il 4 in tb vaksin

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IL-4 in tuberculosis: implications for

vaccine designGraham A.W. Rook1, Rogelio Hernandez-Pando2, Keertan Dheda1 andGeok Teng Seah3

1Centre for Infectious Diseases and International Health, Windeyer Institute for Medical Sciences, Royal Free and

University College Medical School, 46 Cleveland Street, London, UK, W1T 4JF2Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga 15, Tlalpan 14000, Mexico City, Mexico3Department of Microbiology, National University of Singapore MD4, 5 Science Drive 2, Singapore, 117597

Current attempts to find a vaccine for tuberculosis (TB)are based on the assumption that it must drive a Th1

response. We review the evidence that progressive dis-

ease might not be due to absence of Th1, but rather to

the subversive effect of an unusual Th2-like response,

involving interleukin-4 (IL-4) and IL-4d2. This Th2-like

response can impair bactericidal function and lead to

toxicity of tumour necrosis factor-a(TNF-a) and to pul-

monary fibrosis. If this is important, effective vaccines

will need to suppress pre-existing Th2-like activity.

Such vaccines are feasible and are active therapeutically

in mouse TB.

Immunity to tuberculosis (TB) in mice is mediated by Th1lymphocytes. These cells activate macrophages, increase

release of tumour necrosis factor-a (TNF-a)and enhance

formation of cytotoxic T lymphocytes (CTLs)[1]. The same

cytokines are crucial in humans. Children with defective

receptors for interferon-g (IFN-g) or interleukin-12 (IL-12)

are susceptible to mycobacterial disease[2,3]and TB can

be activated when patients are treated with neutralising

antibodies to TNF-a [4]. However, rapid induction of an

IFN-gresponse to antigens ofMycobacterium tuberculosis

is an almost universal consequence of exposure to the

infection[5].Why then, in some individuals, is the disease

not controlled? Here we review the possibility that

Th2-like or regulatory mechanisms undermine the efficacyof the protective response.

Inappropriate cytokine release in human TB

Before the year 2000, some authors reported that, in

addition to Th1 cytokines, there was also increased expres-

sion of IL-4 in TB [6,7].However, other authors failed to

detect raised IL-4 and the issue remained controversial [8].

New data indicate that these earlier failures are attribu-

table to a series of technical problems (outlined inBox 1).

Now, there is therefore a substantial body of evidence that,

in addition to Th1 cytokines, there is an IL-4 response in

human TB, whether the patients are in Europe[9,10]or

in Africa [11,12], although a survey of the literature

(G.A.W. Rooket al., unpublished) suggests that IL-4 levels

could be higher in patients close to the equator, possibly asa consequence of simultaneous infection with helminths

[13]. For instance, before bacillus Calmette Guerin (BCG)

vaccination, more healthy Malawians than UK adoles-

cents made IL-5 in response to purified protein derivative

(PPD). There was a tendency for greater IL-5 production

with increasing numbers of helminth infections in the

Malawians (G.F. Blacket al., pers. commun.). TB patients

have several IL-4-dependent phenomena, including IgE

antibody to M. tuberculosis [14], increased expression of

DC-specific intercellular adhesion molecule (ICAM)-grab-

bing non-integrin (DC-SIGN) [15,16], and antibody to

cardiolipin [17]. Similarly, both IL-4 mRNA, and T cells

containing IL-4, are increased in human pulmonary TB,and correlate significantly with serum IgE, serum soluble

CD30 and the extent of cavitation [911,18]. Interestingly,

CD8 T cells also make IL-4 in TB[10,19], and CD8 cells

secreting IL-4 correlated with cavitation in the work of van

Crevel et al. [10]. IL-4 expression can also be detected in

some pulmonary lesions byin situ hybridisation[20].

