APITOXINA & CANCER
| 1: Cancer Immunol Immunother. 2006 Feb 17; [Epub ahead of print] |
Antitumor
action and immune activation through cooperation of bee venom secretory phospholipase
A2 and phosphatidylinositol-(3,4)-bisphosphate.
Putz
T, Ramoner
R, Gander
H, Rahm
A, Bartsch
G, Thurnher
M.
Department of Urology,
We evaluated tumor cell growth modulation by bee venom secretory phospholipase
A2 (bv-sPLA2) and phosphatidylinositol-(3,4)-bisphosphate as well as potential
cooperative effects. In addition, the immunomodulatory impact of tumor cell
treatment was examined by monitoring changes in phenotype and function of
monocyte-derived dendritic cells (moDCs) cocultured with pretreated tumor
cells. Bv-sPLA2 or phosphatidylinositol-(3,4)-bisphosphate alone displayed
moderate effects on the proliferation of A498 renal cell carcinoma cells,
T-47D breast cancer cells, DU145 prostate cancer cells and BEAS-2B transformed
lung cells. However, when bv-sPLA2 was coadministered with phosphatidylinositol-(3,4)-bisphosphate
a potent inhibition of [(3)H] thymidine incorporation into all tested cell
lines occurred. This inhibition was due to massive cell lysis that reduced
the number of cells with proliferative capacity. Importantly, tumor cell lysates
generated with bv-sPLA2 plus phosphatidylinositol-(3,4)-bisphosphate induced
maturation of human moDCs demonstrated by enhanced expression of CD83 and
improved stimulation in allogeneic mixed leukocyte reactions. Our data demonstrate
that bv-sPLA2 and phosphatidylinositol-(3,4)-bisphosphate synergistically
generate tumor lysates which enhance the maturation of immunostimulatory human
monocyte-derived dendritic cells. Such tumor lysates which represent complex
mixtures of tumor antigens and simultaneously display potent adjuvant properties
meet all requirements of a tumor vaccine.
| 2: Clin Exp Allergy. 2005 Dec;35(12):1591-8. |
Toll-like
receptor ligands as adjuvants in allergen-specific immunotherapy.
Johansen
P, Senti
G, Martinez
Gomez JM, Storni
T, von
Beust BR, Wuthrich
B, Bot
A, Kundig
TM.
Unit for Experimental Immunotherapy, University
BACKGROUND: Allergen-specific immunotherapy (SIT) leads to long-term amelioration
of T-helper type 2 (Th2)-mediated allergic symptoms and is therefore recommended
as a first line therapy for allergies. The major disadvantage of SIT is its
low efficiency, requiring treatment over years. OBJECTIVE: In this study,
we evaluated the potential of Toll-like receptor (TLR) ligands to facilitate
Th1-type immune responses. METHODS: The immunogenicity and therapeutic potential
of the major bee venom allergen phospholipase A2 (PLA2) combined with various
TLR ligands were tested in mice and compared with immune responses induced
by conventional aluminium-based preparations. RESULTS: Regarding total IgG
against PLA2, TLR2/4-binding lipopolysaccharide and TLR3-binding polyriboinosinic
polyribocytidylic (PolyI:C) were the superior adjuvants for prophylactic vaccination.
However, TLR9-binding phosphorothioate-modified cytosine-guanosine-rich oligonucleotide
(CpG), TLR-3-binding PolyI:C, and TLR2/6-binding peptidoglycan skewed the
immune responses more towards IgG2a isotype and Th1 cytokines. Furthermore,
in a therapeutic approach, CpG, PolyI:C and TLR7/8-binding 3M003 had immune
modulating properties as they suppressed established IgE titres. CONCLUSION:
The potential of TLR ligands to adjuvate the immunogenicity of bee venom PLA2
and to skew the Th1-Th2 balance proved very heterogeneous. With respect to
SIT, CpG, PolyI:C, and 3M003 were very promising. Hence, TLR ligands should
be considered as adjuvants or immune modulators in SIT in human as to improve
its efficiency regarding the Th1-Th2 balance of the immune response with a
likely effect on therapy duration.
| 3: Ann N Y Acad Sci. 2005 Nov;1056:279-92. |
Novel Drugs
and Vaccines Based on the Structure and Function of HIV Pathogenic Proteins
Including Nef.
Azad
AA.
Faculty of Health Sciences, Medical School, University of Cape Town, Anzio
Road, Observatory, 7925, Cape Town, South Africa. a_azad05@yahoo.com.au.
Evidence is presented to suggest that HIV-1 accessory protein Nef could be
involved in AIDS pathogenesis. When present in extracellular medium, Nef causes
the death of a wide variety of cells in vitro and may therefore be responsible
for the depletion of bystander cells in lymphoid tissues during HIV infection.
