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Role of Cytokines in Vaccinology

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Title: Role of Cytokines in Vaccinology


1
Lecture No. 13. March 30, 2004 Role of
Cytokines in Vaccinology Amelia Woolums
2
Role of Cytokines in Vaccinology
  • Amelia R. Woolums, DVM PhD
  • Diplomate, ACVM
  • Diplomate, ACVIM
  • University of Georgia, Athens GA 30602

3
Introduction
  • Variety of cytokines impact immune response
  • Complex interactions determine outcome of
    infection
  • Vaccination can influence cytokine profile and
    outcome of immune response

4
Outline
  • Brief review cytokines in response to infection
  • Influence of vaccination on cytokines
  • Adjuvants
  • Use of cytokines as adjuvants

5
Cytokines and acquired response to infection
  • Intracellular pathogens
  • Viruses, intracellular bacteria and parasites
  • Extracellular pathogens
  • Bacteria, parasites, fungi

6
Immune response tointracellular pathogens
  • Block infection with neutralizing antibody
  • IgG, IgA
  • Activate macrophages
  • Increase killing of phagocytized pathogens
  • Increase MHC II expression
  • Induce development of TH1 cells

7
Immune response to intracellular pathogens
  • Induce activation of TH1 cells
  • Activate macrophages
  • Activate TH1 and CTLs
  • Induce activation of CTLs
  • Kill infected targets
  • Cytokine production

8
Immune response to intracellular pathogens
  • In summary, want strong TH1 response
  • Some TH2 for mucosal antibody

9
Response to intracellular pathogens--cytokines
  • Cytokines derived primarily from macrophages or
    other APC
  • IL-12 NK and T cell activation
  • TH1 differentiation
  • suppresses IL-4
  • IL-1b T and B cells activation
  • macrophage, endothelial activation

10
Response to intracellular pathogens--cytokines
  • Cytokines derived primarily from macrophages
  • IL-6 T and B cell expansion
  • plasma cell maturation
  • IgA synthesis (with IL-5)
  • acute phase response
  • TNF-a macrophage, endothelial activation

11
Response to intracellular pathogens--cytokines
  • Cytokines derived primarily from TH1 cells
  • IFN-g macrophage activation
  • B cell class switching IgG2
  • NK, T cell IFN-g production
  • T cell IL-2 and IL-2R expression
  • decreases IL-4 production

12
Response to intracellular pathogens--cytokines
  • Cytokines derived primarily from TH1 cells
  • IL-2 T, B, and NK cell activation
  • TNF-b (LT-a) macrophage activation
  • decreased antibody production

13
Response to intracellular pathogens--cytokines
  • Cytokine derived from other cell types
  • IL-15 produced in many tissues
  • expansion and activation of
  • NK cells
  • CD 8 T cells
  • gd intraepithelial lymphocytes (IEL)

14
  • Summary, cytokines specifically important in
    response to intracellular pathogens
  • IL-12
  • IL-18
  • IFN-g
  • IL-2
  • IL-15

15
Immune response to extracellular pathogens
  • Opsonizing and complement-fixing antibody
  • IgM, IgG
  • Neutralizing antibody
  • IgG, IgA

16
Immune response to extracellular pathogens
  • Want appropriate B cell response
  • TH2 response to induce class switching, affinity
    maturation

17
Response to extracellular pathogens--cytokines
  • Cytokines derived primarily from TH2 cells
  • IL-4 B cell clonal expansion
  • class switching, IgG1 and IgE
  • TH2 differentiation
  • inhibits TH1 activity
  • IL-5 eosinophil expansion
  • IgA and IgE production (species vary)

18
Extracellular pathogens, cont.
  • Cytokines derived primarily from TH2 cells
  • IL-10 suppresses macrophage activation
  • suppresses NK, TH1 activity
  • TGF-b suppresses TH1 activity
  • can suppress or activate macrophages

19
  • Summary, cytokines specifically important in TH2
    responses, antibody production
  • IL-4
  • IL-5
  • IL-6

20
Janeway, 1999
21
Janeway, 1999
22
Other cytokines relevant to vaccinology
  • GM-CSF
  • produced by TH1, TH2, macrophages
  • expansion of bone marrow-derived cells
  • granulocytes neutrophils, eosinophils, basophils
  • monocytes/macrophages
  • granulocyte and macrophage activation

23
Other cytokines relevant to vaccinology
  • IL-3
  • produced by TH1 and TH2 cells
  • effects similar to GM-CSF
  • acts synergistically with GM-CSF

