 |
|
Study reveals current multi-component vaccines may need reworking
May 08, 2009Current strategies for designing vaccines against HIV and cancers, for instance, may enable some components in multi-component vaccines to cancel the effect of others on the immune system, eliminating their ability to provide protection, according to an article to be published shortly in the Proceedings of the National Academy of Sciences (PNAS). The authors also suggest, and successfully test, techniques that offer a solution to newly revealed mechanisms that enable some vaccine components to outcompete others.
Recognizing molecules as part one's self versus foreign invaders is the responsibility of the immune system. The adaptive component of that system creates a great variety of immune cells on the hope that one will be the right shape to become activated by any invader encountered. When one of those immune cells recognizes an invader, it expands into an army of clones specifically selected to attack that organism. In a landmark discovery, researchers discovered that part of the immune system selects certain, small pieces of each disease-causing entity (or pathogen) to trigger immune cell expansion, while ignoring the rest. Those triggering protein fragments, or peptides, are termed "immunodominant." For many years, the field has faced three questions. How does this selectivity evolve? Does the process always focus on the peptid fragments that will provide the strongest immune response/protection? If not, can we make changes to useful peptides that make them the center of the immune system's attention?
One workhorse of the adaptive system is the helper T cell, a white blood cell that partners with dendritic cells to make careful decisions about which disease-causing peptides attract attention. Upon encountering an invader, a dendritic cell will "swallow it," cut it up, and carry the pieces to the nearest lymph node. Once there, major histocompatibility complex (MHC} class II proteins inside the dendritic cells present peptides on the cell's surface for consideration by T cells gathered there. Activated T cells begin dividing, which greatly increase their number, until they become capable of the destroying the pathogen in question when exposed to high enough levels of the peptide representing it.
Andrea Sant, Ph.D., professor within the David H. Smith Center for Vaccine Biology and Immunology at the University of Rochester Medical Center, published a July 2005 article in the journal Immunity which revealed the quality that confers immunodominance on a peptide to be the strength and lifespan (kinetic stability) of its bond to the MHC class II protein. Kinetic stability determines whether, in the face of competing reactions, a peptide:MHC class II complex can accumulate at the surface of the dendritic cell, and then remain intact long enough to sustain T cell expansion. Dr. Sant's team found that immunodominant peptides held onto to MHC molecules ten to one hundred times longer than nondominant, or "cryptic," peptides because they fit together better. In the years since, Sant and colleagues have determined how the kinetic stability of the MHC:peptide bond has its effect.
In 2006, she published a study in the Journal of Experimental Medicine that found an enzyme called human leukocyte antigen-DM opens pockets on the MHC class II molecule for a given peptide to fit into it before the complex heads to the cell's surface to recruit T cells. Within dendritic cells (and related cell types that present peptides to immune cells), DM was found to favor peptides with highly stable MHC interactions, a process dubbed "DM editing." Sant's team found kinetically stable peptide-MHC complexes arrived at the cell surface as much as 100 times more often than cryptic peptides, and thought DM editing was solely responsible for determining immunodominance.
The current paper found, however, that the persistence of peptide-MHC Class II bonds also determines which peptides cause a T cell expansion after the complexes have arrived at the cell surface, as well as through DM editing inside the cell. A peptide's persistence at the cell surface also controls the ability of CD4 T cells to continue to expand. Importantly, this additional level of control over immunodominance by stability was only detected when many peptides were present, and were "competing" to see which would trigger a T cell response.
The team also found that low-stability peptide:class II complexes support the initial priming and expansion of CD4 T cells, but the expansion is "strikingly aborted" in the presence of competitive T cell responses to immunodominant peptides. Peptides that fall off of MHC class II molecules too quickly fail to sustain the expansion.
"What we saw is that if a dendritic cell offers weak or unstable peptides alone, T cell responses move forward," said Sant, the study's lead author. "But if we offered weak peptides in the presence of immunodominant ones, the weak peptides trigger an expansion at first, but then the response stalls. This competitive aspect is a new and has profound implications for vaccine design."
