T-lymphocytes, ontogenesis, T-lymphocytes, ontogenesis, surface markers. surface markers. Subpopulations of T-Subpopulations of T-lymphocytes and their functions. lymphocytes and their functions.

T lymphocytes- T lymphocytes- ontogenesisontogenesis• The undifferentiated stem cell in BM gives rise to the The undifferentiated stem cell in BM gives rise to the

lymphoid precursor cell which matures into 3 types of lymphoid precursor cell which matures into 3 types of lymphocytes:lymphocytes:

• T lymphocytesT lymphocytes• B lymphocytesB lymphocytes• Natural killer (NK) cellNatural killer (NK) cell

• Pro-thymocytes come to the thymus where continue Pro-thymocytes come to the thymus where continue the maturation into T lymphocytesthe maturation into T lymphocytes

• Maturation of B lymphocytes continue in BMMaturation of B lymphocytes continue in BM

Surface markers of T Surface markers of T cellscells• CDCD (cluster of differentiation) proteins- (cluster of differentiation) proteins-

molecules on the cells membrane, molecules on the cells membrane, allow the identification of cellsallow the identification of cells

• TCRTCR- receptor for antigen- receptor for antigen

• MHC gp I or II classMHC gp I or II class

CD proteinsCD proteins• allow an identification of T-cell subsetsallow an identification of T-cell subsets

• CD 3CD 3 = important in intracellular signaling to = important in intracellular signaling to initiate an immune response; closely associated initiate an immune response; closely associated with TCRwith TCR

• CD 4,8CD 4,8 = are expresed on subclasses of mature = are expresed on subclasses of mature T cells; CD4 reacts with MHC gp II.class),CD8 T cells; CD4 reacts with MHC gp II.class),CD8 reacts with MHC gp I. class on macrophagesreacts with MHC gp I. class on macrophages

• CD 28- CD 28- receptor for costimulator molecules receptor for costimulator molecules CD80 and 86CD80 and 86

Maturation of T Maturation of T lymphocyteslymphocytesConsist of three types of processes:Consist of three types of processes:

• Proliferation of immature cellsProliferation of immature cells• Expression of antigen receptors genesExpression of antigen receptors genes• Selection of lymphocytes that express Selection of lymphocytes that express

useful antigen receptor (TCR)useful antigen receptor (TCR)

TCRTCR• Antigen receptors are encoded by several Antigen receptors are encoded by several

gene segments that gene segments that recombinerecombine during during lymphocyte maturationlymphocyte maturation

• Heterodimer consisting of 2 nonidentical Heterodimer consisting of 2 nonidentical polypeptide chains linked together by polypeptide chains linked together by disulfide bondsdisulfide bonds

• TCR heterodimer is noncovalently TCR heterodimer is noncovalently associated with the associated with the γγ,,δδ,,εε chains of the CD3 chains of the CD3 molecule molecule

• COMPLEX TCR- CD3COMPLEX TCR- CD3 makes contact with makes contact with both the both the Ag and MHC gpAg and MHC gp

Subpopulation of T cellsSubpopulation of T cells• Subpopulations of T cells have been defined according Subpopulations of T cells have been defined according

to their particular function and their CD membrane to their particular function and their CD membrane markersmarkers

• Cytotoxic T lymphocytes =Cytotoxic T lymphocytes = TcTc;;CD8+ CD8+ - - recognize the foreign epitope in association recognize the foreign epitope in association with with class I MHCclass I MHC molecules molecules

• Helper Helper T-lymphocytesT-lymphocytes = Th; CD4+ = Th; CD4+ - - recognize the epitopes in association with recognize the epitopes in association with class II MHCclass II MHC molecules molecules

Cytotoxic T lymphocytesCytotoxic T lymphocytes (Tc;(Tc;CD8CD8+)+)• cause lysis of target cells; are active cause lysis of target cells; are active

against tumors, virus-infected cells, against tumors, virus-infected cells, transplanted allogenetic tissuetransplanted allogenetic tissue

