Studies of Adoptively Transferred CMV-Specific T Cells

Studies of Adoptively Transferred CMV-Specific T Cells Group Method of Expansion/Selection Riddell, 1992, 1995 Expansion using CMV-infected fibroblasts Einsele, 2002 Expansion with CMV lysate Cobbold, 2005 Tetramer Selection using magnetic beads Micklethwaite, 2008 Antigen-presenting cells (Dendritic cells) transduced with an adenoviral vector encoding CMVpp65 Peggs, 2011 Selection of T cells secreting IFN-ÃŽÂ ³ after exposure to CMV antigen Blyth, 2013 Antigen-presenting cells (Dendritic cells) transduced with an adenoviral vector encoding CMVpp65 or Dendritic cells pulsed with HLA-A02-restricted peptide NLVPMVATV Quoted from (Hanley and Bollard, 2014). The ability to generate CMV, EBV, and adenovirus-specific CTL from the 20% fraction of a cord blood unit by using dendritic cells transduced with an Ad5/f35-CMV-pp65 vector as well as the cytokines IL-7, IL-12, and IL-15 was reported by Hanley and colleagues in 2009. Responding T cells were shown to be derived from the naÃÆ'Â ¯ve T cell population and responded to typical and atypical, novel CMV-pp65 epitopes. Later on, the ability to generate CMV-specific T cells from CMV-seronegative donors was reported by Jedema et al., 2011 and Hanley et al., 2013. Vaccination: On the basis of the cost to the health care system and the impact of the virus on human suffering, the development of an effective prophylactic vaccine to prevent CMV symptomatic congenital disease and/or to prevent disease in immunocompromised individuals is a high priority and would be a highly cost-effective measure (Khanna and Diamond, 2006). A successful vaccine strategy should aim to stimulate the innate and adaptive immune responses at the appropriate time. Both humoral and cell-mediated immune responses might be necessary to prevent congenital disease, whereas cellular immune response alone might be sufficient to prevent virus-associated complications in transplant patients (Khanna and Diamond, 2006). Cytomegalovirus exhibits a high level of molecular diversity and carries many immune evasion genes (Hansen et al., 2010). Thus, infection within a host can occur with multiple virus strains concomitantly, including at the time of initial infection, or sequentially (Renzette et al., 2011). Broad and cross-neutralizing cellular and humoral responses have therefore become a major goal of vaccine design (Arvin et al., 2004). Various strategies have been developed, though a vaccine against CMV remains elusive. CMV vaccines have been obtained using attenuated or chimeric viruses, DBs, recombinant proteins, DNA, peptides and/or viral vectors (poxvirus/adenovirus) (Khanna and Diamond, 2006). A number of subunit CMV vaccines tested in clinical trials targeted the abundant pp65 protein (Sylwester et al., 2005), which is expressed by CMV-infected cells both early and late after infection (La Rosa et al., 2012). Cytomegalovirus vaccines in clinical trials include: glycoprotein B subunit vaccines; alphavirus replicon particle vaccines; DNA vaccines; and live-attenuated vaccines. A variety of vaccine strategies are also being examined in preclinical systems and animal models of infection. These include: recombinant vesicular stomatitis virus vaccines; recombinant modified vaccinia virus Ankara; replication-deficient adenovirus-vectored vaccines; and recombinant live-attenuated virus vaccines generated by mutagenesis of cloned rodent CMV genomes maintained as bacterial artificial chromosomes in Escherichia coli (Sung and Schleiss, 2010). Trial of a subunit vaccine consisting of recombinant HCMV envelope gB with MF59 adjuvant: All HCMV-infected individuals have a significant proportion of neutralizing antibodies to HCMV being specific for epitopes on gB (Sung and Schleiss, 2010). A study of the use of HCMV gB vaccine plus MF59 adjuvant was reported. It was administered following a 0-, 1- and 6-month schedule (Pass et al., 2009). Although the study demonstrated that the gB vaccine could significantly reduce the risk of acquiring primary maternal HCMV infection, the study did not address the question of whether vaccine-induced HCMV immunity was equivalent to natural immunity in modulating either infection rate or sequelae for the fetus (Dekker and Arvin, 2009). Since re-infection with new strains of HCMV with which the host has no prior experience can lead to transmission to the fetus with subsequent sequelae (Boppana et al., 2001), the issue of cross-protection against diverse clinical isolates following administration of gB vaccine from a single genotype must be defined in future studies (Sung and Schleiss, 2010). Clinical trial evaluation of a two-component alphavirus replicon particle vaccine containing HCMV gB and phosphoprotein 65 (pp65)/immediate early fusion proteins: The gB and the pp65 are the most frequently recognized antigens by CD4+ T cells, and pp65 is also one of the antigens most frequently recognized by CD8+ T cells (Sylwester et al., 2005). The HCMV IE1 is also an important target