TLR's & CD Blockers -- Vitamin D -- Immune Links - Flu Links
randall
Hi,
What's going on today?
I need to buy one of those GPS devices to figure out my spatial co-
ordinates?
http://en.wikipedia.org/wiki/Global_Positioning_System
Then my friends can hit me with a laser guided weaPon. LOL
If they bust up those non-existent plaques. Go for it. ;~/
Who am I aiming at?
How about:
Dynavax Awarded Grant To Support Development Of TLR Inhibitors In Skin
Diseases
http://www.medicalnewstoday.com/articles/150104.php
[...]
Dynavax's first-in-class oligonucleotide-based Toll-like Receptor
(TLR) inhibitors for use in inflammatory skin diseases such as
psoriasis, cutaneous lupus, and dermatomyositis.
[...]
TLR inhibitors, which represent a novel therapeutic approach for the
treatment of inflammatory skin disorders,"
<sniP>
--------------
Their TLR's will clear you with IRS?
OK.. but the irs usually adds to the stress factor. <w>
http://www.dynavax.com/autoimmunity.htm
Autoimmune and Inflammatory Diseases
We have pioneered a new approach to treating autoimmune and
inflammatory diseases with our first-in-class Toll-like Receptor (TLR)
inhibitors called immunoregulatory sequences (IRS). Our lead inhibitor
product candidate is DV1079, a bifunctional inhibitor of TLR7 and
TLR9. We are developing our TLR inhibitor programs under our worldwide
strategic alliance with GlaxoSmithKline established in December 2008.
In animal studies as well as in-vitro, our TLR inhibitors have
demonstrated broad potential in multiple autoimmune disease models,
such as lupus, inflammatory skin disorders, and rheumatoid arthritis.
Our inhibitors have a highly-targeted effect on key immune cells and
pathways that play a role in autoimmune and inflammatory diseases.
Specifically, our TLR inhibitors target two types of immune cells, B
cells and PDC, which selectively express TLR7 and TLR9. These
receptors play a key role in the overproduction of interferon alpha by
PDC and in the presence of anti-nuclear autoantibodies generated by B
cells, which are hallmarks of some autoimmune diseases such as lupus.
Commercial Opportunity
Over 20 million individuals in the United States and Europe have
autoimmune diseases such as lupus, psoriasis, and rheumatoid
arthritis. Analysts estimate that key biologic drugs used to treat
these conditions generate over $20 billion in worldwide sales each
year.
Currently marketed therapies are broadly immunosuppressive with
variable efficacy and substantial toxicity. Our TLR inhibitors have
demonstrated a highly targeted effect on key immune cells and pathways
that play a role in multiple autoimmune and inflammatory diseases.
-----------
TLR
http://en.wikipedia.org/wiki/Toll-like_receptor
================
Here is the dynavax suPPorted abstract by their scientists, Barrat and
Coffman.
http://www.ncbi.nlm.nih.gov/pubmed/18613842
Development of TLR inhibitors for the treatment of autoimmune
diseases.
Barrat FJ, Coffman RL.
Dynavax Technologies Corporation, Berkeley, CA 94710, USA.
fba...@dynavax.com
SUMMARY: The innate immune system is a critical element of protection
from invading pathogens. The specific receptors that recognize various
components of the pathogens trigger signals that result in the
production of proinflammatory cytokines as well as the activation of
antigen-presenting cells, which activate the adaptive immune system.
The discovery of the Toll-like receptors (TLRs) as important
components of pathogen recognition has brought new understanding of
the key signaling molecules involves in innate immune activation.
Interestingly, it appears that most TLRs can recognize self-ligands as
well and that mechanisms are required to discriminate between self and
non-self ligands. One of these mechanisms is the expression of all the
nucleic acid-specific TLR in endosomal compartments and not on the
cell surface. Inappropriate activation of TLRs by self-components can
result in sterile inflammation or autoimmunity. For example, TLR7 and
TLR9 activation by endogenous RNA and DNA, transported to the
endosomes in the form of immune complexes or non-covalently associated
with cationic peptides, could be an important mechanism involved in
promoting diseases such as systemic lupus erythematosus and psoriasis.
In this review, we discuss the rationale for self-recognition by TLR7
and TLR9 as an important part of the development of lupus and other
autoimmune diseases. We describe novel inhibitors of these receptors
and provide evidence to support their use as novel therapeutic agents
for autoimmunity.
PMID: 18613842
-----------
So what?
Well, they want to block: TLR7 and 9
http://en.wikipedia.org/wiki/TLR_7
Toll-like receptor 7, also known as TLR7, is an immune gene possessed
by humans and other mammals and additionally in avian species.