• release TNF- depresses proteosynthesisrelease TNF- depresses proteosynthesis• recognize the foreign epitope in association recognize the foreign epitope in association

with with class I MHCclass I MHC molecules molecules• destroy their target cells by releasing destroy their target cells by releasing

perforin (create poresin the cell membrane perforin (create poresin the cell membrane and cytoplasm escapes) and granzymes and cytoplasm escapes) and granzymes (degrading essential macromolecules)(degrading essential macromolecules)

Helper Helper T-lymphocytesT-lymphocytes(Th; CD4+)(Th; CD4+)

• recognize the epitopes in association recognize the epitopes in association with class II MHC with class II MHC

• help B cells to produce antibodies help B cells to produce antibodies and help phagocytes to destroy and help phagocytes to destroy ingested microbesingested microbes

• subsets of Th cells: Th1, Th2 cellssubsets of Th cells: Th1, Th2 cells

Th1 cellsTh1 cellssecrete: secrete: • INF-INF-γγ ( (gamma interferon) : activates macrophages gamma interferon) : activates macrophages

to become more effective at killing phagocytosed to become more effective at killing phagocytosed microbes, supresses the development of Th2 cells microbes, supresses the development of Th2 cells

• IL- 2 :IL- 2 : stimulates survival and proliferation of T cells, stimulates survival and proliferation of T cells, called T-cell growth factorcalled T-cell growth factor

• TNFTNF (tumor necrosis factor)- stimulates the (tumor necrosis factor)- stimulates the recruitment of neutrophils and monocytes to sites of recruitment of neutrophils and monocytes to sites of infection, activates these cells to eradicate microbesinfection, activates these cells to eradicate microbes

• IL-3 :IL-3 : promotes expansion of immature marrow promotes expansion of immature marrow progenitors of all blood cellsprogenitors of all blood cells

• GM-CSF : GM-CSF : acts on progenitors in the bone marrow to acts on progenitors in the bone marrow to increase production of neutrophils and monocytesincrease production of neutrophils and monocytes

Th1 based immune reactionTh1 based immune reaction• Th1 cells stimulate phagocytes to Th1 cells stimulate phagocytes to

eliminate ingested microbes.eliminate ingested microbes.

• Interferon gamma is the main Th1 Interferon gamma is the main Th1 cytokine. cytokine.

Th2 cellsTh2 cellssecrete: secrete: • IL-4IL-4 : induces differentiation of Th2 cells from : induces differentiation of Th2 cells from

naive CD4+ precursors, stimulation of IgE naive CD4+ precursors, stimulation of IgE production by B cellsproduction by B cells

• IL-5IL-5 : activates mast cells : activates mast cells• IL-6IL-6 : stimulates the synthesis of acute phase : stimulates the synthesis of acute phase

proteins by hepatocytesproteins by hepatocytes• IL-10IL-10 : inhibits activated macrophages, : inhibits activated macrophages,

supresses Th1 productionsupresses Th1 production• IL-3, GM-CSFIL-3, GM-CSF

Th2 based immune reactionTh2 based immune reaction• Th 2 response provide help for B Th 2 response provide help for B

cells and are essential for cells and are essential for antibody-mediated immunityantibody-mediated immunity

• Antibodies are needed to control Antibodies are needed to control extracellularextracellular pathogens pathogens

• The Th2 - type cytokines include IL 4, The Th2 - type cytokines include IL 4, 5, and 13.5, and 13.

Regulatory T cellsRegulatory T cells

• Express CD4, CD25, FoxP3Express CD4, CD25, FoxP3• Regulate the activation or effector Regulate the activation or effector

function of other T cellsfunction of other T cells• Are necessary to maintain tolerance Are necessary to maintain tolerance

to self antigensto self antigens

The role of thymus. The role of thymus. Positive and negative Positive and negative selection selection of Tof T lymphocytes.lymphocytes.