24
Vaccination and cytokines
  • Effect of vaccination on immune response is in
    part through cytokines
  • MANY studies in mice
  • Genetic background may influence results
  • BALBc TH2 bias
  • C57BL/6 TH1 bias

25
Vaccination and cytokines
  • Fewer studies in humans, domestic animals
  • Results in mice not always duplicated in natural
    hosts
  • More research needed in natural hosts

26
MLV vs. inactivated vaccines
  • Viral pathogens MLV generally induce stronger
    CMI with some antibody
  • Killed high levels of antibody, little CMI
  • Antigen presentation pathway involved
  • Exogenous vs. endogenous
  • Cytokines also involved

27
MLV viral vaccines
  • MLV vaccines
  • Infect cells internal processing, MHC I
    presentation
  • Activation of CD8 cells
  • CD8 cytokines
  • IFN-g, IL-2 likely help drive TH1

28
MLV viral vaccines
  • Role of other cells in response to MLV?
  • NK cell activation IFN-g could drive TH1
  • Macrophage involvement through ADCC, uptake of
    opsonized virus
  • IL-12 and TH1 induction

29
NK activation? IFN-g production?
Better CMI (with TH1 bias likely) in response to
MLV viral vaccines
Presentation on MHC I
CD8 activation, IFN-g, IL-2 production
Virus-infected cells
IL-12 production by macrophages?
30
Inactivated viral vaccines
  • Antibody response with poor CMI typical
  • (adjuvants can change this)
  • Exogenous uptake by phagocytes
  • Presentation primarily via MHC II
  • Activation of CD4 with no activation of CD8
  • TH2 bias results

31
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32
RSV example, MLV vs. inactivated
  • Influence of MLV vs. inactivated studied
    thoroughly in context of RSV infection
  • Paramyxovirus
  • Leading cause of respiratory disease in infants
  • Very similar to BRSV in cattle
  • Formalin-inactivated vaccine serious
    vaccine-enhanced disease in children

33
RSV example, MLV vs. inactivated
  • In mouse models, FI-RSV or viral subunit
    vaccination
  • Increased IL-4, IL-5
  • Decreased IFN-g
  • Live virus vaccination
  • Increased IFN-g
  • Decreased IL-4, IL-5

34
RSV example, MLV vs. inactivated
  • Calves vaccinated with FI-BRSV produced less
    IFN-g than calves vaccinated with MLV or calves
    not vaccinated

35
RSV example, MLV vs. inactivated
  • Evidence in several models that inactivated RSV
    or BRSV induces relative TH2 bias
  • May be relevant to other viral pathogens
  • Relevance to MLV vs. inactivated bacterial
    vaccines unclear

36
Adjuvants and cytokines
  • Adjuvants can strongly influence response to
    vaccination
  • Some adjuvants can induce strong CMI to
    inactivated pathogens
  • Nature of adjuvant and impact on cytokine
    responses important

37
Alum and cytokines
  • Aluminum salts (including alum)
  • Used for decades
  • Still only adjuvant approved for humans in US
  • Induce strong TH2 responses
  • Early IL-4 production key
  • IL-4 KO mice have TH1 response to alum!
  • (Brewer, 1997)

38
Alum and cytokines
  • Role of inflammation in adjuvant effect of alum?
  • Alum OVA, IL-6 KO or TNFR-1 KO mice
  • normal to increased TH1 and TH2 cytokines
  • IL-6 and TNF-a inhibit response to alum

39
Alum and cytokines
  • In sheep, efferent lymph contained no IFN-g,
    IL-1b, or TNF-a following alum Taenia ag.
  • Confirms work in mice
  • TH2 bias
  • Proinflammatory cytokines not key to response to
    alum (Brewer, 1998)

40
Freunds adjuvant and cytokines
  • CFA potent CMI, but severe adverse reactions
  • Only used experimentally, and less recently
  • IFA (w/o) weaker CMI, but less reactive

41
Freunds adjuvant and cytokines
  • In mice increased IFN-g, little or no IL-4, IL-5
    and IL-10 to OVA CFA
  • Expected response strong TH1 bias
  • IL-12 KO mice decreased IFN-g, slightly
    increased IL-4 in response to CFA
  • IL-12 induction key to IFN-g response to CFA