When present inside the cell, Nef could prevent the death of infected cells
and thereby contribute to increased viral load. Intracellular Nef does this
by preventing apoptosis of infected cells by either inhibiting proteins involved
in apoptosis or preventing the infected cells from being recognized by CTLs.
Neutralization of extracellular Nef could prevent the death of uninfected
immune cells and thereby the destruction of the immune system. Neutralization
of intracellular Nef could hasten the death of infected cells and help reduce
the viral load. Nef is therefore a very important molecular target for developing
therapeutics that slow progression to AIDS. The N-terminal region of Nef and
the naturally occurring bee venom mellitin have very similar primary and tertiary
structures, and they both act by destroying membranes. Chemical analogs of
a mellitin inhibitor prevent Nef-mediated cell death and inhibit the interaction
of Nef with cellular proteins involved in apoptosis. Naturally occurring bee
propolis also contains substances that prevent Nef-mediated cell lysis and
increases proliferation of CD4 cells in HIV-infected cultures. These chemical
compounds and natural products are water soluble and nontoxic and are therefore
potentially very useful candidate drugs.
PMID: 16387695 [PubMed - in process]
| 4: Eur J Immunol. 2005 Dec;35(12):3591-8. |
Heat denaturation,
a simple method to improve the immunotherapeutic potential of allergens.
Johansen
P, Senti
G, Martinez
Gomez JM, Wuthrich
B, Bot
A, Kundig
TM.
Unit for Experimental Immunotherapy, University Hospital of Zurich, Zurich,
Switzerland.
Allergen-specific immunotherapy (SIT) leads to a long-term amelioration of
IgE- and Th2-mediated allergic diseases. However, SIT efficiency is low, with
years of treatment along with frequent allergic side effects. The goal of
this study was to reduce the side effects by destroying IgE-binding epitopes,
i.e. by heat-denaturation, while preserving the therapeutic effect. Mice were
immunised with bee venom, birch pollen, grass pollen or cat hair allergens,
or with ovalbumin. Heat-denatured allergens bound less IgE but enhanced Th1-dependent
IgG2a production as measured by ELISA. The strong IgG2a antibody responses
also prevented allergic anaphylaxis in mice, as measured by body temperature
drop after a challenge with a high allergen dose. We found that optimal heat-denaturation
of allergens left a small proportion in the native conformation to sufficiently
stimulate B cells, while non-B cell-mediated effects were probably amplified.
The enhanced immunogenicity of heat-denatured allergens is likely explained
by enhanced antigen presentation to T cells due to the particulate nature
of heat-denatured proteins. This enables Th1 skewing of the immune response
with strong production of IgG2a in mice. Therefore, heat-denaturation represents
probably the simplest way to enhance the efficiency of SIT while reducing
its side effects.
PMID: 16285011 [PubMed - in process]
| 5: J Allergy Clin Immunol. 2004 Oct;114(4):943-50. |
Modulation
of allergic responses in mice by using biodegradable poly(lactide-co-glycolide)
microspheres.
Jilek
S, Walter
E, Merkle
HP, Corthesy
B.
Department of Chemistry and Applied BioSciences, Swiss Federal Institute of
Technology Zurich, Zurich, Switzerland.
BACKGROUND: Biodegradable poly(lactide- co -glycolide) (PLGA) microspheres
are a promising carrier for vaccine delivery capable of maturing antigen-presenting
cells to stimulate T-cell-mediated immune responses. However, the potential
of microspheres to downregulate an allergic response in vivo is unknown. OBJECTIVE:
The aim of this study was to determine whether microspheres could potentiate
DNA vaccination against allergy and to evaluate the immunomodulatory properties
of microspheres alone. METHODS: Mice were treated prophylactically with DNA-loaded
plain PLGA microspheres before sensitization with phospholipase A2 (PLA2),
the major allergen of bee venom. PLA2-specific IgG1, IgG2a, IgE in serum were
measured for 8.5 months, and splenocyte proliferative responses and cytokine
profiles were determined. Protection against anaphylaxis was evaluated after
injection of an otherwise lethal dose of PLA2. RESULTS: Phospholipase A2-specific
IgG1 and IgG2a production turned out to be 2 times higher using cationic microspheres
compared with anionic microspheres, but was not influenced by the presence
of DNA. In contrast, reduction in IgE production and T-cell hyporesponsiveness
were observed with all microsphere formulations. Recall challenge with PLA2
triggered combined expression of both IL-4 and IFN-gamma, together with sustained
expression of IL-10 that can explain the protective effect against anaphylaxis.
CONCLUSION: Our data suggest a dual mechanism that does initially rely on
a TH2 to TH1 immune deviation and then on IL-10-mediated suppression. This
is the first physiological demonstration that plain PLGA microspheres can
induce tolerance in mice for as long as 6 months postsensitization.