The role of thymusThe role of thymus

• In the two thymic lobes, lymphocyte In the two thymic lobes, lymphocyte precursors from the bone-marrow become precursors from the bone-marrow become thymocytes, and subsequently mature thymocytes, and subsequently mature into T cellsinto T cells

• Once mature, T cells emigrate from the Once mature, T cells emigrate from the thymus and constitute the peripheral T thymus and constitute the peripheral T cell repertoire responsible for directing cell repertoire responsible for directing many facets of the many facets of the specificspecific immune immune systemsystem

Phases of thymocyte Phases of thymocyte maturationmaturation• A rare population of hematopoietic progenitors enters A rare population of hematopoietic progenitors enters

the thymus from the blood, and expands by cell the thymus from the blood, and expands by cell division to generate a large population of immature division to generate a large population of immature thymocytesthymocytes

• Immature thymocytes each make distinct T cell Immature thymocytes each make distinct T cell receptors by a process of gene rearrangement. receptors by a process of gene rearrangement.

• This process is error-prone, and some thymocytes fail This process is error-prone, and some thymocytes fail to make functional T cell receptors, whereas other to make functional T cell receptors, whereas other thymocytes make T cell receptors that are autoreactivethymocytes make T cell receptors that are autoreactive

Positive and negative Positive and negative selectionselection• Immature thymocytes undergo a Immature thymocytes undergo a

process of selection, based on the process of selection, based on the specificity of their T cell receptors.specificity of their T cell receptors.

• This involves selection of T cells that This involves selection of T cells that are functional (are functional (positive selectionpositive selection), ), and elimination of T cells that are and elimination of T cells that are autoreactive (autoreactive (negative selectionnegative selection))

Thymus – positive selection of T - Thymus – positive selection of T - cellscells

1.1. pprrecursor T cells enter thymus from the blood ecursor T cells enter thymus from the blood 2.2. they they are presented with self-antigens are presented with self-antigens

complexed with MHC molecules on the complexed with MHC molecules on the surface of cortical epithelial cellssurface of cortical epithelial cells

3.3. oonly those thymocytes which bind the nly those thymocytes which bind the MHC/antigen complex with adequate affinity MHC/antigen complex with adequate affinity will receive a vital "survival signal" will receive a vital "survival signal"

4.4. the other thymocytes the other thymocytes diedie (>95%) (>95%)

Thymus – negative selection of T - Thymus – negative selection of T - cellscells

1.1. tthymocytes that survive positive selection hymocytes that survive positive selection migrate towards the boundary of the thymic migrate towards the boundary of the thymic cortex and thymic medullacortex and thymic medulla

2.2. they are again presented with self-antigen in they are again presented with self-antigen in complex with MHC molecules on antigen-complex with MHC molecules on antigen-presenting cellspresenting cells

3.3. tthymocytes that interact hymocytes that interact too stronglytoo strongly with with the antigen receive an the antigen receive an signal for signal for apoptosis apoptosis

Humoral immune Humoral immune responseresponse • The binding of antigen cross-links Ig The binding of antigen cross-links Ig

receptors of specific B cells and then receptors of specific B cells and then activation signals are delivered inside the activation signals are delivered inside the B cell; the necessary second signal is B cell; the necessary second signal is provided by a breakdown product of the provided by a breakdown product of the complement protein C3 complement protein C3

• This process results in cThis process results in clonal expansion of lonal expansion of B cellB cellss and secretion of low levels of IgM and secretion of low levels of IgM

Affinity maturationAffinity maturation= affinity of antibodies for protein = affinity of antibodies for protein

antigens increases with prolonged or antigens increases with prolonged or repeated exposure to the antigens repeated exposure to the antigens

• B cells migrate into follicles and form B cells migrate into follicles and form germinal centersgerminal centers,, proliferate rapidly proliferate rapidly

• B cells that recognize the antigen B cells that recognize the antigen with high affinity are selected to with high affinity are selected to survivesurvive

Phases of humoral immune Phases of humoral immune responsesresponses

Primary immune responsePrimary immune response• Occurs during the fOccurs during the first antigen exposureirst antigen exposure• The amounts of antibody produced is The amounts of antibody produced is

smallersmaller, class IgM, class IgM2 types of antigens:2 types of antigens:• T-T- dependentdependent – help from T helper cells is – help from T helper cells is

required; protein antigensrequired; protein antigens• T-T- independentindependent – antibody production is – antibody production is

induced directly, without the involvement induced directly, without the involvement of T helper cells; typicof T helper cells; typical are al are polysaccharides, lipidspolysaccharides, lipids

