Kofi
2011-10-18 04:45:57 UTC
A few years back, I heard tale of an "alternative" practitioner who
injected allergens with small doses of jet fuel to induce
desensitization. I didn't have any data on it so I ran in the opposite
direction. Turns out fiddling with arylhydrocarbons might not have been
such a looney practice after all.
Antiallergy medicine Tranilast acts as an arylhydrocarbon receptor
agonist (AhR) and interferes in the kynurenine pathway [PMID 21072210].
Kynurenines bind to the arylhydrocarbon receptor and induce Tregs [PMID
20720200, 21068375].
The PGE2 (COX-2) pathway also induces Tregs via EP2/EP4 [PMID 15958566]
and this pathway is heavily involved in suppressing mast cell
degranulation.
Observe that our old friend IgG4 makes an appearance in these networks.
Allergy. 2006 Feb;61(2):151-65
Immune mechanisms of allergen-specific sublingual immunotherapy.
Moingeon P, Batard T, Fadel R, Frati F, Sieber J, Van Overtvelt L.
Research and Development, Stallergenes, 6 rue Alexis de Tocqueville,
92610 Antony, France.
Sublingual immunotherapy has been shown in some clinical studies to
modulate allergen-specific antibody responses [with a decrease in the
immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the
recruitment and activation of proinflammatory cells in target mucosa.
Whereas a central paradigm for successful immunotherapy has been to
reorient the pattern of allergen-specific T-cell responses in atopic
patients from a T helper (Th)2 to Th1 profile, there is currently a
growing interest in eliciting regulatory T cells, capable of
downregulating both Th1 and Th2 responses through the production of
interleukin (IL)-10 and/or transforming growth factor (TGF)-beta. We
discuss herein immune mechanisms involved during allergen-specific
sublingual immunotherapy (SLIT), in comparison with subcutaneous
immunotherapy. During SLIT, the allergen is captured within the oral
mucosa by Langerhans-like dendritic cells expressing high-affinity IgE
receptors, producing IL-10 and TGF-beta, and upregulating indoleamine
dioxygenase (IDO), suggesting that such cells are prone to induce
tolerance. The oral mucosa contains limited number of proinflammatory
cells, such as mast cells, thereby explaining the well-established
safety profile of SLIT. In this context, second-generation vaccines
based on recombinant allergens in a native conformation formulated with
adjuvants are designed to target Langerhans-like cells in the sublingual
mucosa, with the aim to induce allergen-specific regulatory T cells.
Importantly, such recombinant vaccines should facilitate the
identification of biological markers of SLIT efficacy in humans.
Publication Types:
* Review
PMID: 16409190
Mast cells (MCs) have a central role in the induction of allergic
inflammation, such as seen in asthma, and contribute to the severity of
certain autoimmune diseases, such as rheumatoid arthritis. The MC thus
represents an important inflammatory cell, and one which has resisted
therapeutic attempts to alter its role in disease. OBJECTIVE: Because
bone marrow-derived stromal cells (BMSC, also known as mesenchymal stem
cells or MSCs) have been reported to alter allergic inflammation in
vivo, we chose to study the interaction between mouse BMSC and mouse
bone marrow-derived MCs. METHODS: MC degranulation, cytokine production
and chemotaxis were evaluated in vitro following co-culture with BMSCs
either in cell contact or a transwell. In addition, MC degranulation was
assessed in vivo following administration of BMSCs in a model of passive
cutaneous anaphylaxis and a peritoneal degranulation assay. Mechanisms
of MC suppression by BMSCs were determined through use of inhibitors or
antibodies to COX1, COX2, nitric oxide, indoleamine 2, 3-dioxygenase,
EP1-4 receptors, TGF-beta and IL-10. Lastly, we utilized either BMSCs or
MCs deficient in COX1, COX2 or EP1-4 receptors to confirm the mechanisms
of inhibition of MC function by BMSCs. RESULTS: We discovered that BMSCs
will effectively suppress specific MC functions in vitro as well as in
vivo. When MCs are cocultured with BMSCs to allow cell-to-cell contact,
BMSCs suppressed MC degranulation, pro-inflammatory cytokine production,
chemokinesis and chemotaxis. Similarly, MC degranulation within mouse
skin or the peritoneal cavity was suppressed following in vivo
administration of BMSCs. Further, we found that these inhibitory effects
were dependent on up-regulation of COX2 in BMSCs; and were facilitated
through the activation of EP4 receptors on MCs. CONCLUSION AND CLINICAL
RELEVANCE: These observations support the concept that BMSCs have the
ability to suppress MC activation and therefore could be the basis for a
novel cell based therapeutic approach in the treatment of MC driven
inflammatory diseases [PMID 21255158]
immune cells called myeloid-derived suppressor cells (MDSCs) keep other
immune cells in check; they accumulate in cancer, where they probably
contribute to tumor development; tiny vesicles known as exosomes are
released by human and mouse tumor cells; the exosomes express Hsp72 on
