CD103 blockade reduces CD8 T cell accumulation during GVHD, but does not attenuate GVL effects

Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)Purpose: Every four minutes someone in America is diagnosed with a blood cancer, and the Leukemia & Lymphoma Society estimates that over 50,000 people die of a blood cancer each year1. Many blood cancers are caused by white blood cells that undergo uncontrolled cell division. This uncontrolled replication causes the affected cells to be non-functional. Furthermore, normal white blood cells are crowded out by the malignant cells, leaving the patient highly immunosuppressed. Current therapies for blood cancers include radiation therapy and more than 50 chemotherapy drugs1. However, many of these drugs are ineffectual in treating the disease, thus alternative therapies are desired. Bone marrow transplants represent a curative therapy for patients with blood cancers. Immediately preceding a bone marrow transplant, the patient is treated with drugs and/or radiation to destroy their immune system, thereby killing the cancer cells. The patient is then infused with bone marrow cells from a genetically similar individual. Bone marrow cells are the immune cell precursors, so the bone marrow transplant recipient receives the cancer-free donor immune system. The limiting factor to the broad use of bone marrow transplants as a curative therapy for blood cancers is graft verses host disease (GVHD). GVHD is caused by a mature subset of white blood cells (T cells) present in the bone marrow graft that recognize and destroy host tissue, particularly epithelial cells in the gut. Depletion of mature T cells prior to transplant is not a viable treatment strategy because mature T cells facilitate several beneficial effects that are essential to a successful transplant. These effects include controlling opportunistic infections and preventing cancer relapse. Therefore, the goal of our research is to find a way to separate the T cells that cause GVHD from those that facilitate the beneficial effects post transplant. Integrins are molecules that facilitate adhesion between cells. Integrins present on the surface of T cells help determine where T cells are go and how long they stay in a particular location after transplant. Previous work in our lab has shown that the integrin CD103 is expressed on a subset of T cells called CD8+ T cells2. Our work has shown that CD103 expression on CD8+ T cells promotes the association of CD8+ T cells with epithelial cells3. We hypothesize that CD103 will be required for the retention of CD8+ T cells in the epithelium of the gut during GVHD, but will not be required for effective clearance of a blood malignancy. Research Methods: To test our hypothesis, we used murine models of GVHD. Mice were irradiated to destroy the host immune system. Recipients were then transplanted with donor bone marrow to restore immune function and donor T cells to cause GVHD. Following the transplant, mice were monitored daily for clinical signs of GVHD. At predetermined time points, groups of mice were sacrificed for further analysis of T cell migration and expression levels of CD103. To test whether CD103 was required for effective clearance of a blood malignancy, a genetically modified mouse was used. The genetically modified mouse has a DNA mutation that causes a subset of white blood cells (B cells) to proliferate uncontrolled. The disease course in this mouse is very similar to the human disease chronic lymphocytic leukemia (CLL). Recipient mice with murine CLL were transplanted with either normal or CD103 deficient T cells, and the ability to eradicate CLL was compared between the two groups. Findings: Using our model of GVHD, we found that mature donor CD8+ T cells accumulate in the gut of mice with GVHD. Interestingly, CD103 expression levels on CD8+ T cells in the gut increased dramatically over time. Concurrent with increased CD103 expression levels, we noticed progressive intestinal injury in our GVHD recipients. Using transgenic mice, we found that CD103 was required for optimal accumulation of CD8+ T cells in the gut, and without CD103 present, we found dramatically fewer CD8+ T cells in the gut. Studies are underway to determine if the progressive intestinal injury is dependent on CD103. Furthermore, CD103 was not required for clearance of malignant B cells. Both normal CD8+ T cells and CD103 knock out CD8+ T cells were able to clear malignant B cells with the same efficiency. Implications: Our data shows that CD103 promotes accumulation of GVHD causing CD8+ T cells in the gut. We show that CD103 expression levels increase over time, concurrent with severe intestinal injury. This finding suggests that CD103 is promoting the retention of CD8+ T cells in the gut and allowing them to cause more damage. Lastly, our data show that CD103 is not required to kill malignant B cells. Taken together, these data provide insight into the potential of altering integrins as a means to separate GVHD from the beneficial properties T cells possess after a bone marrow transplant. Altering integrin expression can potentially decrease T cell retention in GVHD target organs while maintaining the ability to kill residual blood malignancies and lower relapse rates.A three-year embargo was granted for this item