Secondary immune Secondary immune responseresponse• Occurs during sOccurs during subsequent antigen ubsequent antigen

exposureexposure• Higher amount of antibodies is producedHigher amount of antibodies is produced• secondary responses show increased secondary responses show increased

isotype switching isotype switching (IgG, IgA, IgE) (IgG, IgA, IgE) and and affinity maturation (= production of affinity maturation (= production of antibodies with increased affinity to antibodies with increased affinity to antigen)antigen)

• Gives arise mGives arise memory cells involvementemory cells involvement

Physiological mechanisms of Physiological mechanisms of regulation of the immune regulation of the immune system.system.

Immune mechanisms of Immune mechanisms of regulationregulationImmune system is regulated by:Immune system is regulated by:• AntigenAntigen• Antagonistic peptidAntagonistic peptid• AntibodiesAntibodies• Cytokines and intercellular contactCytokines and intercellular contact• T lymphocytesT lymphocytes• Neuroendocrine regulationNeuroendocrine regulation

REGULATION BY ANTIGENREGULATION BY ANTIGEN

• Antigen competitionAntigen competition – peptides from different – peptides from different antigens compete for binding-sites on the MHC antigens compete for binding-sites on the MHC gp = antigen is able to suppress expression of gp = antigen is able to suppress expression of other antigenother antigen

IMPORTANT IS : IMPORTANT IS : • the binding strenght of peptide to MHC gp IIthe binding strenght of peptide to MHC gp II• density of peptid-MHC gp II complex on the density of peptid-MHC gp II complex on the

surface of APCsurface of APCImmune response finishes after extinction of Immune response finishes after extinction of

antigen – due to a short life-span of effector antigen – due to a short life-span of effector lymphocyteslymphocytes

ANTAGONISTIC PEPTIDESANTAGONISTIC PEPTIDES

• Agonists - Agonists - peptide fragments of antigen peptide fragments of antigen with adequate binding to MHC gp, with adequate binding to MHC gp, recognition by T cells with sufficient recognition by T cells with sufficient affinity – affinity – induce full response of T cellsinduce full response of T cells

• Partial agonistsPartial agonists – induce a – induce a qualitative qualitative different response of T cellsdifferent response of T cells - peptides - peptides have a similar structure, bind adequately have a similar structure, bind adequately to MHC gp, but make too weak or too to MHC gp, but make too weak or too strong interaction with T cellsstrong interaction with T cells

• Antagonists Antagonists – induce – induce anergy of T cellsanergy of T cells

REGULATION MEDIATED BY REGULATION MEDIATED BY ANTIBODIESANTIBODIES• Antibodies have an effector and Antibodies have an effector and

regulatory functionsregulatory functions• Secreted antibodies Secreted antibodies – compete – compete

with BCR for antigen = negative with BCR for antigen = negative regulators ofregulators of B cells stimulation B cells stimulation

• Immune complexes of antibody Immune complexes of antibody and antigen –and antigen – bind to the surface of bind to the surface of B cells – B cells – inhibit B cells activation inhibit B cells activation

REGULATION MEDIATED BY REGULATION MEDIATED BY CYTOKINES AND INTERCELLULAR CYTOKINES AND INTERCELLULAR CONTACTCONTACT• Inhibition of cytokine effect by Inhibition of cytokine effect by

endocytosis of their receptorsendocytosis of their receptors or by or by binding of binding of inhibitors to their receptorsinhibitors to their receptors

• Inhibitory receptors Inhibitory receptors – protection against – protection against too easy T cells activation too easy T cells activation

• Apoptotic receptorApoptotic receptor (Fas) mediates a (Fas) mediates a negative regulation after binding to ligand negative regulation after binding to ligand FasL on activated T cells – causes – lysis FasL on activated T cells – causes – lysis of cellof cell