While still a theory, Sant speculates that losses in some T cell responses can be explained in part by trogocytosis, a process where T cells "steal" key pieces of the dendritic cell each time they dock onto it as a step in their decision to start expanding. Stolen pieces may include the peptide at hand, the MHC class II protein and so called co-stimulatory molecules. If there are many more of immunodominant peptide-MHC class II complexes initially displayed by the dendritic cell due to DM editing, and if cryptic peptides are falling off the MHC class II complex at a faster rate, and if T cells poach from the peptide-bearing dendritic cell with each pass, dominant peptides would continue activating T cells long after responses to cryptic peptides had petered out.
Without causing an actual infection, many modern vaccines introduce detoxified versions of disease-related molecules to the immune system, which remembers them for next time. Once researchers confirm the kind of immune response needed to achieve protection, they can choose for inclusion in a multi-component vaccine the key peptides that trigger the strongest immune response. The immune system reacts, not to the presence of a whole bacterium or virus, but instead to key fragments of those pathogens.
Peptide-based vaccines are already used clinically in cancer, and researchers have made progress determining the specific peptides on the surface of bacteria, viruses and tumors that trigger T cell responses. Oftentimes, vaccine designers will seek to determine several peptides that elicit T cell responses and mix them together to assure greater immune protection. The assumption was that mixing components, each known to elicit a strong T cell response, together would make for a stronger vaccine.
Working in Sant's Lab, Jason Weaver conducted experiments that revealed that including several pathogenic peptides, each known cause a T cell response in isolation, may not be additive when injected into the same dendritic cell. In fact, some of the peptides may cancel out the ability of others to cause T cell expansion because of immunodominance.
Vaccine designers in the future may have to inject the several peptides in multi-component vaccines into different regions of the body so that the strong peptides do not cancel out the weak, researchers said. A second solution may be to change cryptic or weak peptide vaccine components into immunodominant ones. Sant and members of her laboratory including Francisco Chaves, Christopher Lazarski and Weaver have already shown that by switching out single amino acid building blocks, the team was able to drastically increase the potency of the T cell response to target peptides, including those that would otherwise fail to achieve a T cell response in the presence of other immunodominant peptides. Sant's team increased the ability of a cryptic peptide to hold onto MHC class II proteins by making changes to one or more of their four "anchor residues" responsible for binding into the pocket on the MHC Class II proteins, changes that sustained T cell responses.
In addition, peptide vaccines traditionally address just one half of the adaptive immunity system, the cell mediated/T cell system concerned with attacking pathogens once they have already infected their target cells. One of the principle roles of helper CD4+ T cells is to turn on CD8 "killer" T cells that sense infected cells and destroy them before a virus can use the cell as a virus factory. Peptide vaccines work by targeting only T cells, which explains why they have not been widely used against pathogens like the flu viruses, which spend part of their lifecycle in the space between cells. Those invaders must be addressed by antibodies, which directly glom onto invaders, and tag them for further immune attack.
Sant argues that understanding immunodominance has become even more important in light of recent publications that show strong T cell responses to a peptide have a role in the reactions that causes B cells to start mass producing antibodies as well. Activated T cells move into "the B cell area" of the lymph node and encourage B cells to start making antibodies. Recent studies have also shown that this process may be most efficient for stable peptide:MHC class II complexes. Kinetic stability may influence both the B and T cell aspects of the adaptive immune system.
The studies were performed within the Department of Microbiology and Immunology and the David H. Smith Center for Vaccine Biology and Immunology at the University of Rochester Medical Center, and funded by the National Institutes of Health.
"Evolution may have chosen kinetic stability as the way in which it decides which pieces of disease-causing invaders activate a full T cell response because it may make it more likely that T cells can destroy cells infected with viruses, and because it may help B cells produce antibodies to viruses like influenza," Sant said. "It may also make infected cells more vulnerable to CD8+ T cells that kill an infected cell by releasing toxic chemicals before a virus can use the cell to copy itself. Furthermore, it may help keep alive memory T cells that remember a given pathogen and more quickly attack it upon their next encounter."
University of Rochester Medical Center
Andrea Sant, Ph.D., professor within the David H. Smith Center for Vaccine Biology and Immunology at the University of Rochester Medical Center, published a July 2005 article in the journal Immunity which revealed the quality that confers immunodominance on a peptide to be the strength and lifespan (kinetic stability) of its bond to the MHC class II protein. Kinetic stability determines whether, in the face of competing reactions, a peptide:MHC class II complex can accumulate at the surface of the dendritic cell, and then remain intact long enough to sustain T cell expansion. Dr. Sant's team found that immunodominant peptides held onto to MHC molecules ten to one hundred times longer than nondominant, or "cryptic," peptides because they fit together better. In the years since, Sant and colleagues have determined how the kinetic stability of the MHC:peptide bond has its effect.