Well-to-Wheel Energy, Emissions, and Cost Analysis of Electricity and Fuel Used in Conventional and Electrified Vehicles, and Their Connection to a Sustainable Energy Infrastructure

Recent legislation by the United States Environmental Protection Agency (EPA) requires record low vehicle tailpipe emissions, necessitating research and development in the areas of lowering conventional (i.e., internal combustion engine) vehicle emissions rates while facilitating the widespread introduction of electrified vehicles. Currently, the EPA views Battery Electric Vehicles as having zero emissions. However, a number of studies illustrate this is not the case when considering the emissions produced in creating the electricity through a full Life Cycle Analysis. As a result, proper comparison of electrified and conventional vehicles must include a complete Well-to-Wheel (WtW) study including the emissions generated through production and use of liquid petroleum and biofuels. As a result, this work provides a full WtW investigation into fuel, electricity, and production analysis of conventional and electrified vehicles. This is supported by a thorough literature review of current and projected future technology, extrapolating to a fleet analysis, as well as applying the technology to an advanced electricity infrastructure. In the following effort, the first chapter simply provides a background into these different areas in order to help set the stage. Chapter 2 explores conventional vehicle emissions profiles predicting future requirements of engine and catalytic exhaust aftertreatment technologies. Findings illustrate that low temperature climates and aging both adversely affect a vehicle's ability to perform proper emissions reductions. This chapter additionally demonstrates an improvement in the fuel use emissions profiles of Argonne National Laboratories' Greenhouse Gases, Regulated Emissions, and Energy Use in Transportation (GREET) model through the update of embedded time-sheet emissions lookup tables using EPA's Motor Vehicle Emissions Simulator (MOVES). This simulation package utilizes a statistical database of over 3000 counties in the continental United States in calculating the emissions profile of various vehicle and fuel type combinations, updating the current tables utilized in GREET. Chapter 3 utilizes these efforts in performing a life cycle analysis of a 1974 Volkswagen Super Beetle converted to a plug-in series hybrid. This work utilizes GREET in exploring the WtW fuel use emissions profile, as well as estimating the energy and emissions savings through reusing a number of stock vehicle components in the conversion. A vehicle dynamics model supports this analysis, calculating the average fuel use in a typical city/highway drive cycle. The fourth chapter expands upon this work, analyzing an 800+ vehicle fleet in a comparative analysis between electrified vehicles and their conventional counterparts. This work utilizes four simplified vehicle dynamics models, focusing on ten vehicles with various powertrains and fuel use algorithms. These models calculate the average fuel consumption of these vehicles, employing the GREET model in calculating the emissions profiles on a per-mile and yearly total basis. Furthermore, a full cost analysis of fuel and vehicle combinations demonstrates the economic impacts of electrifying the vehicle fleet. Finally, Chapter 5 seeks to support future research into electrified vehicles for vehicle-to-grid technology, energy storage, and infrastructure control through the design and construction of a small-scale smart grid in collaboration with a previous University of Kansas EcoHawks senior design team. This design consists of a renewable and conventional energy source, a grid load, bulk and dynamic grid storage, and a full sensory and control system. The final design meets the two requirements of a smart grid set forth by the Department of Energy: decentralization of energy production and storage, and providing two-way communication from end users or appliances and the energy network

Role of West Virginia School Psychologists in a Response to Intervention Framework

