Cytokines in diseases - PowerPoint PPT Presentation

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Cytokines in diseases

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Title: Cytokines in diseases


1
Cytokines in diseases
  • M.Prasad Naidu
  • MSc Medical Biochemistry, Ph.D,.

2
  • Introduction
  • Cytokines are peptides synthesized and released
    by white blood cells and tissue macrophages that
    stimulate or suppress the functional activity of
    lymphocytes, monocytes, neutrophils, fibroblast
    cells, and endothelial cells.
  • Cytokines are substances released by leukocytes
    and other cells that control the development of
    the immune response.

3
  • Often termed the hormones of the immune system,
    they modulate the differentiation and division of
    hematopoietic stem cells and activation of
    lymphocytes and phagocytes.
  • Corticosteroids were among the earliest compounds
    found to have immuno suppressive activity.

4
  • The binding of the glucocorticoids to their
    receptors blocks the synthesis or release of
    lymphokines and cytokines.
  • This results in an inhibition of T-cell response
    to stimulation, a redistribution of lymphocytes
    from the vascular to the lymphatic system, and a
    decrease in the number of circulating T-cells and
    B-cells.
  • The cellular immune response is blunted, but
    almost no immuno suppressive effect is seen in
    the humoral response (antibody production).

5
  • Cytokines are soluble proteins that interact with
    specific cellular receptors that are involved in
    the regulation of the growth and activation of
    immune cells and mediate normal and pathologic
    inflammatory and immune responses.
  • Cytokines are peptides used by cells for
    intercellular communication and for controlling
    the inner environment of the cells in which they
    operate.

6
  • They are produced by cell types that have
    important roles in the immune response,
    inflammation, hemopoiesis, healing, and systemic
    response to injury.
  • Many cytokines can be measured by bioassay and
    immunoassay.

7
  • Clinical significance
  • Cytokines and the inflammatory process
  • The immunoinflammatory system is a complex
    network of cells and humoral elements that
    includes many cytokines.
  • Typically, an immunoinflammatory response is
    triggered by an antigen.

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  • The antigen is presented by specialized cells
    termed antigen-presenting cells (APCs) that
    present the antigen through either class I or II
    restriction of the major histocompatibility
    complex (MHC).
  • CD4 lymphocytes have two subtypes Th1 and Th2.

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  • The transformation of CD4 lymphocytes into Th1 or
    Th2 subtypes is currently thought to be the
    central stage of the immune response.
  • Although unconfirmed, it is thought that Th0
    lymphocytes can polarize into Th1 or Th2 cells
    according to the cytokines contained in the
    micro-environment in which the cells reside.
  • When CD4 lymphocytes are transformed into Th1 or
    Th2 subtypes, they produce a characteristic
    cytokine profile.

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  • The figure represents a general scheme of the
    development of human CD4 Th1 cells.
  • The figure summarizes the Th2 polarization, which
    usually occurs due to antigenic stimulation by
    allergens or helminthic (parasite) antigens.

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  • Cytokines and cancer
  • Cancers are a very heterogeneous group of
    diseases, and the mechanisms of malignant
    transformation and continuation are very diverse
    in different tumors.
  • They represent diseases in which intercellular
    signalling mechanisms have been damaged so as to
    remove the normal constraints on cellular growth
    and replication.

16
  • In many cases, cytokines form part of these
    control mechanisms or induce other molecules that
    perform these functions.
  • For example, some proto-oncogenes and oncogenes
    code for normal or abnormal components of
    cytokine receptor or signal transduction
    pathways.

17
  • Cytokines may have growth inhibitory properties
    directly on cancer cells, cause tumor regression
    due to modification of the host tumor
    relationship, or enhance anti-tumor immune
    effects.
  • They may also act as growth factors for malignant
    cells.

18
  • As far as the clinical laboratorian is concerned,
    the measurement of cytokines in biological fluids
    may be useful for monitoring progression of some
    tumors and for therapeutic monitoring when they
    are used as anticancer agents.

19
  • Regulation of growth and differentiation
  • The IFNs naturally assumed great importance in
    the search for tumor-modifying cytokines in view
    of their growth inhibitory properties on many
    cells.
  • They can down-regulate the expression of cellular
    proto-oncogenes such as myc, the enzymes
    associated with DNA replication, and the
    receptors for growth factors such as EGF.