In 2006, she published a study in the Journal of Experimental Medicine that found an enzyme called human leukocyte antigen-DM opens pockets on the MHC class II molecule for a given peptide to fit into it before the complex heads to the cell's surface to recruit T cells. Within dendritic cells (and related cell types that present peptides to immune cells), DM was found to favor peptides with highly stable MHC interactions, a process dubbed "DM editing." Sant's team found kinetically stable peptide-MHC complexes arrived at the cell surface as much as 100 times more often than cryptic peptides, and thought DM editing was solely responsible for determining immunodominance.
The current paper found, however, that the persistence of peptide-MHC Class II bonds also determines which peptides cause a T cell expansion after the complexes have arrived at the cell surface, as well as through DM editing inside the cell. A peptide's persistence at the cell surface also controls the ability of CD4 T cells to continue to expand. Importantly, this additional level of control over immunodominance by stability was only detected when many peptides were present, and were "competing" to see which would trigger a T cell response.
The team also found that low-stability peptide:class II complexes support the initial priming and expansion of CD4 T cells, but the expansion is "strikingly aborted" in the presence of competitive T cell responses to immunodominant peptides. Peptides that fall off of MHC class II molecules too quickly fail to sustain the expansion.
"What we saw is that if a dendritic cell offers weak or unstable peptides alone, T cell responses move forward," said Sant, the study's lead author. "But if we offered weak peptides in the presence of immunodominant ones, the weak peptides trigger an expansion at first, but then the response stalls. This competitive aspect is a new and has profound implications for vaccine design."
While still a theory, Sant speculates that losses in some T cell responses can be explained in part by trogocytosis, a process where T cells "steal" key pieces of the dendritic cell each time they dock onto it as a step in their decision to start expanding. Stolen pieces may include the peptide at hand, the MHC class II protein and so called co-stimulatory molecules. If there are many more of immunodominant peptide-MHC class II complexes initially displayed by the dendritic cell due to DM editing, and if cryptic peptides are falling off the MHC class II complex at a faster rate, and if T cells poach from the peptide-bearing dendritic cell with each pass, dominant peptides would continue activating T cells long after responses to cryptic peptides had petered out.
Without causing an actual infection, many modern vaccines introduce detoxified versions of disease-related molecules to the immune system, which remembers them for next time. Once researchers confirm the kind of immune response needed to achieve protection, they can choose for inclusion in a multi-component vaccine the key peptides that trigger the strongest immune response. The immune system reacts, not to the presence of a whole bacterium or virus, but instead to key fragments of those pathogens.
Peptide-based vaccines are already used clinically in cancer, and researchers have made progress determining the specific peptides on the surface of bacteria, viruses and tumors that trigger T cell responses. Oftentimes, vaccine designers will seek to determine several peptides that elicit T cell responses and mix them together to assure greater immune protection. The assumption was that mixing components, each known to elicit a strong T cell response, together would make for a stronger vaccine.
Working in Sant's Lab, Jason Weaver conducted experiments that revealed that including several pathogenic peptides, each known cause a T cell response in isolation, may not be additive when injected into the same dendritic cell. In fact, some of the peptides may cancel out the ability of others to cause T cell expansion because of immunodominance.
Vaccine designers in the future may have to inject the several peptides in multi-component vaccines into different regions of the body so that the strong peptides do not cancel out the weak, researchers said. A second solution may be to change cryptic or weak peptide vaccine components into immunodominant ones. Sant and members of her laboratory including Francisco Chaves, Christopher Lazarski and Weaver have already shown that by switching out single amino acid building blocks, the team was able to drastically increase the potency of the T cell response to target peptides, including those that would otherwise fail to achieve a T cell response in the presence of other immunodominant peptides. Sant's team increased the ability of a cryptic peptide to hold onto MHC class II proteins by making changes to one or more of their four "anchor residues" responsible for binding into the pocket on the MHC Class II proteins, changes that sustained T cell responses.