their surface and this binds TLR2 on human and mouse MDSCs, triggering a
signaling pathway that resulted in enhanced MDSC suppressive function;
decreasing tumor exosome release pharmacologically in vivo enhanced the
antitumor effects of the chemotherapeutic drug cyclophosphamide in three
different mouse models of cancer; Chalmin et al. Membrane-associated
Hsp72 from tumor-derived exosomes mediates STAT3-dependent
immunosuppressive function of mouse and human myeloid-derived suppressor
cells. Journal of Clinical Investigation, 2010; DOI: 10.1172/JCI40483,
<http://www.sciencedaily.com/releases/2010/01/100119224803.htm>
regulatory T cells work by modulating both T and B cell responses;
IL-10-producing Tregs (Tr1) can induce B cells to secrete IgG4 in a
cell-contact-dependent manner, which is why patients with helminth
infections are hyporesponsive (i.e., helminth infections induce IgG4,
IgG4 blocks mast cell degranulation and this is a chief reason why
patients with helminth infections have no allergies); within B:Tr-cell
co-cultures, using IL-10-producing tetanus-toxoid-specific regulatory T
cell lines and clones (Tr-TCC) from human PBMC, it was found that
increasing Foxp3 levels in regulatory T cell lines correlated with their
ability to induce IgG4 in B cells; Tr-TCC showed that blocking
glucocorticoid-induced tumor necrosis factor receptor-related protein
(GITR) molecules selectively prevented IgG4 production as did
neutralizing Ab to glucocorticoid-induced tumor necrosis factor
receptor-related protein ligand (GITR-L), IL-10 and TGF-beta; the
prevention of IgG4 induction by anti-GITR Ab was reversed by excess
rIL-10 but not rTGF-beta; in contrast, anti-ICOS and anti-CTLA-4 Abs had
no effect; compared to Tr-TCC, freshly isolated CD4(+)CD25(+) T cells,
but not effector T cell populations, induced low levels of IgG4, which
were also blocked by anti-GITR and anti-GITR-L Ab; the IgG4 induction by
regulatory cells involves GITR-GITR-L interactions, IL-10 and TGF-beta
[PMID 18924213]
there is an inverse relationship between parasitic infection (especially
worms/helminths) and allergy; as parasitic infections dropped on the
Pacific island of Mauke, allergies increased proportionately; one theory
is that when freed of parasitic targets, the immune system has time on
its hands and turns on innocuous allergens; the body¹s Y-shaped IgG
antibodies usually target bacteria and viruses by latching directly on
to target proteins and recruiting immune cells; parasites activate a
different mechanism - Y-shaped IgE antibodies - which attach their tails
to the surface of mast cells; mast cells are found wherever the body
comes into contact with the outside world and thus multicellular
parasites - mucous membranes of the eyes, nose, and throat, and in the
lining of the lungs and gut; once the initial IgE response is complete,
each mast cell has 100,000 to 500,000 Y-shaped antibodies protruding
from its surface with outstretched arms; usually within two weeks of
worm infestation, the immune system is primed and each mast cell
contains a thousand or more large, globular granules; a worm protein
sticks to the arms of two adjacent IgE antibodies and sets off a
reaction causing the mast cell to burst and spew its granules (mast cell
degranulation) of histamines and other inflammatory chemicals that
infiltrate local tissues; this causes itching; blood vessels dilate and
leak; tissues swell and mucus production increases; this response may
prevent worms from infiltrating further through the skin; other cells
are attracted to dump toxins on the parasites; intestinal worms, on the
other hand, come in through the mouth and attack the GI tract; in this
case, an inflamed gut producing fluid and mucus causes in diarrhea maybe
to flush out worms before they can attach; some worms can also spend
part of their life cycle in the human lung (like schistosomiasis); this
may trigger coughing and sneezing; this responses are all more acute to
newcomers in the tropics when first exposed to parasites; some worms do
get through though mostly the system works to protect people; in the
absence of helminths, IgE antibodies can zero in on airborne allergens
(causing asthma or hayfever) or ingested foods instead; worm infested
rats have weak allergy responses; their IgE antibodies are tied up
fighting worms; however, in rural New Guinea, worm infestation doesn¹t
lessen the asthma rate; there¹s an IgG antibody that competes with IgE;
this G antibody (IgG4) grabs the worm protein before it bumps into the E
antibody attached to a mast cell and this prevents the mast cell
degranulation; IgG4 (1-2%) is the rarest of the IgG¹s; IgG1 targets
viruses and bacteria and is the most common; in people with parasites,
IgG4 jumps to 18%
<http://www.discover.com/issues/sep-93/features/ofparasitesandpo264/>
injected allergens with small doses of jet fuel to induce
desensitization. I didn't have any data on it so I ran in the opposite
direction. Turns out fiddling with arylhydrocarbons might not have been
such a looney practice after all.
