Page 17 - Haematologica-5

Editorials
applications in the management of AA patients. Indeed, deep whole exome sequencing,15 CyTOF14 and deep TCR analysis2 all help to better describe the pathogenic events underlying bone marrow failure syndromes. Even if none of them translates into immediate therapeutic decisions, they are all useful to confirm the diagnosis, to determine the prognosis and possibly to monitor the clinical course of AA patients. Indeed, this latter application may be use- ful for early identification of refractory or relapsing patients, paving the way for pre-emptive therapeutic interventions. Moreover, the deep dissection at the clonal and at the functional levels of the immune T-cell compart- ment (e.g. combining CyTOF and TCR analysis) may also answer some open questions in the field. For example, the differential depletion of some specific T-cell subsets might explain the different outcome seen with different ATG preparations.3 These novel technologies may help identify the specific T-cell subsets which are crucial to the pathophysiology of AA (and possibly differentially depleted by distinct ATG brands), possibly driving the development of future targeted therapies.
References
1. Young NS. Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology Am Soc Hematol Educ Program. 2013;2013:76-81.
2. Giudice V, Feng X, Lin Z, et al. Deep sequencing and flow cytometric characterization of expanded effector memory CD8+CD57+ T cells frequently reveals T-cell receptor Vbeta oligoclonality and CDR3 homology in acquired aplastic anemia. Haematologica. 2018;103(5): 759-769.
3. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365(5):430-438.
4. Zoumbos NC, Gascón P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med. 1985;312(5):257-265.
5. Zoumbos NC, Gascón P, Djeu JY, Young NS. Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possi- bly in vivo. Proc Natl Acad Sci USA. 1985;82(1):188-192.
6. Sloand E, Kim S, Maciejewski JP, Tisdale J, Follmann D, Young NS.
Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood. 2002;100(4):1185- 1191.
7. Selleri C, Maciejewski JP, Sato T, Young NS. Interferon-gamma con- stitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition. Blood: 1996;87(10):4149-4157.
8. Alvarado LJ, Andreoni A, Huntsman HD, et al. Heterodimerization of TPO and IFNγ Impairs Human Hematopoietic Stem/Progenitor Cell Signaling and Survival in Chronic Inflammation Blood. 2017;130(Suppl 1):4.
9. Zeng W, Nakao S, Takamatsu H, et al. Characterization of T-cell repertoire of the bone marrow in immune-mediated aplastic anemia: evidence for the involvement of antigen-driven T-cell response in cyclosporine-dependent aplastic anemia. Blood. 1999;93(9):3008- 3016.
10. Risitano AM, Maciejewski JP, Green S, Plasilova M, Zeng W, Young NS. In-vivo dominant immune responses in aplastic anaemia: molec- ular tracking of putatively pathogenetic T-cell clones by TCR beta- CDR3 sequencing. Lancet. 2004;364(9431):355-364.
11. de Latour RP, Visconte V, Takaku T, et al. Th17 immune responses contribute to the pathophysiology of aplastic anemia. Blood. 2010;116(20):4175-4184.
12. Solomou EE, Rezvani K, Mielke S, et al. Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia. Blood. 2007;110(5):1603-1606.
13. Kordasti S, Marsh J, Al-Khan S, et al. Functional characterization of CD4+ T cells in aplastic anemia. Blood. 2012;119(9):2033-2043.
14. Kordasti S, Costantini B, Seidl T, et al. Deep phenotyping of Tregs
identifies an immune signature for idiopathic aplastic anemia and
predicts response to treatment. Blood. 2016;128(9):1193-1205.
15. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med.
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16. Cooper JN, Young NS. Clonality in context: hematopoietic clones in
their marrow environment. Blood. 2017;130(22):2363-2372.
17. Calis JJ, Rosenberg BR. Characterizing immune repertoires by high throughput sequencing: strategies and applications. Trends
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Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia. J Immunol. 2016;196(4):1568-1578.
Hematopoietic stem cell mobilization with plerixafor in sickle cell disease
Matthew M. Hsieh and John F. Tisdale
Cellular and Molecular Therapeutics Section, Sickle Cell Branch, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland
E-mail: matthewhs@nhlbi.nih.gov doi:10.3324/haematol.2018.190876
AAfter more than a half-century since the molecular basis for sickle cell disease (SCD) was described by Linus Pauling and colleagues, we now possess the molecular tools to contemplate a one-time cure through genetic modification of autologous hematopoietic stem cells (HSC). For these promising gene transfer and gene editing strategies to become a reality, a sufficient number of HSC of high purity must be obtained. Filgrastim, or granulocyte colony-stimulating factor, mobilization and
apheresis is the standard method for HSC collection in healthy adult donors, yet this approach is associated with high rates of adverse events requiring hospitalization in SCD, including vaso-occlusive crises, multi-organ failure, and even death, prompting our call for a moratorium on its use for HSC mobilization in SCD.1 Thus, bone marrow harvesting is the default approach, with evidence support- ing its utility in both animal models and in vitro studies uti- lizing patients’ material.2-4 However, bone marrow harvest-
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