Mechanical clearance of red blood cells by the human spleen: Potential therapeutic applications of a biomimetic RBC filtration method.

During their lifespan, circulating RBC are frequently checked for their deformability. This mechanical quality control operates essentially in the human spleen. RBC unable to squeeze though narrow splenic slits are retained and cleared from the blood circulation. Under physiological conditions this prevents microvessels from being clogged by senescent, rigid RBC. Retention of poorly deformable RBC is an important determinant of pathogenesis in malaria and may also impact the clinical benefit of transfusion. Modulating the splenic retention of RBC has already been proposed to support therapeutic approaches in these research fields. To this aim, the development of microplates for high throughput filtration of RBC through microsphere layers (microplate-based microsphiltration) has been undertaken. This review focuses on potential therapeutic applications provided by this technology in malaria chemotherapy and transfusion.

Recent advances in adult T-cell leukemia therapy: focus on a new anti-transferrin receptor monoclonal antibody.

HTLV-I is an endemic retrovirus responsible for the adult T-cell leukemia/lymphoma (ATLL). This aggressive lymphoid proliferation is associated with a bad prognosis due to the resistance of HTLV-I-infected cells to most classical chemotherapeutic agents. Here we review recent advances in ATLL immunotherapy. We particularly focus on promising data from our group, characterizing a new mouse monoclonal antibody (mAb A24) against the human transferrin receptor (TfR-1). Monoclonal antibodies to target cell differentiation markers on ATLL cells have already been proposed as therapeutic agents. However, in clinical trials acute forms of ATLL were resistant to these immunotherapies. A24 binds TfR-1 (K(d) 2.7 nM) and competes with transferrin for receptor binding. It blocks the proliferation of malignant cells (TfR-1(high)), such as HTLV-I-infected T cells but not of resting cells. A24 induces TfR-1 endocytosis in lysosomal compartments where the receptor is degraded leading to intracellular iron deprivation. In HTLV-I-infected cells, A24 targets and induces apoptosis of both chronic and acute ATLL forms, independent of antibody aggregation, antibody-dependent cellular cytotoxicity and/or complement addition. The antibody efficacy was confirmed in animal models. We are currently developing strategies to use A24 in clinical trials.

[Erythropoiesis: a paradigm for the role of caspases in cell death and differentiation]. / L'erythropoïèse : un paradigme pour l'etude du rôle des caspases dans la mort et la différenciation cellulaire.

Erythroid differentiation involves the transcription factor GATA-1 that positively regulates promoters of erythroid genes (including haemoglobin, glycophorin, erythropoietin receptor) and of erythropoietin. Terminal erythroid differentiation is characterized by major morphological changes that include chromatin condensation and cell size reduction. The morphological changes are partially similar at least to those observed during apoptosis. The production of red cells depends on the apoptosis rate of erythroid progenitors and precursors. Upon erythropoietin starvation or engagement of the death receptor Fas, caspases are activated in erythroid precursors and cleave GATA-1, thus inducing maturation arrest and apoptosis of immature erythroblasts. We have recently demonstrated that, upon erythropoietin stimulation, caspase-3 was also activated, an event required for human terminal erythroblast maturation. Proteins cleaved by caspases in erythroid cells undergoing terminal differentiation include Lamin B and Acinus, which are involved in chromatin condensation. In contrast, despite caspase-3 activation neither GATA-1 degradation nor apoptosis was observed. Thus, the fate of erythroid precursors is determined downstream of caspase activation by the pattern of cleaved targets. Therefore, there are some mechanisms underlying the selective protection of caspase-3 targets during erythropoiesis. This model in which caspases activation is required for differentiation may apply to other haematopoietic or non haematopoietic cellular systems which are described in this review.