External regulation of immune response
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Transcript External regulation of immune response
External regulation of
immune response
J. Ochotná
Causal treatment
a) Stem cell transplantation
for serious congenital disorders of the immune system and some
lymphoproliferative and myeloproliferative disorders
complications: infectious complications
Graft-versus-host
obtaining stem cells - collection from shovel hip bone
- from umbilical cord blood
- from peripheral blood after stimulation
with GM-CSF
b) Gene therapy
with a suitable expression vector is introduced functional
gene (to replace dysfunctional gen) into the lymphocytes
or stem cells
used as a treatment for some cases of SCID
Substitution treatment
autologous stem cell transplantation following
chemotherapy and radiotherapy
treatment with intravenous immunoglobulin (derived from
plasma of blood donors)
substitution of C1 inhibitor for hereditary angioedema
substitution of erythropoietin in patients with chronic renal
failure
substitution of G-CSF in agranulocytosis
Immunomodulation
= medical procedure to adjust the disrupted immune function
Non-specific immunosuppressive therapy
nonspecific = affects not only autoreactive and aloreactive
lymphocytes, but also other components of
immunity
(risk of reduction antiinfectious and antitumor immunity)
used for treatment of autoimmune diseases, severe allergic
conditions and for organ transplantation
Non-specific immunosuppressive therapy
corticosteroids - anti-inflammatory, immunosuppressive
effects
- blocking the activity of transcription
factors (AP-1, NFkB)
- suppress the expression of genes (IL-2,
IL-1, phospholipase A, MHC gp II,
adhesion molecules)
- inhibition of histamine release from basophils
- higher concentrations induce apoptosis
of lymfocytes
immunosuppressants affecting the metabolism of DNA
- cyclophosphamide
- methotrexate
- azathioprine
immunosuppressant selectively inhibiting T lymphocytes
- immunosuppressive ATB: cyclosporine A, tacrolimus,
rapamycin (suppressing the expression of IL-2 and
IL-2R in activated T lymphocytes)
- monoclonal antibody anti-CD3 (Immunosuppression
after transplantation, treatment of rejection crises)
immunoglobulins in the immunosuppressive indication
- Polyspecific intravenous immunoglobulins
(Inhibition of B lymphocytes, antiidiotype activity,
inhibition of cytokines, neutralization of toxins,
inhibition of complement activation ...)
Anti-inflammatory and antiallergic treatment
nonsteroidal anti-inflammatory drugs
antihistamines - blocking H1 receptor
- reduce the expression of adhesion
molecules
- reduce the secretion of histamine ...
inhibitors of inflammatory cytokine
- receptor antagonist for IL-1
- monoclonal antibodies against TNF
- thalidomide (TNF inhibitor)
enzyme therapy - in the enzyme mixture has a major
effect trypsin and bromelain
- anti-inflammatory
and immunomodulatory effects
Non-specific immunostimulant therapy
synthetic immunomodulators
Methisoprinol (Isoprinosine) - used in viral infections with more
severe or relapsing course
bacterial extracts and lysates
Broncho-Vaxom - prevention of recurrent respiratory tract infections
Ribomunyl
products of the immune system
IL-2 - renal adenocarcinoma
IFNa, IFNb - viral hepatitis, some leukemia
Erythropoietin – renal failure
G-CSF, GM-CSF – neutropenia
Transfer factor (blood donors leukocytes undergoing dialysis)
Thymus hormones
Antigen-specific immunomodulatory
therapy
specific immunomodulation = induce an immune
response or tolerance against a specific antigen
a) active immunization
= use of antigen to induce an immune response
that can later protect against a pathogen
bearing the antigen
(or similar antigen)
immunization vaccines are made from
inactivated or attenuated microorganisms or
their antigens (polysaccharide capsule, toxins)
creates long-term immunity
activate cellular and antibody immunity
administration of antigen injectable, oral
prophylaxis
risk of infection or anaphylactic reactions
b) passive immunization
natural - transfer of maternal antibodies in fetal blood
therapeutically - the use of animal antibodies against
various toxins (snake toxins, tetanus
toxin, botulinum toxin)
prophylaxis - the human immunoglobulin from
immunized individuals (hepatitis A,
rabies, tetanus)
- Anti-RhD antibodies - preventing
maternal immunization with RhD+ fetus
provides a temporary (3 weeks) specific humoral
immunity
the risk anaphylactic reactions
c) specific immunosuppression
= induction of tolerance to a specific antigen
ongoing clinical studies
induction of tolerance by oral administration of
antigen (treatment of certain autoimmune
diseases)
allergen immunotherapy (pollen, insect poisons)
d) vaccination against cancer
immunization by dendritic cells
Defence against
extracellular pathogens
Defence against extracellular pathogens
bacteria (gram-negative, gram-positive cocci, bacilli),
unicellular parasites
for their elimination is necessary opsonization (C3b, lectins,
antibodies ...)
