Suppression of Erythroid-Colony Formation by Lymphocytes from Patients with Aplastic Anemia

Hoffman, Ronald; Zanjani, Esmail D.; Lutton, John D.; Zalusky, Ralph; Wasserman, Louis R.

doi:10.1056/nejm197701062960103

Cited by 248 publications

(57 citation statements)

References 17 publications

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“…These results suggest that poor response to IST might possibly be ascribed to higher WBC Early experiments demonstrated inhibitory effects of autologous lymphocytes on hematopoietic progenitor cell growth through overproduction of cytokines such as interferon-γ and tumor necrosis factor-α by activated cytotoxic T cells in AA patients. [20][21][22] More recently, oligoclonal T-cell expansions have been described in AA patients, disappearing with clinical improvement following IST. 23 Taking our results and previous findings together, a higher WBC count before treatment may indicate the presence of numerous autoreactive T cells that need to be eliminated and thus a high potential to destroy marrow function through lymphocytes, rather than better residual marrow function.…”

Section: Resultsmentioning

confidence: 99%

Predicting response to immunosuppressive therapy in childhood aplastic anemia

Yoshida¹,

Yagasaki²,

Hama³

et al. 2011

Haematologica

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9/L or more (P=0.0003), followed by shorter interval between diagnosis and therapy (P=0.01), and male sex (P=0.03). In conclusion, pre-treatment clinical and laboratory findings influence response to therapy. The finding that response rate worsens with increasing interval between diagnosis and treatment highlights the importance of prompt immunosuppressive therapy for patients with aplastic anemia.Key words: aplastic anemia, children, immunosuppressive therapy, predictive marker.Citation: Yoshida N, Yagasaki H, Hama A, Takahashi Y, Kosaka Y, Kobayashi R, Yabe H, Kaneko T, Tsuchida M, Ohara A, Nakahata T, Kojima S. Predicting response to immunosuppressive therapy in childhood aplastic anemia. Haematologica 2011;96(05):771-774. doi:10.3324/haematol.2010 This is an open-access paper. ABSTRACT ISTAll patients were treated with a combination of intravenous ATG (Lymphoglobulin; Genzyme, Cambridge, USA) at 15 mg/kg/day for five days and oral CyA at 6 mg/kg/day. The dose of CyA was adjusted to maintain trough levels between 100 and 200 ng/mL, and the appropriate dose was administered for at least six months. Granulocyte colony-stimulating factor (Filgrastim; Kirin, Tokyo, Japan) was administered intravenously or subcutaneously at 400 mg/m 2 for three months only to patients with very severe disease. 17 Response to IST was evaluated at six months after initiation of therapy. Complete response (CR) was defined as a neutrophil count more than 1.5×10 9 /L, a platelet count more than 100×10 9 /L, and a hemoglobin level more than 11.0 g/dL.17 Partial response (PR) was defined as a neutrophil count more than 0.5×10 9 /L, a platelet count more than 20×10 9 /L, and a hemoglobin level more than 8.0 g/dL in patients with severe or very severe AA, and as a neutrophil count more than 1.0×10 9 /L, a platelet count more than 30 ×10 9 /L, and a hemoglobin level more than 8.0 g/dL in patients with moderate AA.17 Overall response was defined as CR or PR at six months after IST. Statistical analysesParameters for univariate analyses to determine predictors of response to IST included age at diagnosis, sex, interval between diagnosis and treatment, etiology, severity of disease, white blood cell (WBC) count, neutrophil count, lymphocyte count, hemoglobin level, reticulocyte count, and platelet count. Pre-treatment laboratory values were defined as the lowest value without transfusions during the four weeks preceding IST. Continuous variables were divided into quartile categories, and these cut offs were used for categorical analysis. To evaluate correlations between these parameters and response, differences in continuous variables were analyzed using the Mann-Whitney U-test and differences in frequencies were tested using the χ 2 or Fisher's exact test. For multivariate analyses, logistic regression modeling was performed. Important covariates in the multivariate models were chosen using stepwise variable selection procedures. Values of P<0.05 were considered statistically significant. Results and DiscussionPatients' characteristics ...