PMID: 15480340 [PubMed - indexed for MEDLINE]
| 6: Am J Chin Med. 2004;32(3):361-7. |
Anti-inflammatory
effect of bee venom on type II collagen-induced arthritis.
Lee JD, Kim SY, Kim TW, Lee SH, Yang HI, Lee DI, Lee YH.
Research Group of Pain and Neuroscience
in Vision 2000 Project East-West Medical Research Institute, Kyung Hee University,
Seoul, Korea. ljdacu@khmc.or.kr
Bee venom (BV) has been used to relieve pain and reduce inflammation in traditional
Oriental medicine, especially in chronic inflammatory diseases such as rheumatoid
arthritis (RA). We previously reported that the BV injection into a traditional
acupuncture point (Zusanli) reduced arthritis-associated edema and nociceptive
responses in Freund's adjuvant-induced arthritis in rats (Kwon et al., 2001).
This study was designed to evaluate the anti-inflammatory and anti-cytokine
effect of BV on a murine type-II collagen-induced arthritis (CIA) model. Male
mice were immunized by spontaneous injection of 100 microg of an emulsion
of bovine type-II collagen and complete Freund's adjuvant (CFA), with a booster
injection after 2 weeks. In the experimental group, 0.1 ml BV was injected
at acupuncture point (Zusanli) near both knees twice a week for a total of
5 times. In the control group, normal saline was injected at the same frequencies.
These injections began 5 weeks after the first collagen injection. Starting
the 3rd week after the first collagen injection, we examined limb swelling
and severity of arthritis twice a week. At 8 weeks, mice were sacrificed and
synovial tissue was examined with the light microscope and serum cytokines
(IL-1beta and TNF-alpha) were measured by ELISA. The incidence of arthritis,
the mean arthritis index and the number of arthritic limbs were significantly
lower in the treatment compared to the control group (63% versus 75%, 3.4%
versus 8.5%, 23% versus 75%, respectively). Among the serum proinflammatory
cytokines, the production of TNF-alpha in the BV group was suppressed compared
to the control group (59 +/- 4.5 versus 99.5 +/- 6.5, p < 0.05), but IL-1beta
was not suppressed. The examination of the histopathology of the joints of
murine CIA showed decreased inflammation signs and less lymphocyte infiltration
after BV acupuncture therapy. Acupuncture therapy with BV suppressed the development
of arthritis and caused inhibition of the immune responses in type-II collagen-induced
arthritis.
PMID: 15344419 [PubMed - indexed for MEDLINE]
| 7: J Allergy Clin Immunol. 2003 Jun;111(6):1255-61. |
Induction
of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy.
Francis
JN, Till
SJ, Durham
SR.
Upper Respiratory Medicine, National Heart and Lung Institute, Imperial College,
Dovehouse Street, London SW3 6LY, UK.
BACKGROUND: Immunotherapy involves the modulation of allergen-specific T-cell
responses, either T(H)2-to-T(H)1 immune deviation or, in bee venom-treated
patients, induction of IL-10 production by CD4+CD25+ T cells. IL-10-producing
CD4+CD25+ regulatory T cells have emerged as potential mediators of immune
tolerance in numerous murine models of immunopathology. OBJECTIVE: The aim
of this study was to evaluate the role of IL-10 production and CD4+CD25+ T
cells in the response to grass pollen immunotherapy. METHODS: PBMCs were isolated
from patients after 1 year of grass pollen immunotherapy and from matched
untreated atopic and healthy control subjects. After 6 days of in vitro stimulation
with Phleum pratense, production of IL-10, IL-5, IL-4, and IFN-gamma and proliferation
and numbers of CD4+CD25+ T cells were measured. T cells were then stimulated
for a further 5 hours with phorbol 12-myristate 13-acetate and ionomycin and
assessed for intracellular IL-10 by means of flow cytometry. RESULTS: Patients
undergoing immunotherapy produced significantly more IL-10 than atopic control
subjects (patients undergoing immunotherapy, 116 +/- 21 pg/mL [n = 11]; atopic
patients, 30 +/- 5 pg/mL [n = 11]; P <.001), and the number of CD4+CD25+
cells identified after allergen stimulation was also greater in the immunotherapy
group. The numbers of CD4+CD25+ T cells correlated positively with activation
as measured by proliferation in both of the control groups but not in the
immunotherapy group. Moreover, only T cells from patients undergoing immunotherapy
were positive for intracellular IL-10, and these were almost exclusively CD4+CD25+
cells. CONCLUSION: Grass pollen immunotherapy results in a population of circulating
T cells that express the IL-10(+) CD4+CD25+ phenotype in response to allergen
restimulation.
