (FHL) forms. In both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and lifethreatening. Recent studies have attributed the key distal event to excessive IFN-g production; however, the proximal events driving immune dysregulation have remained undefined. Objective: We sought to investigate the role of regulatory T (Treg) cells in the pathophysiology of experimental FHL. Methods: Because mutation in perforin is a common cause of FHL, we used an experimental FHL mouse model in which disease in perforin-deficient mice is triggered by lymphocytic choriomeningitis virus (LCMV). We assessed Treg and CD8 1 T-cell homeostasis and activation during the changing systemic conditions in the mice. In addition, human blood samples were collected and analyzed during the HLH episode. Results: We found no primary Treg cell defects in perforindeficient mice. However, Treg cell numbers collapsed after LCMV inoculation. The collapse of Treg cell numbers in LCMV-triggered perforin-deficient, but not wild-type, mice was accompanied by the combination of lower IL-2 secretion by conventional CD4 1 T cells, increased IL-2 consumption by activated CD8 1 T cells, and secretion of competitive soluble CD25. Moreover low Treg cell numbers were observed in untreated patients experiencing HLH flares. Conclusion: These results demonstrate that excessive CD8 1 T-cell activation rewires the IL-2 homeostatic network away

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“…Both central (thymic) and peripheral tolerance are defective in Scurfy mice [179]. Bone marrow transplantation cures mice with the Scurfy mutation and given the severity of the disease it has been tried in humans [180]. A single child with the disease developed mixed chimerism and the disease remitted for 2 years after bone marrow transplantation but unfortunately the patient eventually succumbed to a poorly characterized haematological disorder.…”

Section: ªMonogenicº Diabetes Syndromesmentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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Treatment of the Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome (IPEX) by Allogeneic Bone Marrow Transplantation

Cited by 245 publications

References 28 publications

Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation

Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation

IL-2 consumption by highly activated CD8 T cells induces regulatory T-cell dysfunction in patients with hemophagocytic lymphohistiocytosis

Genetic control of autoimmunity in Type I diabetes and associated disorders

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