The protein encoded by this gene is a member of the Toll-like receptor
(TLR) family which plays a fundamental role in pathogen recognition
and activation of innate immunity. TLRs are highly conserved from
Drosophila to humans and share structural and functional similarities.
They recognize pathogen-associated molecular patterns (PAMPs) that are
expressed on infectious agents, and mediate the production of
cytokines necessary for the development of effective immunity. The
various TLRs exhibit different patterns of expression. This gene is
predominantly expressed in lung, placenta, and spleen, and lies in
close proximity to another family member, TLR8, on human chromosome X.
[1] Imiquimod acts upon TLR 7.[2]
TLR7 recognises single stranded RNA in endosomes, which is a common
feature of viral genomes which are internalised by macrophages.
<sniP>
And nine does look better for cpg's.
Do a search of this group for unmethylated anything and see for your
self. LOL
http://en.wikipedia.org/wiki/TLR_9
TLR 9 is a toll-like receptor.
It recognizes unmethylated CpG sites on DNA molecules. CpG sites are
relatively rare (~1%) on vertebrate genomes in comparison to bacterial
genomes or viral DNA. TLR9 is expressed by numerous cells of the
immune system such as dendritic cells, B lymphocytes and natural
killer (NK) cells. TLR9 is expressed intracellularly, within the
endosomal compartments and functions to alert the immune system of
viral and bacterial infections by binding to DNA rich in CpG motifs.
TLR9 signals leads to activation of the cells initiating pro-
inflammatory reactions that result in the production of cytokines such
as type-I inteferon and IL-12. There are new immunomodulatory
treatments undergoing testing which involve the administration of
artificial DNA oligonucleotides containing the CpG motif. CpG DNA has
applications in treating allergies such as asthma, immunostimulation
against cancer, immunostimulation against pathogens, and as adjuvants
in vaccines.
<sniP>
But I LIKE TLr4 for LPS blockaids. LOL
http://en.wikipedia.org/wiki/TLR_4
<snip stuff posted a million times already>
45 hits on pubmed for :: psoria* + TLR;s
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=psoria*+AND+toll+like+receptor&log$=activity
-----------------
J&J is bigger then dynavax.
Look at what their doing with cCR2's
http://www.ncbi.nlm.nih.gov/pubmed/19441905
Recent developments in CCR2 antagonists.
Xia M, Sui Z.
Drug Discovery, Johnson & Johnson Pharmaceutical Research and
Development LLC, Cranbury, NJ 08512, USA. mx...@its.jnj.com
Monocyte chemoattractant protein-1 (MCP-1) is a major chemoattractant
for monocytes and memory T cells by means of their binding to its
specific cell-surface receptor, CC-chemokine receptor-2 (CCR2). CCR2
belongs to the G-protein-coupled seven-transmembrane receptor
superfamily. The evidence in favor of CCR2 and MCP-1 having dominant
roles in monocyte chemotaxis and chronic inflammation was provided by
CCR2 and MCP-1 knockout mice. It has been recognized that CCR2
antagonists are potential therapeutic agents in preventing, treating,
or ameliorating a CCR2-mediated inflammatory syndrome or disease such
as psoriasis, uveitis, rheumatoid arthritis, multiple sclerosis,
asthma, obesity, and chronic obstructive pulmonary disease. This
review summarizes recent developments in small-molecule CCR2
antagonists disclosed by patent applications published between 2005
and 2008 and related publications.
PMID: 19441905
----
http://en.wikipedia.org/wiki/CCR2
CCR2, short for chemokine (C-C motif) receptor 2, is a chemokine
receptor.
CCR2 has also recently been designated CD192 (cluster of
differentiation 192).
This gene encodes two isoforms of a receptor for monocyte
chemoattractant protein-1, a chemokine which specifically mediates
monocyte chemotaxis. Monocyte chemoattractant protein-1 is involved in
monocyte infiltration in inflammatory diseases such as rheumatoid
arthritis as well as in the inflammatory response against tumors. The
receptors encoded by this gene mediate agonist-dependent calcium
mobilization and inhibition of adenylyl cyclase. This gene is located
in the chemokine receptor gene cluster region. Two alternatively
spliced transcript variants are expressed by the gene.[1]
<sniP>
I'm working on CD98hc ramifications, as far as CD's go. :)
As it may bring in the culprits and then you don't have to block
ANYTHING.
Stop the work of cd98hc and get clear? I hoPe so.
