Intracellular interferon-γ in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia

Sloand, Elaine M.; Kim, Sonnie; Maciejewski, Jaroslaw P.; Tisdale, John F.; Follmann, Dean; Young, Neal S.

doi:10.1182/blood-2002-01-0035

Cited by 205 publications

(176 citation statements)

References 31 publications

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“…Research laboratory findings that reflect the pathophysiology of AA include an increased ratio of activated T cells, and increased interferon gamma (IFN-γ) expression in bone marrow and peripheral T cells. Sloland et al [21] reported a higher response rate to IST in patients with circulating IFN-γ containing T cells than those without. Interestingly, Chang et al [22] demonstrated an association between the IFN-γ single nucleotide polymorphism +874 (T/A), which can directly affect the expression of the IFN-γ gene, and response to IST in patients with AA.…”

Section: Cytokinesmentioning

confidence: 99%

Biomarkers for predicting clinical response to immunosuppressive therapy in aplastic anemia

Narita

Kojima

2016

Int J Hematol

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Section: Cytokinesmentioning

confidence: 99%

Biomarkers for predicting clinical response to immunosuppressive therapy in aplastic anemia

Narita

Kojima

2016

Int J Hematol

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“…[1][2][3] Overproduction of inflammatory cytokines, including interferon g (IFNg) and tumor necrosis factor a (TNFa), from aberrantly activated immune cells and stromal microenvironments is also suggested to make a significant contribution to BM failure, in which the role of FAS-mediated apoptosis has been implicated. 4 to predict, diagnose, and initiate due interventions to these complications during the course of AA. However, this is often complicated by difficulty in diagnosing MDS among patients with AA, which represents a major challenge to clinicians and hematopathologists.…”

Section: Late Clonal Diseases In Aamentioning

confidence: 99%

“…[1][2][3][4][5][6] Although almost uniformly terminating in a fatal outcome in a previous era, management of AA has drastically improved since the late 1970s with the introduction of allogeneic stem cell transplantation and IST, as well as optimized supportive care. 5 However, the entire picture of the disease is more complicated than expected for a simple immune-mediated marrow failure.…”

Section: Introductionmentioning

confidence: 99%

Clonal hematopoiesis in acquired aplastic anemia

Ogawa

2016

Blood

162

130

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Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA.

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“…The responsiveness of a significant proportion of AA patients to immunosuppressive therapies (IST) is the best evidence of an underlying immune pathophysiology: the majority of patients show hematologic improvement after only transient T-cell depletion by antithymocyte globulins (ATGs). 1,2 Although the immune pathophysiology of AA is well characterized, [3][4][5] there are no biomarkers that would allow a better understanding of the immunological status of an individual AA patient, including disease severity and response to therapy. 6 Reliable biomarkers that correlated with disease severity or response would be useful for individual treatment decisions and in clinical trials.…”

Section: Introductionmentioning

confidence: 99%