of the CD8+ T-cell response (Slezak et al., 2007). Therefore, vaccination strategies that aimed at eliciting T-cell responses has focused on the pp65 protein andIE1 gene product (Sung and Schleiss, 2010). AVX601 is a two-component alphavirus replicon particle vaccine expressing HCMV gB and a fusion protein of pp65-IE1 (Reap et al., 2007). The vaccine was well tolerated, with only mild local reactogenicity, Mild-to-moderate systemic reactogenicity was reported in some subjects (Sung and Schleiss, 2010). Bivalent HCMV DNA vaccine: The use of a HCMV DNA vaccine in immunocompromised subjects, such as transplant recipients, would eliminate the safety concerns of live-attenuated HCMV or live recombinant viral-vectored vaccines (Selinsky et al., 2006). DNA vaccines elicit robust CD4+ and CD8+ T-cell and antibody responses (Sung and Schleiss, 2010). VCL-CB01, a bivalent HCMV DNA vaccine that contains two plasmids encoding HCMV pp65 and gB (LiuÂÂ   and Ulmer, 2005). This vaccine has the ability to prime antigen-specific T cells, with the capacity to proliferate and secrete IFN-ÃŽÂ ³ on restimulation with antigen (Wloch et al., 2008). Further modifications of this vaccine may be required to optimize immunogenicity, particularly to the gB moiety (Sung and Schleiss, 2010). It was generally well tolerated. The most common adverse event was mild site injection pain (Liu and Ulmer, 2005). Live-attenuated HCMV Towne vaccine with or without adjuvant recombinant IL-12 and/or priming by DNA vaccine: Immunization with Towne vaccine prevented HCMV disease in seronegative renal transplant recipients, although it did not prevent infection in these patients or in parents of HCMV-infected children (Sung and Schleiss, 2010). Evidence suggests that the relative defect in Towne vaccine may be related to inadequate antigen-specific IFN-ÃŽÂ ³ responses by CD4+ and CD8+ T cells following vaccination (Jacobson et al., 2006). Approaches to improve the immunogenicity of the Towne vaccine are being explored (Jacobson et al., 2009). One approach was to generate genetic recombinant vaccines containing regions from the genome of the unattenuated Toledo strain of HCMV, substituted for the corresponding regions of the Towne genome (Heineman et al., 2006). In another approach, HCMV DNA vaccine is used to prime for memory immune responses to Towne vaccine (Jacobson et al., 2009). A third approach is to co-administer Towne with recombinant human IL-12 (Jacobson et al., 2006*). 5) Preclinical vaccine development Recombinant vesicular stomatitis virus expressing murine cytomegalovirus gB: As a recombinant vaccine vector, vesicular stomatitis virus (VSV) can induce strong humoral and cellular immunity, particularly at mucosal surfaces. This attribute makes recombinant VSV (rVSV) an attractive candidate for development of a vectored HCMV vaccine (Wilson etal., 2008). Live rVSV vector expressing a murine CMV homolog of the gB protein has been tested in the mouse model (Wilson etal., 2008). This induced neutralizing antibody responses, and resulted in reduced viral titers. Also, splenocytes from immunized mice produced a CD8+ IFN-ÃŽÂ ³ response to gB (Sung and Schleiss, 2010). Recombinant modified vaccinia virus Ankara: The attenuated poxvirus, modified vaccinia virus Ankara (MVA), was established as a safe and potent antigen delivery system. Its genome has undergone six major deletions during serial passage (Sung and Schleiss, 2010), which, in turn, allows the insertion of multiple HCMV genes (Wang et al., 2007). A recombinant MVA vaccine that expresses a soluble, secreted form of HCMV gB, based on the AD169 strain sequence has been constructed (Wang et al., 2004). High levels of gB-specific neutralizing antibodies were elicited in vaccinated mice (Sung and Schleiss, 2010). A trivalent MVA expressing gB, pp65 and IE1 has been developed (Wang et al., 2006) with ability to induce humoral and cellular immunity to gB (Wang et al., 2006). Recombinant MVAs have also been generated expressing both full-length pp65 and exon 4 of IE1 with induction of robust primary cell-mediated immunity and stimulation of vigorous expansion of memory Tcell responses to both antigens (Wang et al., 2007). Another recombinant MVA expressing pp65 and a fusion protein of HCMV IE1 exon 4 and IE2 exon 5 was constructed to maximize the representation of IE-specific immunity (Wang et al., 2008). Replication-deficient adenovirus-vectored polyepitope vaccine: Systemic and mucosal immunity to MCMV could be induced by intranasal immunization using a replication deficient adenoviral vector expressing murine CMV glycoprotein H in a murine model (Shanley and Wu, 2005). Modified adenoviral vector Ad5F35, Ad5F35-AD-1, has been generated, expressing the immunodominant antigenic domain-1 epitope of HCMV gB based on the sequence from the AD169 strain (Zhao et al., 2009). Since the AD-1 epitope is well conserved between different strains of HCMV (Britt et al., 2005), expression of the AD-1 epitope from AD5F35 elicits neutralizing antibody