Publication Types:
PMID: 12789226 [PubMed - indexed for MEDLINE]
| 8: Toxicon. 2003 Jun;41(7):861-70. |
Inhibition
of mammary carcinoma cell proliferation in vitro and tumor growth in vivo
by bee venom.
Orsolic
N, Sver
L, Verstovsek
S, Terzic
S, Basic
I.
Department of Animal Physiology, Faculty of Science, University of Zagreb,
Rooseveltov trg 6, 10 000 Zagreb, Croatia. norsolic@yahoo.com
The possible tumor growth- and metastasis-inhibiting effects of bee venom
in mice and in tumor cell cultures were studied. The tumor was a transplantable
mammary carcinoma (MCa) of CBA mouse. Intravenous administration of bee venom
to mice significantly reduced the number of metastases in the lung. However,
subcutaneous administration of bee venom did not reduce the number of lung
metastases, indicating that the antitumor effect of the venom could be highly
dependent on the route of injection as well as close contact between the components
of the venom and the tumor cells, as was shown by in vitro studies on MCa
cells. We also observed variations in immunological parameter induced by bee
venom. We proposed that bee venom has an indirect mechanism of tumor growth
inhibition and promotion of tumor rejection that is based on stimulation of
the local cellular immune responses in lymph nodes. Apoptosis, necrosis, and
lysis of tumor cells are other possible mechanisms by which bee venom inhibits
tumor growth.
PMID: 12782086 [PubMed - indexed for MEDLINE]
| 9: FASEB J. 2003 Jun;17(9):1026-35. |
T helper
(Th) 2 predominance in atopic diseases is due to preferential apoptosis of
circulating memory/effector Th1 cells.
Akdis
M, Trautmann
A, Klunker
S, Daigle
I, Kucuksezer
UC, Deglmann
W, Disch
R, Blaser
K, Akdis
CA.
Swiss Institute of Allergy and Asthma Research (SIAF), Obere Strasse 22, CH-7270
Davos, Switzerland.
T cells constitute a large population of cellular infiltrate in atopic/allergic
inflammation and a dysregulated, Th2-biased peripheral immune response appears
to be an important pathogenetic factor. In atopic dermatitis, circulating
cutaneous lymphocyte-associated antigen-bearing (CLA+) CD45RO+ T cells with
skin-specific homing property represent an activated memory/effector T cell
subset. They express high levels of Fas and Fas ligand and undergo activation-induced
apoptosis. The freshly purified CLA+ CD45RO+ T cells of atopic individuals
display distinct features of in vivo-triggered apoptosis such as pro-caspase
degradation and active caspase-8 formation. In particular, the Th1 compartment
of activated memory/effector T cells selectively undergoes activation-induced
cell death, skewing the immune response toward surviving Th2 cells in atopic
dermatitis patients. The apoptosis of circulating memory/effector T cells
was confined to atopic individuals whereas non-atopic patients such as psoriasis,
intrinsic-type asthma, contact dermatitis, intrinsic type of atopic dermatitis,
bee venom allergic patients, and healthy controls showed no evidence for enhanced
T cell apoptosis in vivo. These results define a novel mechanism for peripheral
Th2 response in atopic diseases.
PMID: 12773485 [PubMed - indexed for MEDLINE]
| 10: J Allergy Clin Immunol. 2003 Apr;111(4):854-61. |
Allergen-specific
T-cell tolerance induction with allergen-derived long synthetic peptides:
results of a phase I trial.
Fellrath
JM, Kettner
A, Dufour
N, Frigerio
C, Schneeberger
D, Leimgruber
A, Corradin
G, Spertini
F.
Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland.
BACKGROUND: There is a need to improve the safety and efficacy of allergen-specific
immunotherapy. Long synthetic peptide-based immunotherapy was proven safe,
immunogenic, and protective in preclinical trials. OBJECTIVE: To evaluate
the safety and immunogenicity of an allergen-derived long synthetic overlapping
peptide (LSP) immunotherapy, we designed a double-blind, placebo-controlled
phase I clinical trial in patients hypersensitive to bee venom. METHODS: Patients
from the active group were injected at day 0 with a mixture of 3 LSPs mapping
the entire PLA2 molecule, a major bee venom allergen, in a dose-escalating
protocol to a maintenance dose of 100 microg per peptide repeated at days
4, 7, 14, 42, and 70. The control group was injected with human albumin. RESULTS:
Whereas specific T-cell proliferation in the peptide group increased up to
day
PMID: 12704369 [PubMed - indexed for MEDLINE]
| 11: Eur J Immunol. 2002 Nov;32(11):3133-41. |
Reversal
of the adult IgE high responder phenotype in mice by maternally transferred
allergen-specific monoclonal IgG antibodies during a sensitive period in early
ontogeny.