20
  • In vivo they may also activate cytotoxic T cells.
  • IL-6 inhibits the growth of a variety of human
    cell lines derived from malignant tumors of
    breast, ovary, and myeloid cells.
  • IL-6 is a potent growth factor for plasmacytoma
    and myeloma cells.

21
  • Toxicity for Tumor cells
  • The mechanisms are arachidonic acid dependent and
    may involve the production of oxygen free
    radicals that destroy the tumor cell DNA.
  • TheTNFs can inhibit tumor cell growth by a direct
    cytotoxic effect, inhibit proliferation, and
    induce differentiation.

22
  • TNF can also stimulate growth of some malignant
    cells.
  • TNF exhibits protumor effects.

23
  • Immune response to tumor
  • The tumor-suppressor roles of cytokines include
    many regulatory effects on the immune system.
  • The IFNs enhance the expression of MHC class I
    antigens on many different normal and malignant
    cell types, making them susceptible to killing by
    cytotoxic T cells.

24
  • IL-2 stimulates peripheral blood lymphocytes,
    rendering a subpopulation of them more cytotoxic
    for tumor cells.
  • This subpopulation of cells is known as
    lymphokine-activated killer cells (LAK cells).
  • LAK cells probably form part of the NK-cell
    population.

25
  • NK-cell population is responsible for immune
    surveillance of potentially malignant cells.
  • IL-2 is used therapeutically intravenously or
    subcutaneously and in renal cell carcinoma, and
    melanoma gives responses significantly better
    than chemotherapy.

26
  • LAK cells may be stimulated ex vivo using
    lymphocytes derived from plasmapheresis and
    reinfused into the patient.
  • Tumor infiltrating lymphocytes (TILs) may be
    extracted and stimulated.
  • Significant toxicity limits the dose of IL-2.

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  • Mediation of paraneoplastic effects
  • A wide range of paraneoplastic effects seem to be
    mediated by cytokines.
  • The fever that so often accompanies cancer is
    mediated by IL-6, IL-1, and TNF.
  • Fever typically occurs in lymphoid malignancies
    in which these cytokines are released.

29
  • Anemia may be mediated by TNF, thrombocytoses by
    IL-6.
  • Cachexia is mediated by TNF and IFN?.
  • Bone reabsorbtion and hypercalcaemia are induced
    by IL-1.

30
  • Cytokines as tumor markers
  • IL-6 levels are elevated in a significant
    proportion of patients with myeloma and correlate
    broadly with disease activity, proliferation
    index, and survival.
  • Patients with monoclonal gammapathies of
    undetermined significance (MGUS) generally have
    normal or low levels of IL-6.

31
  • In Hodgkins disease and non-Hodgins lymphoma,
    there is a correlation between symptoms of fever
    and malaise and IL-6 level.
  • Elevated concentrations of the soluble IL-2
    receptor (sIL-2R) have been found in a number of
    malignancies of the lymphoid system and the
    leukemias.

32
  • In children with acute lymphoid leukemia, raised
    levels predict relapse and correlate with
    survival.
  • The use of sIL-2R measurements will have a place
    in the management of the hematological
    malignancies.

33
  • TNF expression or protein production has been
    demonstrated in many cancer cell lines and
    biopsies.
  • Serum TNF and sTNFR levels are raised in a wide
    range of malignancies.
  • Their measurement may be useful in follow-up
    studies.

34
  • A high proportion of patients with hematological
    malignancies have raised levels of M-CSF.
  • M-CSF is a tumor marker for ovarian cancer.
  • There is great interest in the use of M-CSF
    together with CA125 as an index of therapy in the
    ovarian cancer.

35
  • A number of the growth factors, such as the IGFs,
    PDGF, and the TGFs, show raised serum
    concentratons in various cancers.
  • Serum TGFa levels is raised in breast cancer,
    hepatocellular cancer.
  • The TGFa urinary levels are raised in head and
    neck cancer.

36
  • Clincal significance
  • Rheumatoid arthritis
  • It is a systemic inflammatory disease in joints
    and other tissues.
  • The disease is initiated, in a genetically
    predisposed individual, by activation of helper T
    cells responding to some arthritogenic agent,
    possibly a microbe.