Source and significance of IL-4 in TB

A variety of different cell types can make IL-4 [T cells,

eosinophils, basophils, mast cells, natural killer (NK) cells

and some antigen-presenting cells (APCs)]. Attention has

been focused recently on the neglected observation that

IL-4 can be involved in driving Th1 responses [21] and

CTLs [22]. This can be IL-4 administered externally orIL-4 from CD11bCD11clo APCs, which are present at an

early stage of Th1 response induction[23]. IL-4 present at

later stages downregulates Th1 responses [21], and this

must be happening in TB, where at least some of the Th2

cytokines are coming from T cells[10,19].

Box 1. Why is assay of interleukin-4 (IL-4) so difficult?

(i)Thelow concentrations andlowmRNAcopynumbersat whichIL-4

is active [59]

(ii) Short half-lifeof mRNA encoding IL-4 in clinical samples (anhour

or less) [60]

(iii) The existence of a splice variant of IL-4, which lacks exon 2 [61]

(Box 2)(iv) Pre-stimulation of cells causes secretion of interferon-g (IFN-g)

and rapidreciprocal downregulation of Th2-cellproliferation,further

depleting an already low copy number cytokine (IL-4)Corresponding author:Graham A.W. Rook ([email protected]).Available online 26 June 2004

Review TRENDS in Immunology Vol.25 No.9 September 2004

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A further possibility is that IL-4 in TB has a necessary

regulatory or anti-inflammatory role. Under some circum-

stances, regulatory T cells express IL-4 in addition to

classical regulatory cytokines, such as IL-10 and trans-

forming growth factor-b (TGF-b) [24]. However, the

evidence is against this role for IL-4. In progressive

disease, IL-4 causes increased, rather than diminished,

immunopathology [25]. The presence of specific IgE

antibody [14] and of T cells that release IL-4 in vitrowhen driven by TB antigen [11] indicates a genuine

antigen-specific Th2 lymphocyte response.

Nevertheless, the increased IL-4 expression in TB is

different from that seen in the partly Th2-mediated

disorder, allergic asthma [26]. In the latter disease, the

increase is mostly due to IL-4 itself, rather than to the

splice variant. By contrast, in TB patients, levels of mRNA

encoding IL-4d2, an inhibitory splice variant, were found

to rise as well [26] (Box 2). Therefore, we refer to this smallIL-4 component in TB as Th2-like.

Bovine TB

Infection of cattle with Mycobacterium bovis (a strain

derived from the human M. tuberculosis) generates both

IFN-g and IL-4 responsiveness to PPD and to ESAT-6

(early secreted antigenic target-6 kDa)[27]. Similarly, the

extent of lung pathology correlates with the production of

IL-4 by peripheral blood mononuclear cells in vitro in

response to PPD [28]. Interestingly, when cattle were

immunised with a DNA vaccine, and then 3 weeks and

6 weeks later, vaccinated again with the protein encoded

by the DNA vaccine emulsified in oil, they were moresusceptible than non-immunised controls. This increased

susceptibility correlated with an increased IL-4 response

to subsequent challenge[28].

Mouse models

Because the increased expression of IL-4 in human

(and bovine) TB is no longer in dispute, the relevant

mouse models are those in which, as in humans, IL-4

production is observed during the progressive phase of the

disease. Studies of Th1 and Th2 cytokine expression reveal

that in some, but not all, murine models of TB there are at

first high IFN-g levels, followed later, in the progressive

phase, by a superimposed IL-4 response [29,30]. Confusion

about this point arose from the study of the effects of IL-4

gene knockout in mouse strains C57Bl 129SvJ[31]and

C57Bl[32], in which IL-4 secretion is not characteristic of

the infection. These are elegant studies, however, C57Bl

mice develop progressively increasing lung granulomas

and eventually drown in Th1 cells, without the switch to

Th2 cytokine production that is seen in Balb/c mice and,

albeit to a lesser extent, in humans.