responses to diverse clinical isolates (Zhao et al., 2009). Another replication deficient adenoviral-vectored vaccine, Ad-gBCMVpoly (Zhong et al., 2008) which encodes 46 HCMV T-cell epitopes from multiple antigens covalently linked to the extracellular domain of HCMV gB antigen (Zhong et al., 2008). This chimeric vaccine elicited neutralizing antibody responses and virus-specific CD4+ and CD8+ T-cell responses (Zhong and Khanna, 2009). Recombinant live CMV vaccine by bacterial artificial chromosome mutagenesis: An ideal live-attenuated HCMV vaccine should grow to high titers in cell culture for easy production, should be severely attenuated in vivo, even in immunocompromised hosts, and should elicit a strong immune response sufficient to protect against HCMV-associated disease (Mohr et al., 2008). An approach to the generation of such a vaccine is the targeted deletion of CMV genes modulating the host immune response (Cicin-Sain et al., 2007). This approach has been facilitated by the advances in mutagenesis of cloned CMV genomes maintained as bacterial artificial chromosomes in Escherichia coli as well as the rapidly expanding knowledge about the role of viral genes in immunopathogenesis and immune evasion (Dunn et al., 2003).

Hando :: Interview Dialogue Essays

Hando "Is it on?" "Yes, Mr....ah..." "Hando, you can just call me that." "Of course, Hando. Well, just start whenever you’re ready." "I hate being recorded, but we might as well get it over with. I am getting a check for this, right?" "Yes sir. Your story will be a great contribution to the civilization of Zyemlya and a wonderful edition to our magazine. It really is quite remarkable after all." "Yeah, well, whatever. As long as I get my check. Social Security just doesn’t cut it these days. Seems if my story was so remarkable, this ungrateful generation wouldn’t have stuck me in this home, after all I’ve done." "Most have forgotten. Maybe you’ll get the respect you deserve after your story is published." "Maybe. Just maybe." "What exactly is it you did?" "Well, I’ll get to it. You want something to eat? Nothing but hospital food, but what can you do?" "No thank you." "Suit yourself. Let’s see, where to begin. We obviously won the Conflict, since we’re here talking to each other right now. After that victory, there were lots of questions about what to do now. There were only about 4 or 5 hundred of us left. Thousands had died off, most of the population of Zyemlya. They resisted the change. Most of them still couldn’t believe what was going on, even after all that happened. They didn’t actually die; it was more that they faded out with the Being. We all lost loved ones; I lost a sister and a groundhog, but we knew it was necessary to destroy the Being. "We had never had our own world before, our own will, our own lives. The Being had made sure of that. We never really knew exactly what it was, or where it came from, or if it even was an "it." We just knew it was there, and what it was doing. "I’ll take credit for that one though. That was a long time ago, and me with my slipshod memory, I don’t know how well I can recount it all. Now you young whippersnappers come in here and want to scoop out my brains to put in your magazine. The way things work around here, this will probably turn into a half page section in some fifth grader’s textbook. "I guess I’ll start with the dreams. I hadn’t always had them; they started when I was about 16. Hando :: Interview Dialogue Essays Hando "Is it on?" "Yes, Mr....ah..." "Hando, you can just call me that." "Of course, Hando. Well, just start whenever you’re ready." "I hate being recorded, but we might as well get it over with. I am getting a check for this, right?" "Yes sir. Your story will be a great contribution to the civilization of Zyemlya and a wonderful edition to our magazine. It really is quite remarkable after all." "Yeah, well, whatever. As long as I get my check. Social Security just doesn’t cut it these days. Seems if my story was so remarkable, this ungrateful generation wouldn’t have stuck me in this home, after all I’ve done." "Most have forgotten. Maybe you’ll get the respect you deserve after your story is published." "Maybe. Just maybe." "What exactly is it you did?" "Well, I’ll get to it. You want something to eat? Nothing but hospital food, but what can you do?" "No thank you." "Suit yourself. Let’s see, where to begin. We obviously won the Conflict, since we’re here talking to each other right now. After that victory, there were lots of questions about what to do now. There were only about 4 or 5 hundred of us left. Thousands had died off, most of the population of Zyemlya. They resisted the change. Most of them still couldn’t believe what was going on, even after all that happened. They didn’t actually die; it was more that they faded out with the Being. We all lost loved ones; I lost a sister and a groundhog, but we knew it was necessary to destroy the Being. "We had never had our own world before, our own will, our own lives. The Being had made sure of that. We never really knew exactly what it was, or where it came from, or if it even was an "it." We just knew it was there, and what it was doing. "I’ll take credit for that one though. That was a long time ago, and me with my slipshod memory, I don’t know how well I can recount it all. Now you young whippersnappers come in here and want to scoop out my brains to put in your magazine. The way things work around here, this will probably turn into a half page section in some fifth grader’s textbook. "I guess I’ll start with the dreams. I hadn’t always had them; they started when I was about 16.

