Acquired Aplastic Anemia in Children

Hartung, Helge; Olson, Timothy S.; Bessler, Monica

doi:10.1016/j.pcl.2013.08.011

Cited by 70 publications

(83 citation statements)

References 84 publications

(111 reference statements)

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“…1 Most cases of acquired AA are idiopathic occurring both in children and adults, with roughly equal frequency in both genders. 1,2 Studies of AA patients and animal models of BMF suggest acquired AA is an immune-mediated disease. 3,4 Aberrant responses mediated by T helper type-1 (Th1), Th17, and cytotoxic CD8 1 T cells, together with impaired function of regulatory T cells, [5][6][7][8][9][10] culminate in BM destruction.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia

Kuksin¹,

González‐Pérez²,

Minter

2015

Blood

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• NF-kB differentially regulates CXCR4 expression on naïve and pathogenic CD8 1 T cells.• CXCR4 expression on pathogenic T cells facilitates their trafficking to the BM in a mouse model of AA.Aplastic anemia (AA) is a disease characterized by T-cell-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells. Physiologically, T cells migrate to the BM in response to chemokines, such as SDF-1a, the ligand for CXCR4. However, how T cells traffic to the BM in AA is poorly understood. CXCR4 is aberrantly expressed in immune-mediated diseases and its regulation by nuclear factor-kB (NF-kB) in cancer models is well documented. In this study, we show that CXCR4 is highly expressed on BM-infiltrating CD4 Studies of AA patients and animal models of BMF suggest acquired AA is an immune-mediated disease.3,4 Aberrant responses mediated by T helper type-1 (Th1), Th17, and cytotoxic CD8 1 T cells, together with impaired function of regulatory T cells, 5-10 culminate in BM destruction. Although the pathophysiology of AA is well defined, the molecular mechanisms responsible for T-cell infiltration into the BM during AA progression are poorly understood.Small populations of mature CD4 1 and CD8 1 T cells reside in the BM. It is a priming site for antigen-specific T cells, 11-13 as well as a homing site for memory T cells.14-16 Physiologically, T cells migrate to the BM in response to chemokines, such as stromal-cell derived factor-1a (SDF-1a) which is highly expressed by BM stromal cells.17,18 SDF-1a, also known as CXCL12, is the natural ligand for the chemokine receptor, CXCR4.19 SDF-1a-CXCR4 interactions initiate multiple signaling pathways that augment T cell co-stimulation, proliferation, cytokine production, migration, and survival. [20][21][22][23][24][25] In T cells, activation through the T-cell receptor, polyclonal stimulation, SDF-1a interaction, and IFN-g are stimuli that downregulate CXCR4, whereas signaling through IL-2, IL-4, IL-7, and IL-15 upregulates its expression. 26-31The nuclear factor-kB (NF-kB) family of transcription factors consists of five subunits, RelA (p65), RelB, c-Rel, NF-kB1 (p50), and NF-kB2 (p52), that function as homo-or heterodimers. NF-kB signaling plays a central role in T-cell activation, proliferation, differentiation, and survival. 32Dysregulated CXCR4 and NF-kB signaling pathways contribute to disease pathology in multiple immune-mediated diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes. [33][34][35][36][37][38][39][40][41] Both signaling pathways have also been associated with hematopoietic and nonhematopoietic malignancies. [42][43][44] Moreover, NF-kB-mediated regulation of CXCR4 expression and function in breast, pancreatic, gastric, prostatic, and ovarian cancers is well documented. [45][46][47][48][49][50][51] However, the contribution of CXCR4 and NF-kB signaling pathways to the pathology of acquired AA has not previously been explored.Through pharmacologic and genetic approaches, we demonstrate tha...

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Section: Introductionmentioning

confidence: 99%

CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia

Kuksin¹,

González‐Pérez²,

Minter

2015

Blood

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“…In addition to failure of the bone marrow's blood-producing function, AA exhibits autoimmune disease characteristics, and an immune-mediated pathogenesis is crucially involved in the occurrence of AA (1)(2)(3)(4)(5). Allogeneic hematopoietic stem cell transplantation and immunosuppressive therapy (IST) are the two primary treatment methods for severe AA (SAA) (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Correlation analysis of severe aplastic anemia immunosuppressive therapy and human leukocyte antigen alleles in pediatric patients

Hou

Zhang

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the correlation between the efficacy of immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA) and human leukocyte antigen (HLA) alleles. The polymerase chain reaction-sequence based typing high-resolution genotyping method was used to profile the HLA alleles of 115 SAA cases that were treated with rabbit-antithymocyte globulin (r-ATG) + cyclosporine (CsA) immunosuppressive therapy and 222 normal control subjects. The aim was to compare the frequency distribution of HLA alleles among the IST-effective group, the IST-ineffective group and the healthy control group.

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“…IST with horse antithymocyte globulin and cyclosporine is the recommended first-line therapy for patients without an HLA-matched sibling donor. 26 Survival rates are similar to those for BMT with a matched sibling donor, but relapse, clonal evolution, and leukemia, remain concerns that require long-term followup. 25,26 BMT with an HLA-matched unrelated donor should be offered to all IST nonresponders early in the course of the disease.…”

Section: Discussionmentioning

confidence: 98%

“…26 Survival rates are similar to those for BMT with a matched sibling donor, but relapse, clonal evolution, and leukemia, remain concerns that require long-term followup. 25,26 BMT with an HLA-matched unrelated donor should be offered to all IST nonresponders early in the course of the disease. 26 Given the historically high risk of mortality, increased risk of graft rejection, and possible clonal evolution associated with IST versus the relatively superior outcomes associated with prompt progression to matched sibling donor BMT, the latter option should be a consideration for patients with pregnancy-associated SAA.…”

Section: Discussionmentioning

confidence: 98%

“…25,26 BMT with an HLA-matched unrelated donor should be offered to all IST nonresponders early in the course of the disease. 26 Given the historically high risk of mortality, increased risk of graft rejection, and possible clonal evolution associated with IST versus the relatively superior outcomes associated with prompt progression to matched sibling donor BMT, the latter option should be a consideration for patients with pregnancy-associated SAA. Further studies are needed among patients with pregnancy-associated aplastic anemia,…”

Section: Discussionmentioning

confidence: 99%

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Successful Bone Marrow Transplantation of an Adolescent Young Adult Female With Pregnancy-associated Aplastic Anemia

Abdel‐Azim

Jovi-Usude

Balian

et al. 2015

Journal of Pediatric Hematology/Oncology

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Cases of pregnancy-associated severe aplastic anemia (SAA) have been reported in the literature with historically high rates of mortality. We report the case of a 17-year-old female diagnosed with SAA at 26 weeks of gestation. She experienced intrauterine fetal demise and did not achieve hematologic remission after delivery. She received a histocompatible sibling donor bone marrow transplant 7 weeks after her diagnosis and remains in remission, at 1-year posttransplant. We review available literature and suggest that when a histocompatible sibling donor is available, bone marrow transplantation should be considered as a first-line therapy for patients with pregnancy-associated SAA.

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Acquired Aplastic Anemia in Children

Cited by 70 publications

References 84 publications

CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia

CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic anemia

Correlation analysis of severe aplastic anemia immunosuppressive therapy and human leukocyte antigen alleles in pediatric patients

Successful Bone Marrow Transplantation of an Adolescent Young Adult Female With Pregnancy-associated Aplastic Anemia

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