NEGATIVE REGULATION NEGATIVE REGULATION mediated by T lymphocytesmediated by T lymphocytes

• Th2 cells produce IL-4, IL-10- suppress Th2 cells produce IL-4, IL-10- suppress immune response of Th1 cellsimmune response of Th1 cells

• CD8+ T cells – secrete soluble forms of CD8+ T cells – secrete soluble forms of TCR - compete with TCR on the surface of TCR - compete with TCR on the surface of other cells- inhibitionother cells- inhibition

• Regulatory Tr1 cells (CD4+)- secrete IL-10-Regulatory Tr1 cells (CD4+)- secrete IL-10-anti-inflammatory effect, induce tolerance anti-inflammatory effect, induce tolerance to autoantigensto autoantigens

NEUROENDOCRINE NEUROENDOCRINE REGULATIONREGULATION

• Neurotrasmiters influence leukocytes by Neurotrasmiters influence leukocytes by binding to the specific receptors (noradrenalin)binding to the specific receptors (noradrenalin)

• CS, growth hormons, thyroxin, endorfins – CS, growth hormons, thyroxin, endorfins – influence the leukocytes by binding to the influence the leukocytes by binding to the specific receptorsspecific receptors

• Leukocytes produce endorfins, TSH, growth Leukocytes produce endorfins, TSH, growth hormon, vitamin D3, ACTHhormon, vitamin D3, ACTH

• Cytokines influence nerve system (IL-1, IL-6)Cytokines influence nerve system (IL-1, IL-6)• Stress influences immune system- Stress influences immune system-

cortocosteroids-activity of phagocytes, NK cellscortocosteroids-activity of phagocytes, NK cells

OTHER FACTORSOTHER FACTORS

• The same antigen can induce active immune The same antigen can induce active immune response or response or active tolerance – depends on:active tolerance – depends on:

• Condition of immune systemCondition of immune system• Character of antigenCharacter of antigen (size, structure of (size, structure of

molecule)molecule)• Dose of antigenDose of antigen (too low or too high doses- (too low or too high doses-

induce tolerance)induce tolerance)• Route of antigen administration Route of antigen administration (s.c.-(s.c.-

induce immune response, p.o. or i.v.- induce induce immune response, p.o. or i.v.- induce tolerance)tolerance)

Cytokines (overview, disposal Cytokines (overview, disposal according their function)according their function)

Cytokines Cytokines • Humoral factors - provide intercellular Humoral factors - provide intercellular

communication between immune cells + communication between immune cells + communication between immune system and communication between immune system and other body systemsother body systems

• Proteins secreted by leukocytes (and by other Proteins secreted by leukocytes (and by other cells of immune system)cells of immune system)

• Influence different cells of immune system Influence different cells of immune system through specific receptorsthrough specific receptors

• Forms- secreted or membraneForms- secreted or membrane• Effects - pleiotropic (1 cytokine has a several Effects - pleiotropic (1 cytokine has a several

fysiological effects)fysiological effects)

Function of cytokinesFunction of cytokines• Activating signals for cells – activate, Activating signals for cells – activate,

regulate cell cycle, mitotic activityregulate cell cycle, mitotic activity• Cause changes of the cell membranes – Cause changes of the cell membranes –

increase of cytokine receptors expressionincrease of cytokine receptors expression• Participate in reparation of tissues in the Participate in reparation of tissues in the

terminal phase of inflammation terminal phase of inflammation • Regulate immune cells proliferation and Regulate immune cells proliferation and

differentiation in the immune organs differentiation in the immune organs • Influence migration of the immune cellsInfluence migration of the immune cells

Classification of cytokinesClassification of cytokines• Pro-inflammatoryPro-inflammatory• Anti-inflammatoryAnti-inflammatory• With growth activity factorWith growth activity factor• Participating in humoral response ISParticipating in humoral response IS• Participating in cell response ISParticipating in cell response IS• With antiviral effectWith antiviral effect