The Th2 response is cause rather than effect

Is the IL-4 response in TB an irrelevant consequence of

the infection, or is it significantly involved in reducing

protection and increasing immunopathology? Simple

experiments where mice were pre-immunised, so that

they had small Th2 responses to one or several components

of M. tuberculosis before infection, have shown thatpre-existing Th2 activity leads to increased severity of

infection and to death[33,34]. Wangooet al. demonstrated

that a pre-existing Th2 response to a single 16 amino

acid epitope expressed within the challenge strain of

M. tuberculosis was sufficient to undermine the efficacy of

the dominant Th1 response, and to aggravate weight loss

and lung fibrosis[35].Further studies in Balb/c mice with

knocked outIL-4genes proved that the absence of IL-4 led

to diminished bacterial growth, and confirmed that IL-4 is

directly involved in TNF-a-mediated immunopathology

and fibrosis in this strain [25] (see later). Interestingly,

although other authors have not studied IL-4 knockout

Balb/c mice, it was found that STAT6 (signal transducerand activator of transcription 6) knockout Balb/c respond

normally to aerosol infection with M. tuberculosis [36].

This implies that the relevant functions of IL-4 (fibrosis

and enhanced toxicity of TNF-a) might be signaled

through insulin receptor substrate-2 (IRS-2) or IRS-1

rather than via STAT6[37].

Fibrosis is a major cause of lung dysfunction in TB

Fibrosis in TB is a major cause of permanent respiratory

dysfunction, however, it has never been satisfactorily

explained. The dominant cytokine in TB, IFN-g, opposes

fibrosis in humans and in mice [38]. Interestingly, in

human diseases characterised by pulmonary fibrosis,

there is usually marked expression of type 2 cytokines

[systemic sclerosis, idiopathic pulmonary fibrosis, radiation-

induced pulmonary fibrosis, chronic lung allograft rejec-

tion (reviewed in Ref. [38])]. These observations have led to

the type 2 cytokine hypothesis of fibrosis [38]. Fibrosis

in human TB might therefore be related to the presence

of the Th2-like response (Figure 1). Interestingly, pul-

monary fibrosis in systemic sclerosis is associated with

CD8 cells secreting IL-4 and IL-4d2 [39], reminiscent of the

CD8cells expressing either IL-4 or IL-4d2 noted previously

in human TB[10,19].

TNF-a is a crucial protective molecule but it is toxic in TB

when IL-4 is presentTNF-a-mediated immunopathology is the other phenom-

enon associated with IL-4 in the mouse models. In IL-4

gene knockout tuberculous Balb/c mice, there is not only

Box 2. Interleukin-4d2 (IL-4d2): a neglected cytokine

IL-4d2 is a splice variant of IL-4 that lacks exon 2 (48 base pairs)

[61,62]

IL-4d2 mRNA isfoundin primates,rabbitsand woodchucks butnot

in rats or mice [63]

Recombinant IL-4d2 functions asa natural antagonist of IL-4[61,62]

Final proof that the IL-4d2 protein is produced in vivohas not yet

been obtained

Because antibodies used in flow cytometry or ELISA assays can

bind either, or both, existing work on IL-4 in humans using these

assays could be uninterpretable

IL-4d2 is easily distinguished by RT PCR [64], however, most

published work uses primers that will amplify both cytokines

IL-4d2 might be the dominant form of IL-4 mRNA in human lungs,

and associated with fibrosis [39]. Possibly an agonist on fibroblasts

IL-4d2 rises little in atopic asthma, in which mRNA encoding IL-4itself rises 1000x more [26]

IL-4d2 mRNA does rise to a variableextent intuberculosis [9]and in

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diminished bacterial proliferation, but also a complete

absence of TNF-a-mediated toxicity following TNF-a

challenge[25]. This observation can explain the paradox-

ical role of TNF-a in TB. TNF-a is crucial for protection

against TB in animals [40] and in humans [4]. Never-

theless, in progressive human disease, as in progressive

TB in the Balb/c mouse [25], itis toxic (Figure 1), and drugs

that shorten the half-life of the mRNA encoding TNF-a

lead to weight gain and symptomatic relief[41]. Because

IL-4 levels are raised in progressive human disease, it islikely that, as in mice, IL-4 is involved in the toxicity of

TNF-a. Examples of interactions between IL-4 and TNF-a

in other diseases, and possible mechanisms for pro-

inflammatory interactions between these cytokines, are

described inBox 3.