Lange
H, Kiesch
B, Linden
I, Otto
M, Thierse
HJ, Shaw
L, Maehnss
K, Hansen
H, Lemke
H.
Biochemical Institute, Medical Faculty, Christian-Albrechts-Universitat at
Kiel, Germany.
IgE is an important trigger in allergy and asthma, diseases whose development
is suggested to depend on an initial sensitization in early life. While induction
of murine IgE responses requires both a genetically based IgE high responder
phenotype and defined experimental conditions, maternally transferred IgG
can override these prerequisites and suppress IgE formation in an allergen-specific
manner. Here, we show that maternally transferred monoclonal IgG, irrespective
of their subclass and recognized epitopes, induce IgE unresponsiveness, which
is effective for parenteral immunization with bee venom phospholipase A2 as
well as for airway-immunization with nebulized ovomucoid-containing ovalbumin.
This IgE suppression is detectable in the offspring during the first 4 months
of life, but not thereafter and not in the dams. However, when the initial
immunization at an age of 3 or 4 months was followed by further application
of both allergens via their respective routes, IgE suppression persisted up
to an age of more than one year. If applicable to man, these findings may
allow the development of a new strategy for the prevention of allergy and
asthma by maternally transferred or neonatally injected allergen-specific
mAb in combination with natural or prophylactic exposure to the respective
allergens during early childhood.
PMID: 12555658 [PubMed - indexed for MEDLINE]
| 12: Arb Paul Ehrlich Inst Bundesamt Sera Impfstoffe Frankf A M. 1999;(93):243-51; discussion 252. |
Differential regulation
of allergen-specific antibodies in allergy and specific immunotherapy.
Blaser
K, Akdis
CA, Faith
A.
Allergen-specific immunotherapy (SIT) aims to specifically skew an allergic
response into a normal immune reaction against an allergen. The response to
bee venom (BV) provides an especially suited model to study the immunological
mechanisms of SIT in human. The BV-phospholipase A2 (PLA) represents the major
antigen/allergen of BV. In SIT of BV allergy both whole BV and T cell epitope
peptides of PLA were successfully applied. It appeared that the induction
of specific anergy in peripheral T cells and reactivation of the T cells by
microenvironmental cytokines represent the basic key steps in the immunological
mechanism of SIT. The proliferative and cytokine responses by specific T cells
were significantly suppressed simultaneously with an increase in IL-10 after
7 days. The anergic state was fully established after 4 weeks. Neutralization
of IL-
| 13: Ther Umsch. 2001 May;58(5):274-7. |
[Principles of specific
immunotherapy of IgE-induced allergic reactions]
[Article in German]
Akdis
CA, Blaser
K.
Schweizerisches Institut fur Allergie- und Asthmaforschung (SIAF), Davos.
Allergen-specific immunotherapy (SIT) aims to selectively skew an allergic
immune response into a normal immunity. It appeared that the induction of
specific anergy in peripheral T cells and reactivation of anergized T cells
by microenvironmental cytokines represent two key steps in the mechanism of
SIT. In SIT of bee venom allergy the proliferative and cytokine responses
were significantly suppressed within seven days, simultaneously with an increase
in IL-10 production. IL-10 induces total anergy in T cells by autokrine interaction.
In addition, it can counter-regulate IgE and IgG4 synthesis. The addition
of blocking anti-IL-10 to stimulated PBMC fully reconstituted the proliferative
and cytokine responses in anergized T-cells. Again, particular cytokines are
able to reactivate anergic T cells to produce distinct IFN-gamma/IL-2 or IL-4/IL-13
dominated T cell cytokine patterns and direct by this way SIT towards successful
or unsuccessful treatment. The suppression of T cells by IL-10 is an active
biochemical process, which depends on the interaction of the ligated IL-10
receptor with the CD28 costimulatory signaling pathway in T cells.
PMID: 11407227 [PubMed - indexed for MEDLINE]
| 14: J Immunol. 2001 Mar 1;166(5):3612-21. |
Antigen-independent
suppression of the allergic immune response to bee venom phospholipase A(2)
by DNA vaccination in CBA/J mice.
Jilek
S, Barbey
C, Spertini
F, Corthesy
B.
Division of Immunology and Allergy, R & D Laboratory, Centre Hospitalier
Universitaire Vaudois, Lausanne, Switzerland.
Phospholipase A(2) (PLA(2)) is one of the major honey bee venom allergens
for humans. To assess the long-term prevention of allergic reactions by DNA
vaccination, a PLA(2)-CBA/J mouse model was employed using empty or PLA(2)
sequence-carrying DNA plasmids. Early skin application of either DNA construct
before (prophylactic approach) or after (therapeutic approach) sensitization
with PLA(2)/alum led to reduced PLA(2)-specific IgE and IgG1 titers at 7 mo,
with concomitant rise in IgG2a and IgG3. Splenocytes recovered at 5-6 mo after
the last DNA administration exhibited a sustained IFN-gamma and IL-10 secretion
and reduced IL-4 production. Recall challenge with PLA(2) boosted IFN-gamma
and IL-10 secretion, suggesting the reactivation of quiescent memory Th1 lymphocytes.
