T cell immunoengineering with advanced biomaterials

Recent advances in biomaterials design offer the potential to actively control immune cell activation and behaviour. Many human diseases, such as infections, cancer, and autoimmune disorders, are partly mediated by inappropriate or insufficient activation of the immune system. T cells play a central role in the host immune response to these diseases, and so constitute a promising cell type for manipulation. In vivo, T cells are stimulated by antigen presenting cells (APC), therefore to design immunoengineering biomaterials that control T cell behaviour, artificial interfaces that mimic the natural APC-T cell interaction are required. This review draws together research in the design and fabrication of such biomaterial interfaces, and highlights efforts to elucidate key parameters in T cell activation, such as substrate mechanical properties and spatial organization of receptors, illustrating how they can be manipulated by bioengineering approaches to alter T cell function

Ruinas, círculos, construcciones

This article is organized around three groups of 'citations' from architectural forms, texts, images, which generate three options of imagination, representation and reading of space: ruins, circular constructions, and rhetoric (in particular figures of repetition). I discuss the story of Borges "Las ruinas circulares" and examples from Iain Sinclair, London orbital (2002), Gianni Biondillo and Michele Monina, Tangenziali. Due viandanti ai bordi della città (2010), and Nicolò Bassetti, Sapo Matteucci, Sacro romano GRA (2013). The circularity generates a repetitive and disparate look allowing the observation of a complementary rhythm of destruction and construction characteristic of progress in the world

Activation of Human Natural Killer Cells by Graphene Oxide-Templated Antibody Nanoclusters

An emerging new paradigm is that immune cell activation is controlled by transient interactions between supramolecular assemblies of receptors and ligands. Current immunotherapy biologic pharmaceuticals that activate or desensitize NK cells are, however, individual molecules that do not replicate this nanoscale organization of proteins. Here, we use nanoscale graphene oxide (NGO) as a template to generate soluble nanoscale clusters of Natural Killer cell-activating antibodies. We control nanocluster size and molecular number to mimic reported values for cell surface proteins. These NGO-templated molecular nanoclusters, used to stimulate NK cells via the CD16 receptor, successfully induced cellular activation, indicated by degranulation of cytolytic granules and IFN-γ secretion. Importantly, activation significantly exceeded that induced by the same antibodies applied as a solution of individual molecules. These results demonstrate that future immunotherapies could be enhanced by assembling immunomodulatory drugs into nanoclusters and establish NGO-templating as a candidate technology

Nanoscale ligand spacing influences receptor triggering in T cells and NK cells

Bioactive nanoscale arrays were constructed to ligate activating cell surface receptors on T cells (the CD3 component of the TCR complex) and natural killer (NK) cells (CD16). These arrays are formed from biofunctionalized gold nanospheres with controlled interparticle spacing in the range 25-104 nm. Responses to these nanoarrays were assessed using the extent of membrane-localized phosphotyrosine in T cells stimulated with CD3-binding nanoarrays and the size of cell contact area for NK cells stimulated with CD16-binding nanoarrays. In both cases, the strength of response decreased with increasing spacing, falling to background levels by 69 nm in the T cell/anti-CD3 system and 104 nm for the NK cell/anti-CD16 system. These results demonstrate that immune receptor triggering can be influenced by the nanoscale spatial organization of receptor/ligand interactions

Identification and survival of carriers of mutations in DNA mis-match repair genes in colon cancer.

Background The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease. Methods Without preselection and regardless of family history, we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer. We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1, MSH2, and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival. Results There were 38 mutations among the 870 participants (4 percent): 15 mutations in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6 percent) and women (3 percent) differed significantly (