Membrane-Bound IL-21 Promotes Sustained Ex Vivo Proliferation of Human Natural Killer Cells

NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy. Genetically-engineered artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL-15 (mbIL15) have been used to propagate clinical-grade NK cells for human trials of adoptive immunotherapy, but ex vivo proliferation has been limited by telomere shortening. We developed K562-based aAPCs with membrane-bound IL-21 (mbIL21) and assessed their ability to support human NK-cell proliferation. In contrast to mbIL15, mbIL21-expressing aAPCs promoted log-phase NK cell expansion without evidence of senescence for up to 6 weeks of culture. By day 21, parallel expansion of NK cells from 22 donors demonstrated a mean 47,967-fold expansion (median 31,747) when co-cultured with aAPCs expressing mbIL21 compared to 825-fold expansion (median 325) with mbIL15. Despite the significant increase in proliferation, mbIL21-expanded NK cells also showed a significant increase in telomere length compared to freshly obtained NK cells, suggesting a possible mechanism for their sustained proliferation. NK cells expanded with mbIL21 were similar in phenotype and cytotoxicity to those expanded with mbIL15, with retained donor KIR repertoires and high expression of NCRs, CD16, and NKG2D, but had superior cytokine secretion. The mbIL21-expanded NK cells showed increased transcription of the activating receptor CD160, but otherwise had remarkably similar mRNA expression profiles of the 96 genes assessed. mbIL21-expanded NK cells had significant cytotoxicity against all tumor cell lines tested, retained responsiveness to inhibitory KIR ligands, and demonstrated enhanced killing via antibody-dependent cell cytotoxicity. Thus, aAPCs expressing mbIL21 promote improved proliferation of human NK cells with longer telomeres and less senescence, supporting their clinical use in propagating NK cells for adoptive immunotherapy

Autonoetic Consciousness in Autobiographical Memories after Medial Temporal Lobe Resection

This study aims to investigate autonoetic consciousness associated with episodic autobiographical memory in patients who had undergone unilateral medial temporal lobe resection for intractable epilepsy. Autonoetic consciousness, defined as the conscious feeling of mentally travelling back in time to relive a specific event, was assessed using the Remember/Know (R/K) paradigm across different time periods as proposed in the autobiographical memory task developed by Piolino et al. (TEMPau task). Results revealed that the two patient groups (left and right temporal resection) gave reduced sense of reliving (R) responses and more familiarity (K) responses than healthy controls. This poor autonoetic consciousness was highlighted when patients were asked to justify their Remember responses by recalling sensory-perceptive, affective or spatiotemporal specific details across all life periods. These results support the bilateral MTL contribution to episodic autobiographical memory covering the entire lifespan, which is consistent with the multiple trace theory of MTL function [7,9]. This study also demonstrates the bilateral involvement of MTL structures in recalling specific details of personal events characterized by autonoetic consciousness

Role of the supplementary motor area in motor deficit following medial frontal lobe surgery.

International audienceOBJECTIVE: Patients undergoing surgical resection of medial frontal lesions may present a transient postoperative deficit that remains largely unpredictable. The authors studied the role of the supplementary motor area (SMA) in the occurrence of this deficit using fMRI. METHODS: Twenty-three patients underwent a preoperative fMRI before resection of medial frontal lesions. Tasks included self-paced flexion/extension of the left and right hand, successively. Preoperative fMRI data were compared with postoperative MRI data and with neurologic outcome. RESULTS: Following surgery, 11 patients had a motor deficit from which all patients recovered within a few weeks or months. The deficit was similar across patients, consisting of a global reduction in spontaneous movements contralateral to the operated side with variable severity. SMA activation was observed in all patients. The deficit was observed when the area activated in the posterior part of the SMA (SMA proper) was resected. CONCLUSIONS: fMRI is able to identify the area at risk in the SMA proper whose resection is highly related to the occurrence of the motor deficit. The clinical characteristics of this deficit support the role of the SMA proper in the initiation and execution of the movement