We must have more research on this CD by Dr. Ginsberg's lab at
UcSD. :)
see:
http://en.wikipedia.org/wiki/CD98
CD98 is a glycoprotein[1][2] that comprises the light subunit of the
Large neutral Amino acid Transporter (LAT1). LAT1 is a heterodimeric
membrane transport protein that preferentially transports neutral
branched (valine, leucine, isoleucine) and aromatic (tryptophan,
tyrosine) amino acids.[3] LAT is highly expressed in brain capillaries
(which form the blood brain barrier) relative to other tissues.[3]
Functional LAT1 transporters are comprised of two proteins encoded by
two distinct genes:
4F2hc heavy subunit protein encoded by the SLC3A2 gene [4]
CD98 light subunit protein encoded by the SLC7A5 gene[5]
<sniP>
-----------
The heavy chain being the target at this point.
See the ginsbergian abstract:
http://www.ncbi.nlm.nih.gov/pubmed/19270713
[...]
CD98hc supports integrin-dependent rapid proliferation of B cells.
<sniP>
Thusly:
http://en.wikipedia.org/wiki/B_cells
http://en.wikipedia.org/wiki/Adaptive_immune_system
http://en.wikipedia.org/wiki/Adaptive_immune_system#Th1_and_Th2:_helper_T_cell_responses
And of course both:
http://en.wikipedia.org/wiki/Regulatory_T_cells
&
gamma delta T cells (havran connection for this group)
http://en.wikipedia.org/wiki/Gamma/delta_T_cells
Gamma delta T cells (γδ T cells) and recognition of lipid antigens
being most likely very imPortant for psoriasis.
------------------------
http://www.sciencedaily.com/releases/2009/05/090520114657.htm
Vitamin D May Halt Lung Function Decline In Asthma And COPD
ScienceDaily (May 20, 2009) — Vitamin D may slow the progressive
decline in the ability to breathe that can occur in people with asthma
as a result of human airway smooth muscle (HASM) proliferation,
according to researchers at the University of Pennsylvania.
The group found that calcitriol, a form of vitamin D synthesized
within the body, reduced growth-factor-induced HASM proliferation in
cells isolated from both persons with asthma and from persons without
the disease. The proliferation is a part of process called airway
remodeling, which occurs in many people with asthma, and leads to
reduced lung function over time.
The researchers believe that by slowing airway remodeling, they can
prevent or forestall the irreversible decline in breathing that leaves
many asthmatics even more vulnerable when they suffer an asthma
attack.
"Calcitriol has recently earned prominence for its anti-inflammatory
effects," said Gautam Damera, Ph.D., who will present the research at
the American Thoracic Society's 105th International Conference in San
Diego on May 20. "But our study is the first to reveal the potent role
of calcitriol in inhibiting ASM proliferation."
The experiments were conducted with cells from 12 subjects, and the
researchers compared calcitriol with dexmethasone, a corticosteroid
prescribed widely for the treatment of asthma. Although, dexmethasone
is also a powerful anti-inflammatory agent, the researchers found that
it had little effect on HASM growth.
Dr. Damera and his colleagues found calcitriol inhibits HASM in a dose-
dependent manner, with a maximum inhibitory effect of 60 percent ± 3
percent at 100nM.
As part of the University of Pennsylvania's Airway Biology Initiative,
the researchers are planning a randomized control trial of calcitriol
in patients with severe asthma and expect to have data from the trial
in about a year's time.
With its anti-inflammatory qualities and its ability to inhibit smooth
muscle proliferation, Dr. Damera said, calcitriol may become an
important new therapy, used alone or in combination with already
prescribed steroids, for treating steroid-resistant asthma.
Dr. Damera and his colleagues have also conducted experiments to
determine the mechanism by which calcitriol retards HASM
proliferation. They believe the vitamin works by inhibiting activation
of distinct set of proteins responsible for cell-cycle progression.
The investigators have also conducted experiments to determine whether
calcitriol, which is currently used to treat psoriasis, could be an
effective therapy for COPD. Although preliminary, their data shows
that calcitriol appears to reduce pro-inflammatory cytokine secretions
in COPD. As with asthma, the researchers believe, calcitriol may also
have the added benefit of slowing, if not stopping, the progression of
airway remodeling. Others in the field believe calcitriol may also
have the potential to inhibit the development and growth of several
types of cancer.
-------------
Immune hits:
Confirmed Link Between Chronic Infection And Immune-System Protein
http://www.medicalnewstoday.com/articles/150203.php
Inflammation-Regulating Protein May Prove Relevant To Controlling
Sepsis
http://www.medicalnewstoday.com/articles/150196.php
Ginseng -- Nature's Anti-Inflammatory?
http://www.medicalnewstoday.com/articles/150036.php
In Chronic Viral Infection Immune Exhaustion Driven By Antigen
http://www.medicalnewstoday.com/articles/150003.php
Vaccination Against Cholera Is Cost Effective In Many Locations
http://www.medicalnewstoday.com/articles/149883.php
New Strategies Help Ensure That Vaccines Remain Effective In
Preventing Disease
http://www.medicalnewstoday.com/articles/149846.php
Infants' Pain Response To Immunization Varies Based On Which Vaccine
Is First
http://www.medicalnewstoday.com/articles/149843.php
When It Comes To Biology Gender Equality Does Not Apply
http://www.medicalnewstoday.com/articles/149765.php
Scientists Discover How Smallpox May Derail Human Immune System
http://www.medicalnewstoday.com/articles/149651.php
=================
Flu links to psoriasis as a Th1 complication. These should go
with the test post, or the one that became it, I suppose.
