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, 50 (3), 131-9

Hematopoietic Cell Transplantation for Hemophagocytic Lymphohistiocytosis: Recent Advances and Controversies


Hematopoietic Cell Transplantation for Hemophagocytic Lymphohistiocytosis: Recent Advances and Controversies

Jong Jin Seo. Blood Res.


Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory clinical syndrome of uncontrolled immune response which results in hypercytokinemia due to underlying primary or secondary immune defect. A number of genetic defects in transport, processing and function of cytotoxic granules which result in defective granule exocytosis and cytotoxicity of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells have been well identified at the cellular and molecular level. Important advances have been made during the last 20 years in the diagnosis and treatment of HLH. The Histiocyte Society has proposed diagnostic guideline using both clinical and laboratory findings in HLH-2004 protocol, and this has been modified partly in 2009. HLH used to be a fatal disease, but the survival of HLH patients has improved to more than 60% with the use of chemoimmunotherapy combined with hematopoietic cell transplantation (HCT) over the past 2 decades. However, HCT is still the only curative option of treatment for primary HLH and refractory/relapsed HLH after proper chemoimmunotherapy. The outcome of HCT for HLH patients was also improved steadily during last decades, but HCT for HLH still carries significant mortality and morbidity. Moreover, there remain ongoing controversies in various aspects of HCT including indication of HCT, donor selection, timing of HCT, conditioning regimen, and mixed chimerism after HCT. This review summarized the important practical issues which were proven by previous studies on HCT for HLH, and tried to delineate the controversies among them.

Keywords: Familial HLH; Hematopoietic stem cell transplantation; Hemophagocytic lymphohistiocytosis.


Fig. 1
Fig. 1. Proposed molecular mechanisms of cytotoxic granule exocytosis illustrated with genetic defects that cause primary HLH. CTL activation by class I MHC-associated antigen of the target cell leads to MTOC polarization and transport of cytotoxic granules. Cytotoxic proteins including granzyme, perforin, and FasL are sorted from the TGN by the M6PR. AP3B1 and LYST are involved in sorting and transport of cytotoxic granules. Using the motor protein dynein-dynactin complex, the granules move along the microtubules toward the MTOC that is polarizing toward the CTL-target cell contact site. The granules then switch from microtubules to the actin filament using another motor protein myosin IIA navigating toward the plasma membrane at the immune synapse, where docking takes place through the interaction of Rab27a and Munc13-4, as well as through the recognition of STX11 and Munc18-2 (STXBP2). After docking, the granules are primed by Munc13-4, which probably triggers the conformational change of STX11 from a closed to an open form by removal of STXBP2. A SNARE complex then forms between a v-SNARE (VAMP) on one side and the t-SNAREs (STX11 and SNAP23) on the other side. Formation of this four-helix SNARE complex bundles leads to membrane fusion and release of the granule contents into the immune synapse. Granzymes enter into the target cell through the pores formed by perforins and provoke apoptosis through activation of caspases. FasL binds to Fas on the target cell surface and initiate apoptosis as well. Various types of primary HLH caused by genetic defects in granule-mediated cytotoxicity are highlighted.
Abbreviations: HLH, hemophagocytic lymphohistiocytosis; CTL, cytotoxic T lymphocyte; MTOC, microtubule organizing center; M6PR, mannose-6-phosphate receptor; AP3B1, AP-3 complex subunit beta-1; LYST, lysosomal trafficking regulator; FasL, Fas ligand; TGN, trans-Golgi network; STX11, syntaxin 11; STXBP2, syntaxin binding protein 2; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; v-SNARE, vesicle membrane SNARE; VAMP, vesicle-associated membrane protein; t-SNARE, target membrane SNARE; SNAP23, synaptosomal-associated protein of 23 kDa; CHS, Chédiak-Higashi syndrome; HPS2, Hermansky-Pudlak syndrome type 2; GS2, Griscelli syndrome type 2; FHL, familial HLH.

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