42
Freunds adjuvant and cytokines
  • Role of proinflammatory cytokines
  • IL-6 and TNFR-1 KO mice
  • GREATER TH1 and IgG2 responses to CFA
  • Suggests these cytokines actually inhibit TH1
    response to CFA (Brewer, 1998)

43
Freunds adjuvant and cytokines
  • Role of proinflammatory cytokines, cont.
  • Studies in rabbits suggest IL-1 not required for
    adjuvant effects of CFA

44
Freunds adjuvant and cytokines
  • In sheep, IFA Taenia ag
  • Increased IFN-g in efferent lymph in 1/3
  • Weaker TH1 than expected with CFA
  • No increase TNF-a, IL-1b
  • Increased GM-CSF in 2/3 (Rothel, 1998)
  • In humans, IFA melanoma peptide
  • Increased IFN-g response to antigen

45
Freunds adjuvant and cytokines
  • Various models suggest proinflammatory cytokines
    (IL-1, TNF-a, IL-6) NOT critical for effect of
    Freunds adjuvant
  • Counter to classical understanding that
    inflammation leads to adjuvant effect
  • Induction of IL-12 and IFN-g is important

46
Oil/water emulsions and cytokines
  • Very common adjuvants in vet med
  • Many in human clinical trials
  • Little information re cytokines
  • MF59 approved in human influenza vaccine in
    Europe
  • Induced TH2 responses in BALBc mice

47
Saponins and cytokines
  • Saponins extracted from bark of tree (Q.
    saponaria)
  • Quil A commonly used in vet med
  • More purified forms in human clinical trials
  • Toxicity can be limiting
  • Decrease dose by combining with other adjuvants

48
Saponins and cytokines
  • In mice, induce TH1,TH2 cytokines, CTL
  • Quil A Taenia ag in sheep
  • Increased IFN-g in efferent lymph in 3/3
  • Both IgG1 and IgG2 increased
  • No clear effect due to IFN-g, unlike mice
  • Increased IL-8 but not IL-1b or TNF-a

  • (Rothel, 1998)

49
Saponins and cytokines
  • SBAS2 QS 21 MPL in oil/water
  • Increased IFN-g (and antibody titers) in human
    malaria trial
  • Significant local reaction
  • May be limited to therepeutic vaccines
  • (Moingeon, 2001)

50
ISCOMS and cytokines
  • ISCOMS purified saponin phospholipids/cholester
    ol antigen
  • Decreases toxicity of saponin
  • Maintains or improves immunogenicity
  • In mice, induce TH1 and TH2, good CTL
  • Can be given by mucosal route

51
ISCOMS and cytokines
  • ISCOMS induce influx and activation of
    neutrophils, dendritic cells, macrophages, mast
    cells, and lymphocytes
  • BUT IL-6 and iNOS KO mice had normal responses
    to ISCOMS
  • Proinflammatory activity not necessary

52
ISCOMS and cytokines
  • In contrast, adjuvant effect significantly
    decreased in IL-12 KO mice
  • However, IFN-g KO mice had normal response to
    ISCOMS!
  • IL-12 is critical for ISCOM effect, but through
    mechanisms other than IFN-g induction
  • (Smith et
    al, 1999)

53
ISCOMS and cytokines
  • In sheep, matrix without antigen increased IL-6
    and IFN-g in efferent lymph
  • Unusual effect of adjuvant without antigen to
    stimulate immunity
  • ISCOMs may uniquely induce lymphocyte and APC
    recruitment (Sjolander, 2001)

54
ISCOMS and cytokines
  • In primate models, ISCOMs induce IL-4, IL-2, and
    IFN-g to co-administered antigen
  • In human clinical trials, improved CTL activity
    to influenza subunits

  • (Sjolander, 2001)

55
ISCOMS and cytokines
  • Results from mouse studies comparable to other
    animal, human trials
  • Balance of TH1 and TH2 cytokines make saponin and
    ISCOMs attractive
  • Induction of IL-12 key to response to ISCOMS

56
Other adjuvants
  • Monophosphoryl lipid A (MPL)
  • Improves TH1 response in adjuvant mixtures
  • Nontoxic mutants of cholera toxin (CT), E. coli
    heat labile toxin (LT)
  • CT strong TH2 LT more TH1
  • Chimeric molecules can have balance of both

57
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59
Cytokines as adjuvants
  • Cytokines used experimentally as adjuvants since
    1980s
  • Much research has focused on immunotherapy or
    therapeutic vaccination for neoplasia
  • Results mixed, but many promising results
  • Will not discuss today