Most existing prophylactic TB vaccine candidates fail as

therapeutic vaccines

Most known vaccine candidates (i.e. effective as prophy-

lactic vaccines in mice) are ineffective as therapeutic

vaccines[42,43]. This is also true of BCG and of various

preparations ofM. tuberculosis itself[43]. The history of

this observation goes back to Robert Koch, who observednecrosis in tuberculous guinea-pigs given injections of

Old Tuberculin (the Koch Phenomenon), and then

repeated the experiment, with the same result, in humans

(reviewed in Ref.[44]). The role of TNF-ain the immuno-

pathology triggered by BCG in tuberculous mice was

highlighted again recently[43].

Vaccines that downregulate IL-4 are active

therapeutically in murine TB

Interestingly, there are two preparations that are excep-

tions to the rule that protective vaccines are not thera-

peutic. One is a DNA vaccine based on heat-shock

protein 65 (hsp65) of Mycobacterium leprae, which, incontrast to a different construct used in an aerosol

model [45], will treat ongoing TB after intravenous

infection, and while doing so, dramatically reduces IL-4

ELISPOT T-cell numbers[46]. In the same experiment, a

BCG vaccine run in parallel neither treated the disease

nor reduced IL-4 production [46]. The other exception,

heat killed Mycobacterium vaccae, is also active as an

immunotherapeutic in mice, in which it strikingly reduces

IL-4 expression when administered 60 days after intra-

pulmonary infection[30]. Its major mode of action is not

the induction of Th1, but rather, suppression of Th2 by

driving CD4CD45RBlow regulatory T cells [47]. Thus,

although these are only correlations, effective therapy

might relate to downregulation of IL-4 (Figure 1).

Efficacy of BCG vaccine varies in different geographicalareas

BCG vaccine is a deletional mutant ofM. bovisderived by

repeated in vitro culture. Like M. bovis itself [27], BCG

primes not only Th1 but also IL-4 responses both in cattle

[48] and in mice [49]. Most workers fail to notice this

induction of IL-4, because it is far weaker that the

concomitant induction of IFN-g, and as discussed earlier,

more difficult to measure. Moreover, we do not know if

BCG induces an IL-4 response in humans, but it is likely to

because peripheral blood mononuclear cells from healthy

BCG-vaccinated donors release IL-4 in response to anti-

gens ofM. tuberculosis[50]. Not only does BCG not down-

regulate Th2 responses in murine TB[46], but BCG itselfevokes IL-4-secreting cells[49].

If this IL-4 component to the response evoked by BCG is

detrimental, then one would expect the efficacy of BCG to

Figure 1. The roles of the subversive Th2-like component of the immune response

in progressive human tuberculosis. This might be primed by bacillus Calmette

Guerin (BCG) vaccination or by environmental mycobacteria but it is then

enhanced following exposure to Mycobacterium tuberculosis. A vaccine, even

if prophylactic, might need to eliminate any pre-existing Th2 component.

Abbreviations: IL-4, interleukin-4; TNF-a, tumour necrosis factor-a.

TRENDS in Immunology

Th1

(IL- 42)

BCG?

M. tuberculosis

Environmental

mycobacteria

IL-5IL-13IL-4

Th2-like

PROPHYLACTICVACCINE

THERAPEUTIC

VACCINE

APOPTOSIS

FIBROSIS

IMMUNOPATHOLOGY

(+TNF-)

BACTERIAL

PROLIFERATION

FAILEDTh1-MEDIATED

IMMUNITY

Box 3. Interleukin-4 (IL-4), decreased immunity and

increased immunopathology in tuberculosis (TB)

There are several reasons why immunity to TB might be particularly

susceptible to detrimental effects of IL-4, even when Th1 cytokines,

such as interferon-g, dominate.

