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.

8

• 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.

9
(No Transcript)
10

• 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.

11
(No Transcript)
12
(No Transcript)
13

• 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.

14
(No Transcript)
15

• 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.

27
(No Transcript)
28

• 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.

42
(No Transcript)
43

• 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.

49
(No Transcript)
50

• (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
THANK YOU