In addition, peptide vaccines traditionally address just one half of the adaptive immunity system, the cell mediated/T cell system concerned with attacking pathogens once they have already infected their target cells. One of the principle roles of helper CD4+ T cells is to turn on CD8 "killer" T cells that sense infected cells and destroy them before a virus can use the cell as a virus factory. Peptide vaccines work by targeting only T cells, which explains why they have not been widely used against pathogens like the flu viruses, which spend part of their lifecycle in the space between cells. Those invaders must be addressed by antibodies, which directly glom onto invaders, and tag them for further immune attack.
Sant argues that understanding immunodominance has become even more important in light of recent publications that show strong T cell responses to a peptide have a role in the reactions that causes B cells to start mass producing antibodies as well. Activated T cells move into "the B cell area" of the lymph node and encourage B cells to start making antibodies. Recent studies have also shown that this process may be most efficient for stable peptide:MHC class II complexes. Kinetic stability may influence both the B and T cell aspects of the adaptive immune system.
The studies were performed within the Department of Microbiology and Immunology and the David H. Smith Center for Vaccine Biology and Immunology at the University of Rochester Medical Center, and funded by the National Institutes of Health.
"Evolution may have chosen kinetic stability as the way in which it decides which pieces of disease-causing invaders activate a full T cell response because it may make it more likely that T cells can destroy cells infected with viruses, and because it may help B cells produce antibodies to viruses like influenza," Sant said. "It may also make infected cells more vulnerable to CD8+ T cells that kill an infected cell by releasing toxic chemicals before a virus can use the cell to copy itself. Furthermore, it may help keep alive memory T cells that remember a given pathogen and more quickly attack it upon their next encounter."
University of Rochester Medical Center
Peptides Current Events and Peptides News RSSHybrid molecules show promise for exploring, treating Alzheimer's
One of the many mysteries of Alzheimer's disease is how protein-like snippets called amyloid-beta peptides, which clump together to form plaques in the brain, may cause cell death, leading to the disease's devastating symptoms of memory loss and other mental difficulties.
Study reveals a 'missing link' in immune response to disease
The immune system's T cells have the unique responsibilities of being both jury and executioner. They examine other cells for signs of disease, including cancers or infections, and, if such evidence is found, rid them from the body. Precisely how T cells shift so swiftly from one role to another, however, has been a mystery.
UM Scientists Create Fruit Fly Model to Help Unravel Genetics of Human Diabetes
As rates of obesity, diabetes, and related disorders have reached epidemic proportions in the US in recent years, scientists are working from many angles to pinpoint the causes and contributing factors involved in this public health crisis.
Penn team uses self-assembly to make molecule-sized particles with patches of charge
Physicists, chemists and engineers at the University of Pennsylvania have demonstrated a novel method for the controlled formation of patchy particles, using charged, self-assembling molecules that may one day serve as drug-delivery vehicles to combat disease and perhaps be used in small batteries that store and release charge.
Aggressive microdermabrasion induces wound-healing response in aging skin
Microdermabrasion using a coarse diamond-studded instrument appears to induce molecular changes in the skin of older adults that mimic the way skin is remodeled during the wound healing process.
'Spaghetti' scaffolding could help grow skin in labs
Scientists are developing new scaffolding technology which could be used to grow tissues such as skin, nerves and cartilage using 3D spaghetti-like structures.
Infant pain, adult repercussions
Scientists at Georgia State University have uncovered the mechanisms of how pain in infancy alters how the brain processes pain in adulthood.
UCI researchers create new strategy for highly-selective chemotherapy delivery
UC Irvine researchers have created a new approach that vastly improves the targeting of chemotherapeutic drugs to specific cells and organs.
University of Iowa scientists use blood-brain barrier as therapy delivery system
The blood brain barrier is generally considered an obstacle to delivering therapies from the bloodstream to the brain. However, University of Iowa researchers have discovered a way to turn the blood vessels surrounding brain cells into a production and delivery system for getting therapeutic molecules directly into brain cells.
University of Georgia researchers show component of mothballs is present in deep-space clouds
Interstellar clouds, drifting through the unimaginable vastness of space, may be the stuff dreams are made of. But it turns out there's an unexpectedly strange component in those clouds, and it's not dreams but-mothballs?