Global Warming (Cause and Effects)

GLOBAL WARMING Since the late 19th century Earth’s atmosphere and oceans have been getting warmer. According to a research by America’s Climate Choices the average temperature of Earth’s surface increased by about 0. 8 Â °C over the past 100 years. There are a lot of causes of global warming. The causes can be split up into two groups’ natural causes and man-made causes. Natural causes occur without the effect of humans. There are two natural causes one of them is the earth goes through a cycle of climate change that lasts about 40. 00 years. The other cause is release of methane gas from some part of the earth. Man-made causes are the biggest affection of global warming. According to National Geographic, there are several greenhouse gases responsible for warming and humans emit them in a variety of ways. Pollution is the one of the biggest man-made problems. Pollution occurs in many ways. For example, burning fossil fuels, when fossil fuels are burned th ey give off a kind of greenhouse gas. Another major man-made cause is population. More people mean more food.And to provide more food, fossil fuels are used more often. And more people mean more transportation. This is one of the biggest problem increasing use of fossil fuel. Global warming has observable effects on environment. There are a lot of effects for example: -Ice is melting worldwide. -Sea level rise became faster over the last century. According to the NASA effects that scientists had predicted in the past would result from global climate change are now occurring for example: loss of sea ice, accelerated sea level rise and longer, more intense heat waves.And if warming continuous, other effects could happen, for instance: -Hurricanes and other storms are likely to become stronger. -Ecosystems will change, some species will become extinct. -Less fresh water will be available. -Floods and droughts will become more common. So, we can contribute to this global cause with pers onal actions. Our individual efforts are especially significant. We can help immediately by becoming more energy efficient. Reducing our use of oil, gasoline and coal also sets an example for others to follow. Global Warming (Cause and Effects) GLOBAL WARMING Since the late 19th century Earth’s atmosphere and oceans have been getting warmer. According to a research by America’s Climate Choices the average temperature of Earth’s surface increased by about 0. 8 Â °C over the past 100 years. There are a lot of causes of global warming. The causes can be split up into two groups’ natural causes and man-made causes. Natural causes occur without the effect of humans. There are two natural causes one of them is the earth goes through a cycle of climate change that lasts about 40. 00 years. The other cause is release of methane gas from some part of the earth. Man-made causes are the biggest affection of global warming. According to National Geographic, there are several greenhouse gases responsible for warming and humans emit them in a variety of ways. Pollution is the one of the biggest man-made problems. Pollution occurs in many ways. For example, burning fossil fuels, when fossil fuels are burned th ey give off a kind of greenhouse gas. Another major man-made cause is population. More people mean more food.And to provide more food, fossil fuels are used more often. And more people mean more transportation. This is one of the biggest problem increasing use of fossil fuel. Global warming has observable effects on environment. There are a lot of effects for example: -Ice is melting worldwide. -Sea level rise became faster over the last century. According to the NASA effects that scientists had predicted in the past would result from global climate change are now occurring for example: loss of sea ice, accelerated sea level rise and longer, more intense heat waves.And if warming continuous, other effects could happen, for instance: -Hurricanes and other storms are likely to become stronger. -Ecosystems will change, some species will become extinct. -Less fresh water will be available. -Floods and droughts will become more common. So, we can contribute to this global cause with pers onal actions. Our individual efforts are especially significant. We can help immediately by becoming more energy efficient. Reducing our use of oil, gasoline and coal also sets an example for others to follow.

