Transcript External regulation of immune response

Antiinfection immunity
J. Ochotná
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
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 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
parasites
Defense against protozoa parasites
Toxoplasma gondii, Leishmania,
Trypanosoma
 defense against protozoa parasites is similar to bacteria
 extracellular parasites - antibodies
 intracellular parasites - TH1 lymphocytes and activated
macrophages
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
External regulation of
immune response
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 disease
 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 (alkylating agent)
- methotrexate (antimetabolite)
- azathioprine (purine analogue)
 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
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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