Further examples of immunopathology attributable to Th11 Th2 1

tumour necrosis factor-a(TNF-a)

In Trichinella spiralis infection, immunopathology in the gut is

attributable to TNF-ain a mixed Th1 Th2 response. No immuno-

pathology in IL-4 knockout mice [65]

The mixed Th1/Th2 granulomata of Schistosomiasis are exqui-

sitely sensitive to systemic cytokine release triggered by lipopoly-

saccharide (LPS) [66,67]

Possible mechanisms of increased toxicity of TNF-a in mixed

Th1 1 Th2 lesions

Induction of cortisol-resistance in T cells exposed simultaneously

to Th1 and Th2 cytokines [68]

Synergistic induction of vascular cell adhesion molecule-1(VCAM-1) on endothelial cells leading to increased recruitment of

inflammatory cells [69]

Downregulation of TRAF-2 (TNF receptor-associated factor-2)

biases functions of TNF-a away from activation and towards cell

death, which was observed in CD30 T cells incubated with TB

antigen [50]

Why is expression of IL-4 detrimental to immunity to TB?

Inappropriate type of macrophage activation [57]

Decreased expression of, and signalling through, Toll-like receptor 2

(TLR2) [56]

Downregulated inducible nitric oxide synthase (iNOS) [55];

iNOS might be fundamental to the induction and maintenance of

latency [70]

Review TRENDS in Immunology Vol.25 No.9 September 2004 485



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be variable, particularly in areas close to the equator [51]

where the Th2 response to M. tuberculosis is likely to be

particularly high[13].Similarly, repeat BCG vaccination

might be hazardous in the same environments because it

might boost the IL-4, rather than the IFN-g? component.

Repeat BCG vaccination of cattle reduced the protective

efficacy of a single vaccination, and the effects of repeat

vaccination in humans are variable, as reviewed in a paper

on cattle[48].

IL-4 and IL-4d2 in contacts of TB patients

Is expression of IL-4, or of the potential antagonist IL-4d2,

increased in latent TB, and if so, how does this differ from

what happens in those in whom the disease progresses?

Recent studies have focused on healthy individuals in

The Gambia and Ethiopia, whose peripheral blood mono-

nuclear cells give IFN-g responses to the TB-specific

antigen, ESAT-6. These people have latent TB and it hasemerged that they have significantly raised levels of

mRNA encoding IL-4d2 in their unstimulated peripheral

blood mononuclear cells [52,53]. In The Gambia, expres-

sion of IL-4 is also increased [53]. These findings fuel

speculation that the balance of the agonist (IL-4) and

potential antagonist (IL-4d2) might be relevant to whether

or not the disease progresses, and current studies are

addressing this question. Crucial questions include whether

IL-4d2 is present only as mRNA or also active protein, and

which cell types are expressing these mRNAs in the

latently infected contacts [52]. These experiments are

currently in progress. Meanwhile, a study of healthcare

workers in Portugal has revealed that those individualswhose peripheral blood mononuclear cells synthesised

IL-4 in response to M. tuberculosis in vitro went on to

develop overt TB within 2 4 years [54]. The methods used,

however, will not have distinguished between IL-4 and

IL-4d2. Further work will be required to discover whether it

is high IL-4, rather than IL-4d2, that predisposes to disease.

Conclusions

A Th1 response to M. tuberculosis develops rapidly fol-

lowing exposure and diagnostic methods detect this Th1

activity [5]. Why, then, does the disease progress? And why

do the Th1-inducing vaccine candidates that have been

tried as therapeutic vaccines cause necrosis and make the

disease worse? We have reviewed evidence that the Th1

response fails because a smaller Th2 response (IL-4, parti-

ally opposed by the antagonist, IL-4d2) is undermining its

efficacy and driving immunopathology in synergy with

TNF-a. We have also considered the more conventional

views of the role of IL-4 in TB, which are that it is needed to

drive CTLs, that it has a useful anti-inflammatory role, or

that it is merely a late consequence of progressive disease.