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Section: Resultsmentioning

confidence: 99%

Predicting response to immunosuppressive therapy in childhood aplastic anemia

Yoshida¹,

Yagasaki²,

Hama³

et al. 2011

Haematologica

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“…Previous reports demonstrated that lymphocytes from AA patients could inhibit allogeneic and autologous hematopoietic colony formation in vitro 32 and removal of lymphocytes improved colony numbers in tissue culture. 33 To address whether defective AA Tregs could contribute to the impaired hematopoiesis by effector T cells, we assessed influence of the supernatants obtained from effector T cells/Treg coculture systems on CFU formations of cord blood CD34 ϩ cells.…”

Section: Defective Immunosuppression By Aa Tregs Contributed To Impaimentioning

confidence: 96%

Intrinsic impairment of CD4+CD25+ regulatory T cells in acquired aplastic anemia

Shi

et al. 2012

Blood

113

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IntroductionAcquired aplastic anemia (AA), characterized by pancytopenia in peripheral blood (PB) and bone marrow (BM) hypoplasia, is a bone marrow failure syndrome attacked by autologous T cells, such as CD8 ϩ cytotoxic T cells, CD4 ϩ Th1 cells, and Th17 cells, on BM hematopoietic progenitors. [1][2][3][4] Hematopoiesis recovery after successful immunosuppressive treatment provided powerful evidence for the core role of the immune-mediated destruction of hematopoietic progenitor/stem cells. Mechanisms of immunemediated destruction of hematopoiesis include Th1 polarization response conferring immoderate production of inhibitory cytokines such as interferon-␥ (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and interleukin-2 (IL-2), direct toxicity to autologous CD34 ϩ cells by T-cell populations, and Th17 immune response. [4][5][6][7] In that sense, AA is a specific autoimmune disease because of aberrant T-cell immune homeostasis and BM is the main target organ.It is now well established that CD4 ϩ T-cell subpopulations constitutively expressing the surface protein CD25 and the transcription factor FoxP3 are indispensable for the maintenance of immunologic self-tolerance and immunosuppression. [8][9][10][11] There is also accumulating evidence that impaired function of CD4 ϩ CD25 ϩ regulatory T cells (Tregs) has been implicated in the development of several common autoimmune diseases, 8,10 myelodysplastic syndromes, 12 and AA. 13 Until now, the only report of Treg abnormality in AA has shown that the numbers of circulating Tregs decreased in most patients. Meanwhile, almost all patients had low levels of nuclear factor of activated T cells, cytoplasmic 2 (NFAT1/ NFATc2) which could explain decreased FoxP3 expression in Tregs from AA patients. 13 But little is known regarding the function of Tregs in AA.Physiologically, induction of immune tolerance and suppression of autoreactive effector T-cell proliferation were the critical function of CD4 ϩ CD25 ϩ Tregs through cell contact-inhibition mechanisms and/or production of inhibitory cytokine. Furthermore, BM is a reservoir for CD4 ϩ CD25 ϩ Tregs that home to and are retained in BM through the stromal-derived factor-1␣ (SDF-1␣)/ CXCR4 signal. 14 Previous data demonstrated that the only way for Tregs homing to BM was via the SDF-1␣/CXCR4 signal. 14,15 It was believed that CXCR4 was the only receptor of SDF-1␣ for years. However, several reports recently provided evidence that SDF-1␣ also bound to another 7 transmembrane span receptor CXCR7. 16,17 Thus, the role of the SDF-1␣/CXCR4 axis in regulating Treg trafficking between BM and PB becomes more complex. Combined with the fact that BM is the target organ attacked by autoreactive effector T cells leading to hematopoiesis destruction, we hypothesized that Tregs in AA might have impaired homing potential to BM so as to be less efficient to suppress the effector T-cell proliferation and Th1-type cytokine production. We also hypothesized that Tregs in AA had intrinsic deficiencies of immunosuppression for autologous effector T...

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“…For example, T lymphocytes promote the growth of pluripotent (1-3) and committed (4)(5)(6)(7)(8) hemopoietic progenitor cells and interact with mononuclear phagocytes to regulate granulopoiesis in vitro (8). In vitro studies in a number of laboratories, including our own (9)(10)(11)(12), have also provided evidence that a major pathophysiologic abnormality in some patients with bone marrow failure derives from T lymphocytes that inhibit hematopoiesis (9)(10)(11)(12)(13)(14). While the term "suppressor" has been sometimes used to describe the hemopoietic activity of these T lymphocytes, it is not yet known whether these cells are the same as those more widely recognized (and more thoroughly studied) suppressor T lymphocyte subpopulations that inhibit certain phases of the immune response.…”

Section: Introductionmentioning

confidence: 99%

T lymphocytes involved in inhibition of granulopoiesis in two neutropenic patients are of the cytotoxic/suppressor (T3+T8+) subset.

Bagby¹

1981

J. Clin. Invest.

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Suppression of Erythroid-Colony Formation by Lymphocytes from Patients with Aplastic Anemia

Cited by 248 publications

References 17 publications

Predicting response to immunosuppressive therapy in childhood aplastic anemia

Predicting response to immunosuppressive therapy in childhood aplastic anemia

Intrinsic impairment of CD4+CD25+ regulatory T cells in acquired aplastic anemia

T lymphocytes involved in inhibition of granulopoiesis in two neutropenic patients are of the cytotoxic/suppressor (T3+T8+) subset.

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