Antiallergy medicine Tranilast acts as an arylhydrocarbon receptor
agonist (AhR) and interferes in the kynurenine pathway [PMID 21072210].
Kynurenines bind to the arylhydrocarbon receptor and induce Tregs [PMID
20720200, 21068375].
The PGE2 (COX-2) pathway also induces Tregs via EP2/EP4 [PMID 15958566]
and this pathway is heavily involved in suppressing mast cell
degranulation.
Observe that our old friend IgG4 makes an appearance in these networks.
Allergy. 2006 Feb;61(2):151-65
Immune mechanisms of allergen-specific sublingual immunotherapy.
Moingeon P, Batard T, Fadel R, Frati F, Sieber J, Van Overtvelt L.
Research and Development, Stallergenes, 6 rue Alexis de Tocqueville,
92610 Antony, France.
Sublingual immunotherapy has been shown in some clinical studies to
modulate allergen-specific antibody responses [with a decrease in the
immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the
recruitment and activation of proinflammatory cells in target mucosa.
Whereas a central paradigm for successful immunotherapy has been to
reorient the pattern of allergen-specific T-cell responses in atopic
patients from a T helper (Th)2 to Th1 profile, there is currently a
growing interest in eliciting regulatory T cells, capable of
downregulating both Th1 and Th2 responses through the production of
interleukin (IL)-10 and/or transforming growth factor (TGF)-beta. We
discuss herein immune mechanisms involved during allergen-specific
sublingual immunotherapy (SLIT), in comparison with subcutaneous
immunotherapy. During SLIT, the allergen is captured within the oral
mucosa by Langerhans-like dendritic cells expressing high-affinity IgE
receptors, producing IL-10 and TGF-beta, and upregulating indoleamine
dioxygenase (IDO), suggesting that such cells are prone to induce
tolerance. The oral mucosa contains limited number of proinflammatory
cells, such as mast cells, thereby explaining the well-established
safety profile of SLIT. In this context, second-generation vaccines
based on recombinant allergens in a native conformation formulated with
adjuvants are designed to target Langerhans-like cells in the sublingual
mucosa, with the aim to induce allergen-specific regulatory T cells.
Importantly, such recombinant vaccines should facilitate the
identification of biological markers of SLIT efficacy in humans.
Publication Types:
* Review
PMID: 16409190
Mast cells (MCs) have a central role in the induction of allergic
inflammation, such as seen in asthma, and contribute to the severity of
certain autoimmune diseases, such as rheumatoid arthritis. The MC thus
represents an important inflammatory cell, and one which has resisted
therapeutic attempts to alter its role in disease. OBJECTIVE: Because
bone marrow-derived stromal cells (BMSC, also known as mesenchymal stem
cells or MSCs) have been reported to alter allergic inflammation in
vivo, we chose to study the interaction between mouse BMSC and mouse
bone marrow-derived MCs. METHODS: MC degranulation, cytokine production
and chemotaxis were evaluated in vitro following co-culture with BMSCs
either in cell contact or a transwell. In addition, MC degranulation was
assessed in vivo following administration of BMSCs in a model of passive
cutaneous anaphylaxis and a peritoneal degranulation assay. Mechanisms
of MC suppression by BMSCs were determined through use of inhibitors or
antibodies to COX1, COX2, nitric oxide, indoleamine 2, 3-dioxygenase,
EP1-4 receptors, TGF-beta and IL-10. Lastly, we utilized either BMSCs or
MCs deficient in COX1, COX2 or EP1-4 receptors to confirm the mechanisms
of inhibition of MC function by BMSCs. RESULTS: We discovered that BMSCs
will effectively suppress specific MC functions in vitro as well as in
vivo. When MCs are cocultured with BMSCs to allow cell-to-cell contact,
BMSCs suppressed MC degranulation, pro-inflammatory cytokine production,
chemokinesis and chemotaxis. Similarly, MC degranulation within mouse
skin or the peritoneal cavity was suppressed following in vivo
administration of BMSCs. Further, we found that these inhibitory effects
were dependent on up-regulation of COX2 in BMSCs; and were facilitated
through the activation of EP4 receptors on MCs. CONCLUSION AND CLINICAL
RELEVANCE: These observations support the concept that BMSCs have the
ability to suppress MC activation and therefore could be the basis for a
novel cell based therapeutic approach in the treatment of MC driven
inflammatory diseases [PMID 21255158]
immune cells called myeloid-derived suppressor cells (MDSCs) keep other
immune cells in check; they accumulate in cancer, where they probably
contribute to tumor development; tiny vesicles known as exosomes are
released by human and mouse tumor cells; the exosomes express Hsp72 on
their surface and this binds TLR2 on human and mouse MDSCs, triggering a