There have been a handfull of people who have died in the US
of the swine flu. One of them did have psoriasis, though
we don't know the extent of it and her husband saying it
wasn't a factor.
Oh well.
Do like RW Dutton, the author of this one.
(1.8): J Immunol. 2009 Mar 15;182(6):3469-81.
http://www.ncbi.nlm.nih.gov/pubmed/19265125
Tc17, a unique subset of CD8 T cells that can protect against lethal
influenza challenge.
Hamada H, Garcia-Hernandez Mde L, Reome JB, Misra SK, Strutt TM,
McKinstry KK, Cooper AM, Swain SL, Dutton RW. - Trudeau Institute,
Saranac Lake, NY 12983, USA.
We show here that IL-17-secreting CD4 T (Th)17 and CD8 T (Tc)17
effector cells are found in the lung following primary challenge with
influenza A and that blocking Ab to IL-17 increases weight loss and
reduces survival. Tc17 effectors can be generated in vitro using naive
CD8 T cells from OT-I TCR-transgenic mice. T cell numbers expand 20-
fold and a majority secretes IL-17, but little IFN-gamma. Many of the
IL-17-secreting cells also secrete TNF and some secrete IL-2.
Tc17 are negative for granzyme B, perforin message, and cytolytic
activity, in contrast to Tc1 effectors. Tc17 populations express
message for orpha n nuclear receptor gammat and FoxP3, but are
negative for T-bet and GATA-3 transcription factors. The FoxP3-
positive, IL-17-secreting and IFN-gamma-secreting cells represent
three separate populations. The IFN-gamma-, granzyme B-, FoxP3-
positive cells and cells positive for IL-22 come mainly from memory
cells and decrease in number when generated from CD44(low) rather than
unselected CD8 T cells.
Cells of this unique subset of CD8 effector T cells expand greatly
after transfer to naive recipients following challenge and can protect
them against lethal influenza infection.
Tc17 protection is accompanied by greater neutrophil influx into the
lung than in Tc1-injected mice, and the protection afforded by Tc17
effectors is less perforin but more IFN-gamma dependent, implying that
different mechanisms are involved.
PMID: 19265125
http://en.wikipedia.org/wiki/Effector_cell
Effector cells are a type of lymphocyte that are actively engaged in
fighting pathogens, as opposed to memory cells which are dormant.
Effector cells may include effector B cells which secrete antibodies,
T helper cells, or active cytotoxic T cells. The clonal selection
theory stipulates that when naïve cells encounter antigens for the
first time, they are stimulated to proliferate and differentiate into
effector cells and memory cells.
The specific immunity class cells releas e effector cells after being
activated by an antigen. When antigens are presented by the class II
MHC molecules on an infected cell's surface, Helper T-cells will
produce effector cells and memory cells. When presented by class I
MHC, Cytotoxic T-cells along with the activation by cytokines from
helper T-cells will produce effector cells and memory cells as well.
--------------
Do you want to know about p53, psoriasis and the flu?
I do.
(1.3): Biochem Biophys Res Commun. 2009 Mar 7. [Epub ahead of print]
Influenza A virus induces p53 accumulation in a biphasic pattern.
Shen Y, Wang X, Guo L, Qiu Y, Li X, Yu H, Xiang H, Tong G, Ma Z. -
Shanghai Veterinary Research Institute, Chinese Academy of
Agricultural Science, No. 518, Ziyue Road, Shanghai, 200241, PR China.
Tumor suppressor p53, the major cellular defense against tumor
development, has recently been implicated in host antiviral defense.
Previous studies have shown that p53 was induced at the apoptotic
stage of influenza virus-infected cells. However, we found that p53
was induced not only at the apoptotic stage but also at the beginning
phase of infection, showing a biphasic pattern with a first transient
elevation apparent at the beginning phase of infection and a second
elevation observable at the middle-late phase of infection.
This up-regulation of p53 was independent of increased p53
transcription, but dependent on virus adsorption and replication. The
increased p53 was active and able to transactivate its downstream
target genes, such as interferon regulatory factor 9 (IRF9) and Bax.
To our knowledge, this is the first report to describe a biphasic
pattern of p53 accumulation in influenza virus-infected cells.
PMID: 19275889
================
randall... what about farrah today? Search me... still needs a
miracle?