Showing papers by "Mark M. Davis published in 2008"
TL;DR: The swift IL-17 response mounted by antigen-naive gammadelta T cells suggests a critical role for these cells at the onset of an acute inflammatory response to novel antigens, and thymic selection determines the effector fate of gammad delta T cells rather than constrains their antigen specificities.
440 citations
TL;DR: Inbred mice have been an extremely successful tool for basic immunology, but much less so as models of disease, so more strategically directed efforts in human immunology are needed to maximize the use of immunologic approaches to improve human health.
326 citations
TL;DR: It is shown that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days.
Abstract: Given their self-renewing and pluripotent capabilities, human embryonic stem cells (hESCs) are well poised as a cellular source for tissue regeneration therapy. However, the host immune response against transplanted hESCs is not well characterized. In fact, controversy remains as to whether hESCs have immune-privileged properties. To address this issue, we used in vivo bioluminescent imaging to track the fate of transplanted hESCs stably transduced with a double-fusion reporter gene consisting of firefly luciferase and enhanced GFP. We show that survival after transplant is significantly limited in immunocompetent as opposed to immunodeficient mice. Repeated transplantation of hESCs into immunocompetent hosts results in accelerated hESC death, suggesting an adaptive donor-specific immune response. Our data demonstrate that transplanted hESCs trigger robust cellular and humoral immune responses, resulting in intragraft infiltration of inflammatory cells and subsequent hESC rejection. Moreover, we have found CD4+ T cells to be an important modulator of hESC immune-mediated rejection. Finally, we show that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days. Taken together, these data suggest that hESCs are immunogenic, trigger both cellular and humoral-mediated pathways, and, as a result, are rapidly rejected in xenogeneic hosts. This process can be mitigated by a combined immunosuppressive regimen as assessed by molecular imaging approaches.
291 citations
TL;DR: The mode of secretion seems to be tailored to the intended function of the secreted molecule, and it is shown that T cells release chemokines and certain inflammatory factors through a multidirectional pathway directed away from the synapse.
Abstract: T cells use secreted soluble factors for highly specific intercellular communication and targeted cell killing This specificity is achieved first through T cell receptor–mediated recognition of complexes of peptide and major histocompatibility complex displayed by appropriate antigen-presenting cells and then by the directed secretion of cytokines and lytic factors into the immunological synapse between the T cell and antigen-presenting cell Studies have begun to probe the molecular basis for this synaptic secretion and have also shown that T cells release chemokines and certain inflammatory factors through a multidirectional pathway directed away from the synapse Thus, the mode of secretion seems to be tailored to the intended function of the secreted molecule
178 citations
TL;DR: A "gauntlet" model in which thymocytes mature by continually acquiring and reacquiring positively selecting signals without sustained contact with epithelial cells is suggested, thereby allowing them to sample many cell surfaces for potentially negatively selecting ligands.
54 citations
TL;DR: Evidence for a new mechanism of T cell receptor regulation is provided that prior to activation, basic residues in the cytoplasmic domain of the signaling subunits of the T cell receptors associate with the plasma membrane such that the key signaling tyrosines are sequestered in the bilayer.
40 citations
Book•
Max Planck Society1, Columbia University2, Rockefeller University3, Robert Koch Institute4, New York University5, National Institutes of Health6, Memorial Sloan Kettering Cancer Center7, Stanford University8, Pasteur Institute9, University of Colorado Denver10, Umeå University11, University of Memphis12, University of Bologna13, Harvard University14, Yale University15, Medical Research Council16, University of Oxford17, University of California, Santa Cruz18, Indiana University19, University of Helsinki20, University of British Columbia21, University of Washington22, University of Kiel23, Uppsala University24, University of Pittsburgh25, St Mary's Hospital26, University of Konstanz27, University of Kentucky28, Wistar Institute29, London School of Economics and Political Science30, University of California, San Diego31, University College London32, University of Wisconsin-Madison33, University of Toronto34, University of Rochester35, Medical University of South Carolina36, University of Buenos Aires37, Stockholm University38, University of Illinois at Chicago39, California Institute of Technology40, University of Canterbury41, Humboldt University of Berlin42, Kyoto University43, Weizmann Institute of Science44, University of California, Los Angeles45, Massachusetts Institute of Technology46, Ludwig Maximilian University of Munich47, Washington University in St. Louis48, Scripps Research Institute49, University of Cambridge50, Université libre de Bruxelles51
TL;DR: A first-hand account of the rise and fall of a scientific paradigm shows how scientific fiction turns to fact and develops a general perspective on how solid knowledge is derived from error-prone scientific methodology, namely by exposure of scientific notions to the scrutiny of reality.