Mice from the prophylactic groups were fully protected against anaphylaxis,
whereas 65% of the animals recovered in the therapeutic groups. Th1-polarized
immune responses were also active in mice vaccinated with an empty plasmid
32 wk before sensitization with another Ag (OVA). This is the first demonstration
that the Ag-coding sequence in DNA vaccine is not necessary to promote immune
modulation in naive and sensitized animals for a prolonged period, and has
relevance for the understanding of the innate and induced mechanisms underlying
gene immunotherapy in long-term treatment of allergy.
PMID: 11207323 [PubMed - indexed for MEDLINE]
| 15: J Immunol. 2000 Sep 15;165(6):3497-505. |
Inducing
tolerance by intranasal administration of long peptides in naive and primed
CBA/J mice.
Astori
M, von
Garnier C, Kettner
A, Dufour
N, Corradin
G, Spertini
F.
Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland.
To assess the capacity of a peptide-based immunotherapy to induce systemic
tolerance via the nasal route, we designed three long overlapping peptides
of 44-60 aa covering the entire sequence of phospholipase A2 (PLA2), a major
bee venom allergen. Both prophylactic and therapeutic intranasal administrations
of long peptides to PLA2-hypersensitive CBA/J mice induced specific T cell
tolerance to the native allergen. In prophylactic conditions, this tolerance
was marked by a suppression of subsequent specific IgE response, whereas the
therapeutic approach in presensitized mice induced a more than 60% decrease
in PLA2-specific IgE. This decline was associated with a shift in the cytokine
response toward a Th1 profile, as demonstrated by decreased PLA2-specific
IgG1 and enhanced IgG2a levels, and by a decline in the specific IL-4/IFN-gamma
ratios. T cell transfer from long peptide-tolerized mice to naive animals
abrogated the expected anti-PLA2 IgE and IgG1 Ab response, as well as specific
T cell proliferation, but enhanced specific IgG2a response upon sensitization
with PLA2. These events were strongly suggestive of a clonal anergy affecting
more profoundly Th2 than the Th1 subsets. In conclusion, these results demonstrate
that allergen-derived long peptides delivered via the nasal mucosa may offer
an alternative to immunotherapy with native allergens without the inherent
risk of systemic anaphylactic reactions. Moreover, long peptides, in contrast
to immunotherapy strategies based on short peptides, have the advantage of
covering all potential T cell epitopes, and may represent novel and safe tools
for the therapy of allergic diseases.
PMID: 10975871 [PubMed - indexed for MEDLINE]
| 16: J Allergy Clin Immunol. 2000 Aug;106(2):228-38. |
Structural
biology of allergens.
Aalberse
RC.
Department of Allergy, CLB and the Laboratory for Experimental and Clinical
Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The
Netherlands.
One of the major challenges of molecular allergy is to predict the allergenic
potential of a protein, particularly in novel foods. Two aspects have to be
distinguished: immunogenicity and cross-reactivity. Immunogenicity reflects
the potential of a protein to induce IgE antibodies, whereas cross-reactivity
is the reactivity of (usually preexisting) IgE antibodies with the target
protein. In addition to these two issues, the relation between IgE-binding
potential and clinical symptoms is of interest. This is influenced by physical
properties (eg, stability and size) and immunologic properties (affinity and
epitope valence). Discussions on immunogenicity and cross-reactivity of allergens
rely on the establishment of structural similarities and differences among
allergens and between allergens and nonallergens. For comparisons between
the 3-dimensional protein folds, the representation as 2-dimensional proximity
plots provides a convenient visual aid. Analysis of approximately 40 allergenic
proteins (or parts of these proteins), of which the protein folds are either
known or can be predicted on the basis of homology, indicates that most of
these can be classified into 4 structural families: (1) antiparallel beta-strands:
the immunoglobulin-fold family (grass group 2, mite group 2), serine proteases
(mite group 3, 6, and 9), and soybean-type trypsin inhibitor (Ole e 1, grass
group 11); (2) antiparallel beta-sheets intimately associated with one or
more alpha-helices: tree group 1, lipocalin, profilin, aspartate protease
(cockroach group 2); (3) (alpha+beta) structures, in which the alpha- and
beta-structural elements are not intimately associated: mite group 1, lysozyme/lactalbumin,
vespid group 5; and (4) alpha-helical: nonspecific lipid transfer protein,
seed 2S protein, insect hemoglobin, fish parvalbumin, pollen calmodulin, mellitin
from bee venom, Fel d 1 chain 1, serum albumin. Allergens with parallel beta-strands
(in combination with an alpha-helix linking the two strands, a motif commonly
found in, for example, nucleotide-binding proteins) seem to be underrepresented.
