Natural Killer Lysis Receptor (NKLR)/NKLR-Ligand Matching as a Novel Approach for Enhancing Anti-Tumor Activity of Allogeneic NK Cells

NK cells are key players in anti tumor immune response, which can be employed in cell-based therapeutic modalities. One of the suggested ways to amplify their anti tumor effect, especially in the field of stem cell transplantation, is by selecting donor/recipient mismatches in specific HLA, to reduce the inhibitory effect of killer Ig-like receptors (KIRs). Here we suggest an alternative approach for augmentation of anti tumor effect of allogeneic NK cells, which is founded on profile matching of donor NK lysis receptors (NKLR) phenotype with tumor lysis-ligands.We show that an NKLR-mediated killing directly correlates with the NKLR expression intensity on NK cells. Considerable donor variability in the expression of CD16, NKp46, NKG2D and NKp30 on circulating NK cells, combined with the stability of phenotype in several independently performed tests over two months, indicates that NKLR-guided selection of donors is feasible. As a proof of concept, we show that melanoma cells are dominantly recognized by three NKLRs: NKG2D, NKp30 and NKp44. Notably, the expression of NKp30 on circulating NK cells among metastatic melanoma patients was significantly decreased, which diminishes their ability to kill melanoma cells. Ex vivo expansion of NK cells results not only in increased amount of cells but also in a consistently superior and predictable expression of NKG2D, NKp30 and NKp44. Moreover, expanded NK cultures with high expression of NKG2D or NKp30 were mostly derived from the corresponding NKG2D(high) or NK30(high) donors. These NK cultures subsequently displayed an improved cytotoxic activity against melanoma in a HLA/KIR-ligand mismatched setup, which was NKLR-dependent, as demonstrated with blocking anti-NKG2D antibodies.NKLR/NKLR-ligand matching reproducibly elicits enhanced NK anti-tumor response. Common NKLR recognition patterns of tumors, as demonstrated here in melanoma, would allow implementation of this approach in solid malignancies and potentially in hematological malignancies, either independently or in adjunction to other modalities

Safe asleep? Human-machine relations in medical practice

In the process of anaesthesia the patient must surrender vital functions to the care of clinicians and machines who will act for, and advocate for the patient during the surgical procedure. In this paper, we discuss the practices and knowledge sources that underpin safety in a risky field in which many boundaries are crossed and dissolved. Anaesthetic practice is at the frontier not only of conscious/unconsciousness but is also at the human/machine frontier, where a range of technologies acts as both delegates and intermediaries between patient and practitioner. We are concerned with how practitioners accommodate and manage these shifting boundaries and what kinds of knowledge sources the ‘expert’ must employ to make decisions. Such sources include clinical, social and electronic which in their various forms demonstrate the hybrid and collective nature of anaesthetised patients. In managing this collective, the expert is one who is able to judge where the boundary lies between what is routine and what is critical in practice, while the junior must judge the personal limits of expertise in practice. In exploring the working of anaesthetic hybrids, we argue that recognising the changing distribution of agency between humans and machines itself illustrates important features of human authorship and expertise

A selection of cases on constitutional law,

"To accompany The general principles of constitutional law. By Thomas M. Cooley."Mode of access: Internet

Illustrative cases on insurance /

"A companion book to Vance on insurance" -- t.p.Mode of access: Internet

Illustrative cases on the law of sales /

Mode of access: Internet