Abstract: First-hand account of the rise and fall of a scientific paradigm Shows how scientific fiction turns to fact Highlights the origin of scientific hype Includes interviews with prominent scientists The network paradigm dominated immunological research from the early 1970s to the late 1980s. The originator, Niels Jerne, hypothesized that the vast diversity of antibodies in each individual forms a network of mutual "idiotypic" recognition, thus regulating the immune system. In context of emerging concepts of systems biology such as cybernetics and autopoesis, the "Eigenbehavior" of the immune system fascinated an entire generation of young immunologists. But fascination led to experimental errors and overinterpretation, eventually magnifying the immune system from a mere infection-fighting device to a substrate of personality and individuality. As a result, what initially appeared as an exciting new perspective of the immune system is now viewed as a scientific vagary, and is largely abandoned. The author, himself a participant in the network vagary, begins with a description of the leading theoretical concepts on fact finding in science. This is followed by a historical account of the rise and fall of the network paradigm, complemented by personal interviews with some of the prominent protagonists. By comparing the network paradigm to other, more lasting concepts in life science, the author develops a general perspective on how solid knowledge is derived from error-prone scientific methodology, namely by exposure of scientific notions to the scrutiny of reality.
21 citations
01 Nov 2008
TL;DR: ImmuneXpresso is described, an information extraction system, tailored for parsing the primary literature of immunology and relating it to experimental data, and this system can be used to guide experimentalists in interpreting multi-scale, experimental data.
Abstract: The immune system of higher organisms is, by any standard, complex. To date, using reductionist techniques, immunologists have elucidated many of the basic principles of how the immune system functions, yet our understanding is still far from complete. In an era of high throughput measurements, it is already clear that the scientific knowledge we have accumulated has itself grown larger than our ability to cope with it, and thus it is increasingly important to develop bioinformatics tools with which to navigate the complexity of the information that is available to us. Here, we describe ImmuneXpresso, an information extraction system, tailored for parsing the primary literature of immunology and relating it to experimental data. The immune system is very much dependent on the interactions of various white blood cells with each other, either in synaptic contacts, at a distance using cytokines or chemokines, or both. Therefore, as a first approximation, we used ImmuneXpresso to create a literature derived network of interactions between cells and cytokines. Integration of cell-specific gene expression data facilitates cross-validation of cytokine mediated cell-cell interactions and suggests novel interactions. We evaluate the performance of our automatically generated multi-scale model against existing manually curated data, and show how this system can be used to guide experimentalists in interpreting multi-scale, experimental data. Our methodology is scalable and can be generalized to other systems.
18 citations
TL;DR: IT-101 is safe, tolerable, and is associated with acceptable toxicity at the MTD, and twice monthly regimens maintained SD with minimal drug-related toxicity.
Abstract: Background: IT-101 is the first de novo designed experimental nanoparticle therapeutic for cancer and is comprised of a cyclodextrin-based polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles with diameter of ca. 40 nm and near neutral surface charge. The nanoparticle properties have been designed to accomplish extended circulation, tumor penetration, and slow intracellular drug release to enhance the mechanism of action of the CPT. Methods: Patients with refractory solid tumors received IT-101 by 90 minute IV infusions on days 1, 8, and 15 of a 28 day cycle over a dose range of 6 mg/m^2/wk to 18 mg/m^2/wk. Dose escalation was conducted with a Simon’s design. Dose limiting toxicity (DLT) was determined over the first cycle. Progressive disease (PD) was defined by RECIST (CT) results. Pharmacokinetics of free and total CPT in blood and urine were collected over after the 1st dose. Patients completing 6 cycles with stable disease (SD) or better were eligible to receive compassionate IT-101 at the same dose level every other week (QOW). Results: Twelve patients [6 (6 mg/m^2), 3 (12 mg/m^2), and 3 (18 mg/m^2)] were enrolled. 4 of 12 (33%) had PD by CT. 8 of 12 (66%) did not have PD. (6-SD and 2 clinical deterioration (CD). Hematologic toxicity was the DLT. The MTD was 2 cycles, SD was observed at cumulative doses of 18 mg/m^2/mo to 27 mg/m^2/mo. Three patients (pancreatic, renal cell, NSCLC) completed 6 cycles and received treatment QOW with a PFS of ≥18, 14, and 11 months, respectively. Over 7 days, the mean plasma total CPT and free CPT t_(½ β) were 39 ± 1.1 and 51 ± 1.5 hrs, respectively. The AUC of free and total CPT were linear with 9.9 ± 4.0 % of the CPT dose free. Urinary excretion averaged 16 ± 9.1% of the total CPT dose in the first 48 hrs. Conclusions: These data appear to demonstrate that IT-101 is safe, tolerable, and is associated with acceptable toxicity at the MTD. SD was maintained in patients treated beyond 6 cycles QOW at doses of 6 to 9 mg/m^2/wk. In addition, twice monthly regimens maintained SD with minimal drug-related toxicity. A QOW schedule (allowing for 99% elimination of CPT) is warranted in future clinical trial.
16 citations