neutrophilic granulocytes are chemotactic attracting to the site
of the infection (C5a, C3a and chemotactic products of
bacteria)
absorbed bacteria are destroyed by the microbicidal systems
(products of NADP-H oxidase, hydrolytic enzymes and
bactericidal substances in lysosomes)
phagocytes produce proinflammatory cytokines
(IL-1, IL-6, TNF) that induce an increase in temperature,
metabolic response of the organism and synthesis of
acute phase proteins
in later stages of infection are stimulated antigen-specific
mechanisms
plasma cells initially produce IgM isotype after isotype
switching produce IgG1 and IgA (opsonization)
sIgA protect against intestinal and respiratory infections
by bacteria
bacteria with a polysaccharide capsule may cause
T-independent IgM antibody production (after the
establishment to the bacteria activate the classical
complement path)
after infection persist IgG, IgA (protective effect) and
memory T and B lymphocytes
in the defense against bacterial toxins apply neutralizing
antibodies (Clostridium tetani and botulinum ...)
"indirect toxins - bacterial Lipopolysaccharide (LPS)
stimulates big number of monocytes to release TNF,
which can cause septic shock
extracellular bacterial infections are especially at risk
individuals with disorders in the function of phagocytes,
complement and antibody production
Defence against
intracellular pathogens
Defense against intracellular pathogens
bacteria, fungi and unicellular parasites
intracellular parasites are resistant to the microbicidal
mechanisms of phagocytes
macrophages, which absorbed them, produce IL-12 → TH1
differentiation, production of IFNg and membrane TNF →
activation of macrophages and induction of iNOS
plasma cells under the influence of IFNg produce IgG2,
immune complexes containing IgG2 bind to Fc receptors on
macrophages and thus stimulate them
-
in the defense against intracelular parasites, which
escape from phagolysosomes apply TC lymphocytes
intracellular microorganisms infections are at risk
individuals with certain disorders of phagocytes and
defects of T lymphocytes
Defense against intracellular pathogens
Anti-viral defence
Anti-viral defence
interferons - in infected cells is induced production of
IFNa and IFNb (prevents viral replication and in
uninfected cells cause the anti-virus status); IFNg
stimulates the conversion to activated macrophages
(iNOS)
NK cells - ADCC (Antibody-dependent cell-mediated
cytotoxicity) = cytotoxic reaction depends on the
antibodies; the NK-lymphocyte recognizes cell opsonized
with IgG by stimulation Fc receptor CD16 and then
activate cytotoxic mechanisms (degranulation)
infected macrophages produce IL-12 (a strong activator
of NK cells)
in the defense against cytopathic viruses mostly applied
antibodies:
sIgA inhibit mucosal adhesion of viruses (defense
against respiratory viruses and enteroviruses)
neutralizing IgG and IgM antibodies activate
the classical way of complement, which is capable
of some viruses lysis
IgA and IgG derived in viral infection have
a preventive effect in secondary infection
effector TC lymphocytes destroy infected cells in direct
contact (granzym/perforin; FasL) and by produced
cytokines (lymfotoxin)
some viruses after infection integrate into the host
genome, where persist for years (varicella zoster, EBV,
papillomavirus)
by these infections are at risk individuals with T lymphocyte
immunodeficiency and with combined immune disorders
increased susceptibility to herpes infections in individuals
with dysfunction of NK cells
Defense against
multicellular parasites
Defense against multicellular parasites
contact of mast cells, basophils and eosinophils with
parasite antigens
TH2 stimulation under the influence of IL-4 (mast cells
and other APC stimulated by parasite)
TH2 stimulate B cells with BCR-specific parasite antigens
isotype switching under the influence of IL-4 to IgE
IgE bind to FceRI on mast cells and basophils („antigenspecific receptors“)
establish of multivalent antigen (multicellular parasite)
using the IgE to highafinity Fc receptor for IgE (FceRI)
aggregation of several molecules FceRI
initiate mast cell degranulation (cytoplasmic granules
mergers with the surface membrane and release their
contents)
activation of arachidonic acid metabolism (leukotriene
C4, prostaglandin PGD2) - amplification of inflammatory
responses
cytokine production by mast cell (TNF, TGFb, IL-4, 5,6
...)