The Life of a College Athletes - Free Essay Example

Sample details Pages: 2 Words: 734 Downloads: 8 Date added: 2019/05/28 Category Career Essay Level High school Tags: Should College Athletes Be Paid Essay Did you like this example? The life of a college athlete is not easy. Managing both academics and sports life is challenging. These hard workers sacrifice many things to compete well in their sport, but none of these athletes get paid. Don’t waste time! Our writers will create an original "The Life of a College Athletes" essay for you Create order Scholarships are given out to talented individuals, but not many of those are full ride scholarships, and that does not really help when many students are troubled with student loans that they are not able to pay off (Orshaughnessy). I have concluded after reading many articles that I agree with, that college athletes should be paid for their performance in athletic events because they sacrifice much educational time for their sports, subject their bodies to intense training, and bring entertainment to many fans.In order to perform well at events, college athletes must sacrifice much educational time for their sports. This includes waking up extremely early in the morning for practice sessions, and after classes in the afternoon. Morning sessions can leave students exhausted, which may also make paying attention in class difficult. Collegiate student-athletes may spend more than 40 hours a week practicing, leaving little time to keep up with academic commitments (Jacobs). Practice, however, is not the only thing that takes up valuable school hours. Big competitions are also in a college athleters schedule. Travelling out of town, for sure, is time consuming, taking into consideration the travel time, day of competition, and travelling back. The main struggle for athletes is finding the time to make up that class period and what they missed, especially when they are consistently missing class (Cornick). Missing all of these class periods, college athletes must work harder academically to keep up with those who do not participate in sports.To compete at a high level, college athletes also subject their bodies to intense training.Many, if not all, college athletes wake up earlier than normal students in the morning for a grueling practice session. Tired, groggy, and worn out from either studying or a training session from the day before, these hard workers continue to put themselves in what seems like an agonizing torture. There is a rule and limit set by the NCAA for how many hours a team/athlete can train, but some coaches dont always follow this rule(Unfortunately, coaches may). Training, however, is not limited to just working out. Eating healthy is also important for hard working athletes. Having a proper diet is crucial to recovering faster for another practice, and being able to compete well. Unlike normal people, these athletes may not be able to eat that much junk food like fast food, candy, or anything related to those because it could slow down their performance. As an athlete at the Division I level, your dietary routines must be aligned with your training and practice regimens to maximize your potential (Below is a ). These athletes obviously have to make many sacrifices, whether itrs dieting or waking up for prac tice, the life of a college athlete is not easy. Because of the competitive spirit of the future pros, many college athletic events are broadcasted on television and these athletes bring entertainment to many fans. Channels like ESPN produce a lot of money while they give a spotlight to the athletes. Many have also said that college level sports are more thrilling to watch than the actual professional level of the sport. For example a variety of football fans agree that college football brings more entertainment to them than the actual NFL. College football this year has been a better, more exciting version of the sport than the NFL, and viewers have made their relative preference clear (Kilgore). The same can be said also be said for other sports. There is no comparison between college basketball and the pros. Itd be like pitting ice cream against kelp, Seinfeld against The Single Guy or everything to soccer (Chase). These college athletes work for every moment in-game and display their passion for their sport. These collegiate athletes work and sacrifice as much as professional athletes do. After college, some of the athletes may even start playing against professional players. Beforehand, the athletes must go through the college level where they first experience the hardships of being a high level athlete. The harsh conditions of being a college-athlete may lead to some of the athletes giving up on the sport, but with pay, chances of talented athletes dropping out could decrease.