Proinflammatory cytokinesProinflammatory cytokines• IL-1IL-1 – produced by macrophages and T cells; – produced by macrophages and T cells;

activates neutrophils, endothelial cells and T cells, activates neutrophils, endothelial cells and T cells, induces synthesis of acute phase proteins in liver, induces synthesis of acute phase proteins in liver, causes fevercauses fever

• IL-6IL-6 – produced by T and B cells, monocytes; – produced by T and B cells, monocytes; regulates B cell differentiation and proliferation, regulates B cell differentiation and proliferation, synthesis antibodies; stimulates hepatocytes to synthesis antibodies; stimulates hepatocytes to produce acute phase proteinsproduce acute phase proteins

• IL-8IL-8 – produced by monocytes, macrophages, – produced by monocytes, macrophages, endothelial cells; chemotactic factor for neutrophilsendothelial cells; chemotactic factor for neutrophils

• TNFTNF

TNFTNF• TNF TNF αα – produced by macrophages (+T a – produced by macrophages (+T a

B cells, NK cells, neutrophiles,..) B cells, NK cells, neutrophiles,..) – – participates on early phase of participates on early phase of

inflammation, induces expression of inflammation, induces expression of adhesive molecules on endothelial cells adhesive molecules on endothelial cells and leukocytes; stimulates and leukocytes; stimulates proinflammatory protein productionproinflammatory protein production

• TNF TNF ββ- produced by T and B cells; - produced by T and B cells; similar effects similar effects

Anti-inflammatory Anti-inflammatory cytokinescytokines• IL-10IL-10 – produced by Th2 cells, monocytes, – produced by Th2 cells, monocytes,

macrophages, activated B cells; inhibits macrophages, activated B cells; inhibits cytokine Th1, Tc and NK cells production; cytokine Th1, Tc and NK cells production; inhibits synthesis of pro-inflammatory inhibits synthesis of pro-inflammatory cytokines by macrophagescytokines by macrophages

• TGF-TGF-ββ – growth activator but also inhibitor of – growth activator but also inhibitor of different cell typesdifferent cell types

• RegulatesRegulates damaged tissues reparation by damaged tissues reparation by stimulation of intercellular substances stimulation of intercellular substances synthesis; can inhibite T and B cell proliferationsynthesis; can inhibite T and B cell proliferation

• IL-4IL-4

CYTOKINES with activity of CYTOKINES with activity of growth factorsgrowth factors

• SCFSCF- stimulates stem cell proliferation, - stimulates stem cell proliferation, their release to the peripheral bloodtheir release to the peripheral blood

• IL-3IL-3 – influences maturation of all cell – influences maturation of all cell lineslines

• IL-7IL-7 – growth factor of T cells – growth factor of T cells• IL-11IL-11 – growth factor of megakaryocytes – growth factor of megakaryocytes• IL-15IL-15 – induces proliferation of mast – induces proliferation of mast

cells, Th and Tc cellscells, Th and Tc cells

CYTOKINES with activity of growth CYTOKINES with activity of growth factorsfactors• G-CSF, M-CSF, GM-CSFG-CSF, M-CSF, GM-CSF – stimulate – stimulate

granulocytes and/or granulocytes and/or monocytes/macrophages proliferation and monocytes/macrophages proliferation and differentiation, prolongate their survival differentiation, prolongate their survival and increase their functional capacity and increase their functional capacity during inflammationduring inflammation

• EPO EPO = erythropoetin- stimulates red cells = erythropoetin- stimulates red cells differentiation differentiation

CYTOKINE participating in CYTOKINE participating in humoral response of IShumoral response of IS

• IL-4IL-4 – produced by – produced by Th2 cellsTh2 cells, mast cells , mast cells and basophils; stimulates B and T cells and basophils; stimulates B and T cells proliferation, activates macrophages; growth proliferation, activates macrophages; growth factor of mast cells (anti-inflammatory effect)factor of mast cells (anti-inflammatory effect)

• IL-13IL-13 – see IL-4 + chemotactic factor for – see IL-4 + chemotactic factor for monocytes and macrophagesmonocytes and macrophages