in later stages are activated TH1 and are produced
antibodies of other classes
eosinophils fagocyte complexes of parasitic particles with
IgE via their receptors for IgE
eosinophils use against parasites extracellular
bactericidal substances released from granules
(eosinophil cationic protein, protease)
Activation of mast cell
Anti-tumour immunology
Malignant transformation
failure of regulation of cell division and regulation of
"social" behavior of the cells
the uncontrollable proliferation, dissemination to other
tissues
mutations in protoonkogenes and antionkogenes
Tumor cells
unlimited growth
growth without stimulating growth factors
immortality
often altered number of chromosomes as frequent
chromosomal alteration
TSA ...
Tumor antigens
a) Antigens specific for tumors (TSA)
complexes of MHCgp I with abnormal fragments of
cellular proteins - chemically induced tumors
- leukemia with chromosomal translocation
complexes of MHC gp with fragments of proteins of
oncogenic viruses - tumors caused by viruses (EBV, SV40,
polyomavirus)
abnormal forms of glycoproteins - sialylation of tumor cells
surface proteins
idiotypes of myeloma and lymphoma - clonotyping TCR
and BCR
b) Antigens associated with tumors (TAA)
present also on normal cells
differences in quantity, time and local expression
auxiliary diagnostic markers
1) onkofetal antigens
on normal embryonic cells and some tumor cells
a-fetoprotein (AFP) - hepatom
carcinoembryonic antigen (CEA) - colon cancer
2) melanoma antigens
MAGE-1, Melan-A
3) antigen HER2/neu
receptor for epithelial growth factor
mammary carcinoma
4) EPCAM
epithelial adhesion molecule
metastases
5) differentiation antigens of leukemic cells
present on normal cells of leukocytes linage
CALLA -acute lymphoblastic leukemia (CD10 pre-B cells)
Anti-tumor immune mechanisms
Immune control
tumor cells normally arise in tissues
and are eliminated by T lymphocytes
probably wrong hypothesis
Defensive immune response
tumor cells are weakly immunogenic
occurs when tumor antigens are presented to T lymphocytes
by dendritic cells activated in the inflammatory environment
if tumor cells are detected, in defense may be involved nonspecific mechanisms (neutrophilic granulocytes,
macrophages, NK cells) and antigen-specific mechanisms
(complement activating antibodies or ADCC, TH1 and TC)
cancer-associated antigens are processed by APC and
recognized by T lymphocytes in complex with HLA I.
and II. class with providing costimulus signals
predominance of TH1 (IFN g, TNFa)
specific cell-mediated cytotoxic reactivity – TC
activation of TH2 → support B lymphocytes→ tumor
specific antibodies (involved in the ADCC)
tumor cells are destroyed by cytotoxic NK cells (ADCC)
Anti-tumor immune mechanisms
Mechanisms of tumor resistance to the
immune system
-
high variability of tumor cells
low expression of tumor antigens
sialylation
tumor cells signals do not provide costimulus → T
lymphocyte anergy
some anticancer substances have a stimulating effect
production of factors inactivating T lymphocytes
expression of FasL → T lymphocyte apoptosis
inhibition of the function or durability dendritic cells (NO,
IL-10, TGF-b)