60
Cytokines as adjuvants
  • Problems
  • Toxicity or adverse reactions
  • Local targeting can help
  • Short half-life
  • Delayed-release carriers or DNA vectors
    expressing cytokine can help
  • Often species specific
  • Expense may limit veterinary applications

61
Cytokines as adjuvants
  • MANY mouse studies
  • IL-1b, IL-2, IL-6, IFN-g, GM-CSF, and IL-12 most
    often tested
  • Usually have expected effects
  • TH2 strong antibody, poor CMI
  • TH1 strong CMI, with increased antibody over
    antigen alone

62
Cytokines as adjuvants
  • In calves, IL-1b once or IL-2 five times improved
    in vitro responses to BHV-1/PI3 vaccination
  • Some effect on temperature but not clinical
    scores post challenge
  • (Reddy et al,
    1993)
  • Multiple dose IL-2 requirement not practical
  • Lack of clear effect on clinical signs

63
Cytokines as adjuvants
  • In cattle, BHV-1 subunit IL-1b improved mucosal
    IgA and resistance to challenge over subunit
    alone (Gao, 1995)
  • In sheep, IL-1b improved response to some
    parasite vaccines, enhanced disease after others
  • (Lofthouse, 1996)

64
Cytokines as adjuvants
  • Ruminant IL-1b can sometimes enhance response to
    vaccines
  • Lack of clear and consistent clinical benefit may
    not justify expense of recombinant cytokines
  • Adverse effects and inconsistent results seemed
    to limit human applications

65
Cytokines as adjuvants
  • BHV-1 expressing bo IFN-g
  • Clinical signs similar to wt virus
  • No effect on in vitro IFN-g production
  • Stable following reactivation
  • Value as vaccine not evaluated

  • (Raggo, 2000)

66
Cytokines as adjuvants
  • IL-12
  • Focus of recent research
  • In human clinical trials of cancer vaccines
  • Mixed results, but research ongoing

67
Cytokines as adjuvants
  • In goats, vaccinia expressing ca IL-12 vaccinia
    expressing CAEV protein
  • No effect on IgG isotypes
  • Increased IFN-g, IL-4 by lymphocytes in vitro
  • No change in IFN-g/IL-4

  • (Cheevers, 2000)
  • No clear TH1 bias in vitro
  • Effect of vaccine on challenge not tested

68
Cytokines as adjuvants
  • In cats, vaccination with DNA encoding FIV gp140
    fe IL-12
  • Complete resistance to challenge in 3/4 cats,
    compared to 0/4 controls
  • Both IL-10 and IFN-g expression increased
    relative to controls
  • No clear-cut TH1 bias (Leutenegger, 2000)

69
Cytokines as adjuvants
  • In outbred species, in vitro response to IL-12 as
    adjuvant may not show strong TH1 bias
  • In vitro correlate of protection unclear

70
Cytokines as adjuvants
  • GM-CSF
  • Ongoing research in human vaccine trials
  • Good results, therapeutic vaccine for Leishmania
    some cancer vaccines

71
Cytokines as adjuvants
  • In sheep, DNA vaccine expressing GM-CSF
    Echinococcus ag
  • Higher antibody titers than vaccine expressing
    IFN-g, IL-4, or IL-15
  • Other cytokines no clear effect on antibody or
    lymphocyte proliferation
  • No clear TH1 or TH2 bias due to IFN-g, IL-4

72
Cytokines as adjuvants
  • Compared to protein subunit, GM-CSF increased
    IgG1/IgG2
  • IL-4 also gave high IgG1/IgG2
  • Similar to mice (TH2 high IgG1)
  • IFN-g had no effect on IgG1/IgG2
  • Protection against challenge not measured
  • (Scheerlinck, 2001)

73
Cytokines as adjuvants
  • Cytokines in avian vaccines
  • Recent work in chickens
  • Variety of cytokines show promise
  • As adjuvants
  • As therapeutics
  • (Min et al,2002 Hilton et al, 2002)

74
Cytokines as adjuvants, summary
  • MUCH research in mice
  • Much less in domestic mammals, humans
  • In vitro responses in outbred species often do
    not parallel results seen in mice

75
Role of cytokines in vaccinology, summary
  • In vitro correlates of protection vary for
    different diseases, species
  • In vitro correlates do not always predict
    response to challenge

76
Role of cytokines in vaccinology, summary
  • Optimum interplay of vaccine, adjuvant, and
    cytokine expression should be evaluated
    independently for each host, disease
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