signaling pathway that resulted in enhanced MDSC suppressive function;
decreasing tumor exosome release pharmacologically in vivo enhanced the
antitumor effects of the chemotherapeutic drug cyclophosphamide in three
different mouse models of cancer; Chalmin et al. Membrane-associated
Hsp72 from tumor-derived exosomes mediates STAT3-dependent
immunosuppressive function of mouse and human myeloid-derived suppressor
cells. Journal of Clinical Investigation, 2010; DOI: 10.1172/JCI40483,
<http://www.sciencedaily.com/releases/2010/01/100119224803.htm>
regulatory T cells work by modulating both T and B cell responses;
IL-10-producing Tregs (Tr1) can induce B cells to secrete IgG4 in a
cell-contact-dependent manner, which is why patients with helminth
infections are hyporesponsive (i.e., helminth infections induce IgG4,
IgG4 blocks mast cell degranulation and this is a chief reason why
patients with helminth infections have no allergies); within B:Tr-cell
co-cultures, using IL-10-producing tetanus-toxoid-specific regulatory T
cell lines and clones (Tr-TCC) from human PBMC, it was found that
increasing Foxp3 levels in regulatory T cell lines correlated with their
ability to induce IgG4 in B cells; Tr-TCC showed that blocking
glucocorticoid-induced tumor necrosis factor receptor-related protein
(GITR) molecules selectively prevented IgG4 production as did
neutralizing Ab to glucocorticoid-induced tumor necrosis factor
receptor-related protein ligand (GITR-L), IL-10 and TGF-beta; the
prevention of IgG4 induction by anti-GITR Ab was reversed by excess
rIL-10 but not rTGF-beta; in contrast, anti-ICOS and anti-CTLA-4 Abs had
no effect; compared to Tr-TCC, freshly isolated CD4(+)CD25(+) T cells,
but not effector T cell populations, induced low levels of IgG4, which
were also blocked by anti-GITR and anti-GITR-L Ab; the IgG4 induction by
regulatory cells involves GITR-GITR-L interactions, IL-10 and TGF-beta
[PMID 18924213]
there is an inverse relationship between parasitic infection (especially
worms/helminths) and allergy; as parasitic infections dropped on the
Pacific island of Mauke, allergies increased proportionately; one theory
is that when freed of parasitic targets, the immune system has time on
its hands and turns on innocuous allergens; the body¹s Y-shaped IgG
antibodies usually target bacteria and viruses by latching directly on
to target proteins and recruiting immune cells; parasites activate a
different mechanism - Y-shaped IgE antibodies - which attach their tails
to the surface of mast cells; mast cells are found wherever the body
comes into contact with the outside world and thus multicellular
parasites - mucous membranes of the eyes, nose, and throat, and in the
lining of the lungs and gut; once the initial IgE response is complete,
each mast cell has 100,000 to 500,000 Y-shaped antibodies protruding
from its surface with outstretched arms; usually within two weeks of
worm infestation, the immune system is primed and each mast cell
contains a thousand or more large, globular granules; a worm protein
sticks to the arms of two adjacent IgE antibodies and sets off a
reaction causing the mast cell to burst and spew its granules (mast cell
degranulation) of histamines and other inflammatory chemicals that
infiltrate local tissues; this causes itching; blood vessels dilate and
leak; tissues swell and mucus production increases; this response may
prevent worms from infiltrating further through the skin; other cells
are attracted to dump toxins on the parasites; intestinal worms, on the
other hand, come in through the mouth and attack the GI tract; in this
case, an inflamed gut producing fluid and mucus causes in diarrhea maybe
to flush out worms before they can attach; some worms can also spend
part of their life cycle in the human lung (like schistosomiasis); this
may trigger coughing and sneezing; this responses are all more acute to
newcomers in the tropics when first exposed to parasites; some worms do
get through though mostly the system works to protect people; in the
absence of helminths, IgE antibodies can zero in on airborne allergens
(causing asthma or hayfever) or ingested foods instead; worm infested
rats have weak allergy responses; their IgE antibodies are tied up
fighting worms; however, in rural New Guinea, worm infestation doesn¹t
lessen the asthma rate; there¹s an IgG antibody that competes with IgE;
this G antibody (IgG4) grabs the worm protein before it bumps into the E
antibody attached to a mast cell and this prevents the mast cell
degranulation; IgG4 (1-2%) is the rarest of the IgG¹s; IgG1 targets
viruses and bacteria and is the most common; in people with parasites,
IgG4 jumps to 18%
<http://www.discover.com/issues/sep-93/features/ofparasitesandpo264/>