The conclusion is that allergens have no characteristic structural features
other than that they need to be able to reach (and stimulate) immune cells
and mast cells. Within this constraint, any antigen may be allergenic, particularly
if it avoids activation of T(H)2-suppressive mechanisms (CD8 cells and T(H)1
cells).
Publication Types:
· Review
PMID: 10932064 [PubMed - indexed for MEDLINE]
| 17: J Am Vet Med Assoc. 1999 Apr 1;214(7):1026-7, 1021. |
Bee sting envenomation
resulting in secondary immune-mediated hemolytic anemia in two dogs.
Noble
SJ, Armstrong
PJ.
Department of Small Animal Clinical Sciences, College of Veterinary Medicine,
University of Minnesota, St Paul 55108, USA.
Immune-mediated hemolytic anemia secondary to bee envenomation developed in
2 dogs. Clinical signs included lethargy, hematuria, ataxia, and seizures;
1 dog died. Clinicopathologic data included nonregenerative anemia, spherocytosis,
positive results for Coombs' test, and occult hematuria. Treatment included
oral administration of corticosteroids at immunosuppressive dosages and supportive
care. The surviving dog initially responded to corticosteroids, but hemolysis
recurred as the dosage was tapered. Hemolysis resolved with prolonged administration
of corticosteroids. Bee venom contains hyaluronidase, histamines, and hemolysins
that cause toxic and hemolytic effects. Envenomation should be considered
in any dog with hemolytic anemia in which other causes are ruled out and exposure
to bees is known.
Publication Types:
PMID: 10200797 [PubMed - indexed for MEDLINE]
| 18: Int Arch Allergy Immunol. 1998 Sep;117(1):1-10. |
Determinants
and mechanisms of human immune responses to bee venom phospholipase A2.
Blaser
K, Carballido
J, Faith
A, Crameri
R, Akdis
C.
Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
kblaser@siaf.unizh.ch
The elicitation of an immune response to protein antigens depends on the specific
recognition of antigenic determinants (epitopes) by T and B lymphocytes. Bee
venom phospholipase A2 (PLA) represents the major antigen/allergen of honey
bee venom. It displays three dominant immunogenic peptide and one glycopeptide
T cell recognition sites. These epitopes are equally recognized by both allergic
and nonallergic individuals. A mixture of the three epitope containing peptides
was successfully used in specific immunotherapy of bee venom-allergic patients.
Both peptide and whole bee venom immunotherapy induced a state of specific
anergy in T cells. The production of specific IgE and IgG4 antibodies directly
correlated with the secreted interleukin-4:gamma-interferon (IL-4:IFNgamma)
ratio, which itself depended on the concentration of available antigen and
the strength of the T cell-activating signal. This signal comprises accumulated
molecular interactions delivered by engagement of the antigenic peptide/MHC
class II complex with the T cell receptor (TcR). Indeed the thermodynamic
laws of chemical equilibrium reactions reveal that the antigen concentration,
together with the equilibration constant Ki and the related Gibbs standard
free energy DeltaG degrees of the MHC-II/Ag/TcR complex reaction, may govern
the secreted IL-4:IFNgamma ratio, and in consequence, differential IgE and
IgG4 antibody formation. Ki includes epitope and MHC-II haplotype variability
and therefore represents a measure of immunological individuality. A major
B cell epitope was determined by using point-mutated PLA. Specific antigen
recognition by B cells can trigger distinct cytokine profiles in T cells and
contribute to the differential regulation of specific IgE and IgG4 antibodies.
Our results indicate that distinct cytokine profiles inducing allergic and
nonallergic responses can be attributed to thresholds of T cell activation
generated by the specific binding properties of individual MHC-II molecules
to immunogenic T cell epitopes and their presentation to TcR.
Publication Types:
· Review
PMID: 9751842 [PubMed - indexed for MEDLINE]
| 19: Eur J Immunol. 1998 Jul;28(7):2124-30. |
Antigen-independent
suppression of the IgE immune response to bee venom phospholipase A2 by maternally
derived monoclonal IgG antibodies.
Seeger
M, Thierse
HJ, Lange
H, Shaw
L, Hansen
H, Lemke
H.
Biochemisches Institut, Medizinische Fakultat, Christian-Albrechts-Universitat,
Kiel, Germany.
The IgE immune response to ovalbumin in rats can be suppressed by prior immunization
of the dams. The results reported in this paper extend this observation to
include a different antigen and another species, namely the IgE immune response
to bee venom phospholipase A2 (PLA2) in CBA/J mice. The degree of suppression
seemed to depend on the amount of IgG antibodies transferred to the offspring.