We have shown that recent findings make all of these

views very difficult to sustain.

IL-4, with its ability to downregulate inducible nitric

oxide synthase (iNOS) [55], Toll-like receptor 2 (TLR2) [56]

and macrophage activation [57], is potentially an early

player in the events that determine whether the infectionbecomes latent or progressive. Recent studies of contacts

with latent disease [52], and of healthcare workers who

subsequently developed the disease[53,54], lend support

to this possibility. Now that we can distinguish IL-4 from

the antagonist IL-4d2, the role of IL-4 can be more pre-

cisely delineated. If this role is important, effective vac-

cines against TB might need to concentrate on elimination

of the IL-4 response, rather than on boosting the Th1

response, which develops spontaneously as a consequence

of infection (Figure 1). This principle might be equally

applicable to pre-exposure vaccines, post-exposure vac-

cines and therapeutic vaccines, because in each case a pre-

existing IL-4 response will exist, whether induced by BCG

vaccination, exposure toM. tuberculosis or cross-reactive

organisms in the environment.

How might such vaccines be achieved? The components

ofM. tuberculosisresponsible for driving the IL-4-secreting

T cells could be identified. It has been shown, using IL-4

ELISPOTs, that ESAT-6 and peptides derived from it do

not do so[58]. The components that do drive IL-4 can be

identified by ELISPOT or by monitoring their ability to

drive expression of IL-4 mRNAin vitro. Such antigens are

present in crude sonicated M. tuberculosis [50]. IL-4-

driving components could be combined with adjuvants

capable of converting the response to Th1 or of driving a

regulatory T-cell response.

To be a pathogen, an organism can either fail to evoke

the protective response or it can drive the protective

mechanisms and then deliberately sabotage them. Recent

data suggest that this might be how M. tuberculosis ope-

rates. If this proves to be correct, radically new approaches

to vaccine design will be needed, and this train of thought

will deserve to be extended into the fields of HIV and

certain parasitic diseases.

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Immunology online

General information

An Immune System Glossary: http://www.molbiol.ox.ac.uk/pathology/tig/gloss.html AMADEO: Free Medical Literature Guide: http://www.amedeo.com/

Immunology Index: http://www.keratin.com/am/

Glossary of Immunology: http://www-micro.msb.le.ac.uk/MBChB/ImmGloss.html

Molecular Immunology: http://www.mi.interhealth.info/

Spiders and Immunology: http://www.xs4all.nl/~ednieuw/

Societies

British Society for Immunology: http://www.immunology.org/

American Academy of Allergy, Asthma and Immunology: http://www.aaaai.org/

Clinical Immunology Society: http://www.clinimmsoc.org/

Society for Mucosal Immunology: http://www.socmucimm.org/

Australasian Society for Immunology: http://www.wehi.edu.au/collegiate/ASI/

Canadian Society of Allergy and Clinical Immunology: http://csaci.medical.org/

International Society for Interferon and Cytokine Research: http://www.isicr.org/ Federation of Clinical Immunology Societies: http://www.focisnet.org/

Discussion groups:

BioWWW.net: http://biowww.net/

Nomenclature

CD: http://www.immunologylink.com/cdantigen1.htm

HLA: http://www.ebi.ac.uk/imgt/hla/

KIR: http://www.gene.ucl.ac.uk/nomenclature/genefamily/kir.html

http://www.ncbi.nlm.nih.gov/prow/guide/679664748_g.htm

LILR: http://www.gene.ucl.ac.uk/nomenclature/genefamily/lilr.html

Immunoglobulins

Immunoglobulin Structure/Function: http://www.path.cam.ac.uk/~mrc7/mikeimages.html

Porcine Immunology Resources: http://eis.bris.ac.uk/~lvkh/welpig.htm

If you know of any other useful online resources that you think should be featured in Trends in Immunologyplease let us know at

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