• IL-5IL-5 – produced by – produced by Th2 cellsTh2 cells, lymphocytes , lymphocytes and mast cells; activates and stimulates B and mast cells; activates and stimulates B cells and eosinophils proliferation, stimulates cells and eosinophils proliferation, stimulates Tc cellsTc cells

CYTOKINES participating in CYTOKINES participating in cell mediated response cell mediated response • IL-2IL-2 – produced by Th cells after stimulation by – produced by Th cells after stimulation by

antigen, autocrine effect to Th cells; activating antigen, autocrine effect to Th cells; activating signal for Tc cells and NK cells; 2. signal for signal for Tc cells and NK cells; 2. signal for activation and differentiation of B cellsactivation and differentiation of B cells

• IL-12IL-12 – produced by monocytes, – produced by monocytes, macrophages; stimulates maturation Th0 into macrophages; stimulates maturation Th0 into Th1 cells; activates NK cells; stimulates INF- Th1 cells; activates NK cells; stimulates INF- γγ production by Th1 cells; inhibites IgE secretion production by Th1 cells; inhibites IgE secretion

• IFN-IFN-γγ, GM-CSF, GM-CSF

CYTOKINE with antiviral CYTOKINE with antiviral effecteffect• Interferons-Interferons- anti-inflammatory, anti- anti-inflammatory, anti-

prolifferativeprolifferative• IFN-IFN-αα, IFN, IFN--ββ - produced by cells with - produced by cells with

nucleus after stimulation by virusesnucleus after stimulation by viruses• Induce decomposition of viral nucleus acids Induce decomposition of viral nucleus acids

and influence into translation of viral and influence into translation of viral proteinsproteins

• IFN- IFN- αα - in recombinant form – therapy of - in recombinant form – therapy of chronic active hepatitis B, hepatitis Cchronic active hepatitis B, hepatitis C

Regulation of local Regulation of local concentration of cytokinesconcentration of cytokines

• Biological effects are neutralized by Biological effects are neutralized by binding to nature inhibitors and binding to nature inhibitors and soluble forms of receptors for soluble forms of receptors for cytokinescytokines

• MMP (matrix metaloproteases) MMP (matrix metaloproteases) release cytokines from molecules of release cytokines from molecules of intercellular substance intercellular substance

• Elastases release binded cytokinesElastases release binded cytokines

External regulation of immune External regulation of immune responseresponse• Substitutive therapySubstitutive therapy – –

immunoglobulins, C1-inhibitorimmunoglobulins, C1-inhibitor• Non-specific immunostimulation Non-specific immunostimulation : :

Isoprinosine, bacterial lysates, cytokinesIsoprinosine, bacterial lysates, cytokines• Ag- specific immunotherapy: Ag- specific immunotherapy: active immunisation – prophylaxisactive immunisation – prophylaxis pasive immunisation – prophylaxis, pasive immunisation – prophylaxis,

therapytherapy

Therapy- Non-specific Therapy- Non-specific immunosupresionimmunosupresion• corticosteroidscorticosteroids• anti- inflamatory drugs (antihistaminics, inhibitors anti- inflamatory drugs (antihistaminics, inhibitors

of pro-inflamatory cytokines-monoclonal Ab of pro-inflamatory cytokines-monoclonal Ab agains TNF, nonsteroid anti-inflamatory drugs- agains TNF, nonsteroid anti-inflamatory drugs- metabolites of arachid acid)metabolites of arachid acid)

• drugs affecting the proliferation of both T cells drugs affecting the proliferation of both T cells and B cells (Cyclophosphamide, Methotrexate, and B cells (Cyclophosphamide, Methotrexate, Azathioprine, Mycophenolate mofetil)Azathioprine, Mycophenolate mofetil)

• drugs blocking the activation of lymphocytes drugs blocking the activation of lymphocytes (Tacrolimus, Sirolimus, Cyclosporin A)(Tacrolimus, Sirolimus, Cyclosporin A)

• monoclonal antibodies – against IL-2 receptormonoclonal antibodies – against IL-2 receptor