Moreover, we found that the maternally mediated suppression of the IgE response
could be achieved in a completely antigen-free system in which exogenous monoclonal
anti-PLA2 IgG antibodies were transferred from the dams to the offspring.
The following results were obtained: (i) The IgE suppression by monoclonal
IgG antibodies was induced as efficiently with one single anti-PLA2 IgG1 antibody
as with a mixture of ten antibodies (nine IgG1, one IgG2b). (ii) Even after
several immunizations up to an age of 6 months with a dose of PLA2 that normally
induces IgE production, none of the F1 mice developed an IgE response. (iii)
This long-lasting suppression was observed in mice which were first immunized
at an age of 4 weeks (i.e. when low amounts of maternally derived monoclonal
IgG were still present), as well as in mice which were first immunized at
an age of 8 weeks, when no such maternal antibodies could be detected in their
sera. The corresponding IgG responses showed, compared to normal mice, a transient
enhancement in the maternally influenced mice. It is concluded that the immunological
experience of the mother is of particular importance for the isotype regulation
in the newborns, especially with respect to the ability to elicit an IgE response.
The possible implications for the development of allergic diseases in humans
are discussed.
PMID: 9692881 [PubMed - indexed for MEDLINE]
| 20: J Clin Invest. 1998 Jul 1;102(1):98-106. |
Role of interleukin
10 in specific immunotherapy.
Akdis
CA, Blesken
T, Akdis
M, Wuthrich
B, Blaser
K.
Swiss Institute of Allergy and Asthma Research, CH-7270 Davos, Switzerland.
akdisac@isac@siaf.unizh.ch
The induction of allergen-specific anergy in peripheral T cells represents
a key step in specific immunotherapy (SIT). Here we demonstrate that the anergic
state results from increased IL-10 production. In bee venom (BV)-SIT the specific
proliferative and cytokine responses against the main allergen, the phospholipase
A2 (PLA), and T cell epitope-containing PLA peptides were significantly suppressed
after 7 d of treatment. Simultaneously, the production of IL-10 increased
during BV-SIT. After 28 d of BV-SIT the anergic state was established. Intracytoplasmic
cytokine staining of PBMC combined with surface marker detection revealed
that IL-10 was produced initially by activated CD4(+)CD25(+), allergen-specific
T cells, and followed by B cells and monocytes. Neutralization of IL-10 in
PBMC fully reconstituted the specific proliferative and cytokine responses.
A similar state of IL-10-associated T cell anergy, as induced in BV-SIT, was
found in hyperimmune individuals who recently had received multiple bee stings.
The addition of IL-10 to soluble CD40 ligand IL-4-stimulated PBMC or purified
B cells inhibited the PLA-specific and total IgE and enhanced the IgG4 formation.
Accordingly, increased IL-10 production by SIT causes specific anergy in peripheral
T cells, and regulates specific IgE and IgG4 production toward normal IgG4-related
immunity.
PMID: 9649562 [PubMed - indexed for MEDLINE]
| 21: J Allergy Clin Immunol. 1998 Jun;101(6 Pt 1):747-54. |
Successful
immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces
specific T-cell anergy in patients allergic to bee venom.
Muller
U, Akdis
CA, Fricker
M, Akdis
M, Blesken
T, Bettens
F, Blaser
K.
Medical Division, Zieglerspital, Bern, Switzerland.
BACKGROUND: Specific immunotherapy with honeybee venom (BV) is highly effective,
but allergic side effects can occur during treatment. Immunotherapy with peptides
containing major T-cell epitopes of the relevant allergen or allergens provides
an alternative strategy without these problems. OBJECTIVE: The study investigates
the immunologic mechanisms and clinical effects of immunotherapy with T-cell
epitope peptides of the major BV allergen, the phospholipase A2 (PLA). METHODS:
Five patients with IgE-mediated systemic allergic reactions to bee stings
were treated with a mixture of three T-cell epitope peptides of PLA. Ten patients
allergic to BV receiving whole BV immunotherapy served as control subjects.
Increasing doses of the peptide mixture, up to a maintenance dose of 100 microg,
were administered subcutaneously within 2 months. The patients were then challenged
with PLA and 1 week later with a bee sting. The cellular and humoral immune
response was measured in vitro. RESULTS: No allergic side effects were caused
by the peptide immunotherapy, and all patients tolerated the challenge with
PLA without systemic allergic symptoms. Two patients developed mild systemic
allergic reactions after the bee sting challenge. After peptide immunotherapy,
specific proliferative responses to PLA and the peptides in peripheral blood
mononuclear cells were decreased in successfully treated patien