More Peptides Current Events and Peptides News Articles
 |
Derma e Peptides Plus Double-Action Wrinkle Reverse Creme, 2 oz (56 g) by derma e This revolutionary double-action peptide creme includes two of the most powerful peptides that bio-science has to offer. Formulated with Palmitoyl Pentapeptide to smooth away wrinkles and Acetyl Hexapeptide to relax muscles for healthier, younger-looking skin. Improves skin's resilience, tone and texture and also helps increase collagen and elastin production. A rich and luxurious moisturizing creme that saturates your skin with nutrients and softens even the deepest wrinkles. No animal testing. Made in USA. |
 |
Handbook of Biologically Active Peptides by Abba J. Kastin (Editor) Peptides play a crucial role in many physiological processes including actions as neurotransmitters, hormones, and antibiotics. Research has shown their importance in such fields as neuroscience, immunology, pharmacology, and cell biology. The Handbook of Biologically Active Peptides presents, for the first time, this tremendous body of knowledge in the field of biologically active peptides in one single reference. The section editors and contributors represent some of the most sophisticated and distinguished scientists working in basic sciences and clinical medicine. The Handbook of Biologically Active Peptides is a definitive, all-encompassing reference that will be indispensable for individuals ranging from peptide researchers, to biochemists, cell and molecular biologists,... |
 |
Derma e Peptide Plus Wrinkle Reverse Cream by Derma e Wish you could turn back the clock to re-live your glory days? You can do so for your skin with derma ® Peptide Plus Wrinkle Reverse Cream. Backed by a unique combination of anti-aging ingredients, it transforms wrinkled to wow with each use. |
 |
Gat L-glutamine Peptide Powder, 1000 Grams, 2 Bottle by GAT GAT L-Glutamine Peptide Powder, 1000g |
|
Peptide Science by Protein Research Foundation | |
 |
L-Glutamine Peptide Powder French Vanilla 2.2 lbs by GERMAN AMERICAN TECHNOLOGIES This breakthrough secret delivery formula supplies critical building blocks for lean muscle tissue. Scientific research has shown that Glutamine Peptide enhances BCAA's absorption and increases muscle glycogen for faster recovery, and increases lean muscle mass by 10 to 20% when added to your favorite protein powder. Studies also show that peptide-bound amino acids have superior absorption over free-form amino acids such as L-Glutamine. Glutamine Peptide is one of the best forms of l-glutamine available. Recent clinical research has shown that under stress conditions the human body requires increased amounts of glutamine, because the body's potential to synthesize this amino acid is insufficient to fulfill the needs. Extra intake of l-glutamine results in improved nitrogen... |
 |
Stereo Stereo by Peptides |
 |
Lift-SP Multi Peptide Youth Serum with Acai, .5 fl. oz. LiftSP was created by Dr. Steven Jepson MD, a Skin Care Specialist. Lift SP was designed to make your skin healthier, eliminate wrinkles, make you look years younger and more radiant without the use of imitation products that can cause irreversible damage to your skin. Lift SP benefits include: - No needles or harmful products - An immediate younger appearance - Eliminates Wrinkles - Firmer, Healthier skin - Can lasts for up to 8 hours! - Instant visable results |
 |
Olay Regenerist Daily Regenerating Serum, Concentrated Amino-Peptide Complex, Fragrance Free - 1.7 fl oz by Olay Regenerates Skin's Appearance, One Cell At A Time Concentrated Amino-Peptide Complex Fragrance FreeOlay Regenerist helps regenerate your skin's appearance without such drastic measures as chemical peels, cosmetic surgery or laser. Clinical tests have proven that amino-peptides can help regenerate damaged skin. Now Olay Regenerist uses this technology to beautifully regenerate skin by renewing its outer layer, revealing newer skin. Regenerist Daily Regenerating Serum Fragrance Free uses a concentrated form of an exclusive amino-peptide complex and combines it with Olay moisture to offer the maximum regeneration and hydration within the Regenerist line. This gentle, dermatologist-tested formula is 100% fragrance and color free and has been designed for everyday... |
 |
Far Away From the Maddening Crowd The Peptides (Primary Contributor) |
| © 2009 BrightSurf.com |