37
  • Activated CD4 cells produce a number of
    cytokines that have two principal effects
  • Activation of macrophages and other cells in the
    joint space, which release tissue-destructive
    enzymes and other factors that perpetuate
    inflammation, and
  • Activation of the B-cell system, resulting in the
    production of antibodies, some of which are
    directed against self-constituents.

38
  • The resultant auto-immune reactions damage the
    joints and are believed to play an important role
    in disease progression.
  • The rheumatoid synovium is embarassingly rich in
    both lymphocye and monocytes desired cytokines.

39
  • The activity of these cytokines can account for
    many features of rheumatoid synovitis.
  • IL-1 and TGF-ß, cause proliferation of synovial
    cells and fibroblasts.
  • They also stimulate synovial cells and
    chondrocytes to secrete proteolytic and
    matrix-degrading enzymes.

40
  • In RA, a role for IL-15, secreted by activated T
    cells and macrophages, seems prominent.
  • TNF, IL-1, IL-6, IL-15, interferon-?, and growth
    factors (GM-CSF, TGF-ß) as well as proteases and
    elastases released by leukocytes and
    synoviocytes.
  • TNF-a and IL-1 upregulate expression of adhesion
    molecules by endothelial cells, resulting in the
    accumulation of white cells in the inflammed
    synovium.

41
  • Cartilage destruction, both at the interface with
    the pannus and distant from it, is further
    enhanced by IL-1 and TNF-a as these cytokines
    also stimulate the chondrocytes to produce more
    degradative enzymes and inhibit their synthesis
    of reparative proteoglycans.
  • There is a sustained, irreversible cartilage
    destruction.

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  • Septic shock
  • Shock or cardiovascular collapse is the final
    common pathway for a number of potentially lethal
    clinical events, including severe hemorrhage,
    extensive trauma or burns, large myocardial
    infarction, massive pulmonary embolism and
    microbial sepsis.
  • Shock constitutes systemic hypoperfusion due to
    reduction either in cardiac output or in the
    effective circulating blood volume.

44
  • The end results are hypotension, followed by
    impaired tissue perfusion and cellular hypoxia.
  • The mononuclear phagocytes respond to
    lipopolysaccharides (LPS) by producing TNF, which
    in turn induces IL-1 synthesis.

45
  • TNF and IL-1 both act on endothelial cells to
    produce further cytokines (e.g., IL-6 and IL-8),
    as well as induce adhesion molecules.
  • Thus, the initial release of LPS results in a
    circumscribed cytokine cascade intended to
    enhance the local acute inflammatory response and
    improve clearance of the infection.

46
  • With moderately severe infections, and therefore
    with higher levels of LPS ( and a consequent
    augmentation of the cytokine cascade ),
    cytokine-induced secondary effectors ( e.g.,
    nitric oxide and platelet-activating factor )
    become significant.
  • In addition, systemic effects of TNF and IL-1 may
    begin to be seen, including fever and increased
    synthesis of acute-phase reactants.

47
  • Tuberculosis
  • Tuberculosis is a communicable chronic
    granulomatous disease caused by mycobacterium
    tuberculosis.
  • It usually involves the lungs but may affect any
    organ or tissue in the body.
  • Typically, the centre of tubercular granulomas
    undergo caseous necrosis.

48
  • The sequence of events following an initial lung
    infection are
  • Antigen from the tubercle bacillus reaches
    draining lymph nodes and is presented to T cells.
  • CD4 cells of the THI type are sensitized
    and recirculate to the site of infection.
  • Critical in this initial generation of
    sensitized THI cells is elaboration of IL-12 by
    the macrophages.

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  • (ii) Sensitized CD4 cells release cytokines when
    exposed to antigen at the site of infection.
  • (iii) Monocytes are recruited and activated
    (particularly by ?-interferon from the CD4
    cells) to kill or inhibit the growth of the
    organism.

51
  • (iv) In response to cytokines and possibly the
    constituents of the cell wall of the bacillus,
    some of the activated macrophages form
    granulomas, which may subsequently entrap the
    residual microorganisms.
  • (v) CD4 helper T cells also facilitate the
    development of CD8 cytotoxic T cells, which can
    not only kill tuberculosis-infected macrophages
    but also produce IFN-?.

52
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