With the passage of No Child Left Behind in 2001, schools were required to prepare students using research-based teaching methods, interventions, and approaches. Response to Intervention (RTI) is an evidence-based practice that allows schools to assess student responses to interventions. RTI was implemented as a pilot program in West Virginia beginning from 2007 to 2010. Although research has been frequent on implementing RTI, little research has been conducted analyzing RTI and school psychologist involvement, particularly in West Virginia. The purpose of this study was to examine what factors serve as predictors of RTI involvement in West Virginia. The examiner used data from the 2011 West Virginia School Psychologists Association survey to predict RTI Involvement by West Virginia school psychologists. The results indicated no variables significantly predict RTI involvement for West Virginia school psychologists

Building Regional Security: Cooperation in the 21st Century: The Case of the Caribbean Regional Security System [RSS]

Small states that lack capacity and act on their own may fall victim to international and domestic terrorism, transnational organized crime or criminal gangs. The critical issue is not whether small Caribbean states should cooperate in meeting security challenges, but it is rather in what manner, and by which mechanisms can they overcome obstacles in the way of cooperation. The remit of the Regional Security System (RSS) has expanded dramatically, but its capabilities have improved very slowly. The member governments of the RSS are reluctant to develop military capacity beyond current levels since they see economic and social development and disaster relief as priorities, requiring little investment in military hardware. The RSS depends on international donors such as the USA, Canada, Great Britain, and increasingly China to fund training programs, maintain equipment and acquire material. In the view of most analysts, an expanded regional arrangement based on an RSS nucleus is not likely in the foreseeable future. Regional political consensus remains elusive and the predominance of national interests over regional considerations continues to serve as an obstacle to any CARICOM wide regional defense mechanism. Countries in the Caribbean, including the members of the RSS, have to become more responsible for their own security from their own resources. While larger CARICOM economies can do this, it would be difficult for most OECS members of the RSS to do the same. The CARICOM region including the RSS member countries, have undertaken direct regional initiatives in security collaboration. Implementation of the recommendations of the Regional Task Force on Crime and Security (RTFCS) and the structure and mechanisms created for the staging of the Cricket World Cup (CWC 2007) resulted in unprecedented levels of cooperation and permanent legacy institutions for the regional security toolbox. The most important tier of security relationships for the region is the United States and particularly USSOUTHCOM. The Caribbean Basin Security Initiative [CBSI] in which the countries of the RSS participate is a useful U.S. sponsored tool to strengthen the capabilities of the Caribbean countries and promote regional ownership of security initiatives. Future developments under discussion by policy makers in the Caribbean security environment include the granting of law enforcement authority to the military, the formation of a single OECS Police Force, and the creation of a single judicial and law enforcement space. The RSS must continue to work with its CARICOM partners, as well as with the traditional “Atlantic Powers” particularly Canada, the United States and the United Kingdom to implement a general framework for regional security collaboration. Regional security cooperation should embrace wider traditional and non-traditional elements of security appropriate to the 21st century. Security cooperation must utilize to the maximum the best available institutions, mechanisms, techniques and procedures already available in the region. The objective should not be the creation of new agencies but rather the generation of new resources to take effective operations to higher cumulative levels. Security and non-security tools should be combined for both strategic and operational purposes. Regional, hemispheric, and global implications of tactical and operational actions must be understood and appreciated by the forces of the RSS member states. The structure and mechanisms, created for the staging of Cricket World Cup 2007 should remain as legacy institutions and a toolbox for improving regional security cooperation in the Caribbean. RSS collaboration should build on the process of operational level synergies with traditional military partners. In this context, the United States must be a true partner with shared interests, and with the ability to work unobtrusively in a nationalistic environment. Withdrawal of U.S. support for the RSS is not an option

Thermal kinetic inductance detectors for ground-based millimeter-wave cosmology

We show measurements of thermal kinetic inductance detectors (TKID) intended for millimeter wave cosmology in the 200-300 GHz atmospheric window. The TKID is a type of bolometer which uses the kinetic inductance of a superconducting resonator to measure the temperature of the thermally isolated bolometer island. We measure bolometer thermal conductance, time constant and noise equivalent power. We also measure the quality factor of our resonators as the bath temperature varies to show they are limited by effects consistent with coupling to two level systems.Comment: 8 pages, 4 figures. Submitted to Journal of Low Temperature Physic