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Cytokine Therapy

ANTONY CUTLER AND FRANK BROMBACHER

University of Cape Town, Health Science Faculty, Institute for Infectious Disease and Molecular Medicine (IIDMM), Cape Town, South Africa

ABSTRACT: Cytokines are a unique class of intercellular regulatory proteins that play a crucial role in initiating, maintaining, and regulating immunologic homeostatic and inflammatory processes. Indeed, measurement of cytokine profiles in patients provides a useful indication of disease status. Due to their multiple functions, including regulatory and effector cellular function in many diseases, these molecules, their receptors, and their signal transduction path- ways are promising candidates for therapeutic interference. The therapeutic administration of cytokines, modulation of cytokine action, or at times gene therapy is being used for a wide range of infectious and autoimmune diseases, in immunocompromised patients with AIDS, and in neoplasia.

KEYWORDS: interleukin; monoclonal antibody; autovaccination; inflammation

INTRODUCTION

Cytokines are not produced constitutively. Indeed, cytokines are usually pro- duced upon stimulation and are secreted by a variety of cell types, and distinct cy- tokines often have redundant or overlapping functions. They are extremely potent biomolecules acting at a picomolar, sometimes femtomolar range and may have mul- tiple (pleiotropic) actions on different target cells. Cytokine released by a cell may act in a short radius on its own (autocrine) or on other cells (paracrine), thus provid- ing a means for cross-talk at the cellular level (FIG. 1). Common structural features of interleukins make it possible to group cytokines within “families,” and tremendous progress in the cloning of genes for cytokine re- ceptors and their characterization has led to the recognition that cytokine receptors may be grouped into four principal families based on common structural features. Most of these receptors form heterodimers, but some form homodimers or heterot- rimers. Interestingly, many of the multiple chain receptors form subfamilies with one chain shared by all members of the subfamily. Due to their multiple functions, in- cluding regulatory and effector function in many diseases, these molecules, their re- ceptors, and their signal transduction pathways are promising candidates for therapeutic interference. Advances in the understanding of the role of cytokines in immune and inflamma- tory disorders have led to the development of cytokine-based therapies. Therapies

Address for correspondence: Frank Brombacher, Institute for Infectious Disease and Molecu- lar Medicine, University of Cape Town, S1. 27, Observatory 7925, Anzio Road, South Africa. Voice: +27-21-406-6616\6147; fax: +27-21-406-6029.

brombac@uctgsh1.uct.ac.za

Ann. N.Y. Acad. Sci. 1056: 16–29 (2005). © 2005 New York Academy of Sciences. doi: 10.1196/annals.1352.002

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CUTLER & BROMBACHER: CYTOKINE THERAPY

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CUTLER & BROMBACHER: CYTOKINE THERAPY 17 FIGURE 1. Functional roles of cytokines. have been developed with

FIGURE 1. Functional roles of cytokines.

have been developed with the express aim to block/inhibit or restore the activity of specific cytokines. A variety of approaches have been employed to produce thera- peutics with the aim of manipulating cytokine function. Cytokines have been cloned and produced in recombinant form; coupled to toxin, recombinant cytokine and receptor molecules have been fused to the Fc portion of human IgG1 or to albumin to stabilize and increase the serum half-life of the protein. Natural and synthetic antagonist proteins have been cloned/produced to interfere with ligand/receptor interaction. Cytokines delivered by gene therapy and antisense oligonucleotide treat- ment are also being assessed. Currently, the most utilized approach to cytokine ther- apy is that of blocking or neutralizing cytokine action with monoclonal antibodies (mAbs) (TABLE 1a and b). Mouse mAbs with specificity for human cytokines have been “humanized” by grafting the mouse CDR onto the Fc portion of the human IgG1. Fully human anticytokine mAbs have now been approved for clinical use (TABLE 1a). Drugs that block inflammatory cytokines, such as tumor necrosis factor (TNF)- α, are among the most successful therapeutics approved for clinical use. 13 Of pa- tients with rheumatoid arthritis (RA), 60–70% exhibit amelioration of disease upon treatment with anti-TNF-α. Fusion proteins of sTNF receptor 4 and interleukin (IL)- 1Rα antagonist 5 are also routinely used in the treatment of RA. It has become appar- ent that TNF blockers are more efficient than therapies aimed at IL-1 antagonism or blocking. The scope of therapy using TNF-α and IL-1 blockers/antagonists is now evolving to target other inflammatory diseases. Targeting inflammatory cytokines has been a fruitful approach in treating inflammatory autoimmune disease. This suc- cess has led to the development of mAbs targeting a number of cytokines/cytokine

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ANNALS NEW YORK ACADEMY OF SCIENCES

TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial

 

Clinical

 

Trade name/

trial phase/

Ref/

Cytokine

Drug

code

Application

outcome

Company

Link

IL-1Rα

Recombinant

Kineret /

Rheumatoid arthri-

Approved

Amgen

5

IL-1Rα

Anakinra

tis (RA)

antagonist

Sepsis

Approved

 

Osteoarthritis

Phase II

IL-2

Recombinant

Proleukin

Metastatic renal cell carcinoma Metastatic mela- noma Non-Hodgkin’s lym- phoma

Approved

Chiron

6

IL-2

 
 

Approved

Phase II

IL-2

Humanized

Daclizamab

Renal transplanta-

Licensed

PDL/

IL-2Rα-chain

tion

Roche

blocking mAb

Asthma

Phase II

 

GvHD

Phase III

[1]

Multiple sclerosis

Phase II

38

HIV

Phase I

[2]

Psoriasis

Phase I/II

[3]

Ulcerative uveitis

Halted

[4]

 

Humanized

Simulect /

Renal transplanta-

Licensed

Novartis

39

IL-2Rα-chain

Basiliximab

tion

blocking mAb

IL-11

Recombinant

Oprelvekin /

Chemotherapy-

Approved

Genetics

34

IL-11

Neumega

induced thrombo-

Institute,

 

cytopenia

Inc/

Crohn’s disease

Phase III

Wyeth

RA

Phase II

Psoriasis

Phase II

Colitis

Phase I

TNF-α

Human anti-

Adali-

RA Juvenile RA Ankylosing spondylitis Psoriatic arthritis Crohn’s disease Chronic plaque pso- riasis

Approved

CAT/

3

TNF-α mAb

mumab/

Phase II

Abbott

 

Humira/

Phase III

D2E7

 

Phase III

Phase III

Phase II

TNF-α

Humanized

Remicade

RA

Approved

Centocor

1, 2

anti-TNFα

/Infliximab

Crohn’s disease

Approved

mAb

Ulcerative colitis

Phase II

 

Psoriasis

Phase II

Psoriatic arthritis

Phase II

Ankylosing

Phase II

spondylitis

Juvenile idiopathic

Phase II

arthritis

Pediatric Crohn’s

Phase II

disease

CUTLER & BROMBACHER: CYTOKINE THERAPY

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TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial

 

Clinical

 

Trade name/

trial phase/

Ref/

Cytokine

Drug

code

Application

outcome

Company

Link

TNF-α

Soluble p75

Etanercept/

RA

Approved

Amgen

4

TNF recep-

Enbrel

Juvenile RA

Approved

tor-Fc

Ankylosing

Approved

fusion

spondylitis

 

Psoriatic arthritis

Approved

Psoriasis

Approved

Severe plaque

Approved

psoriasis

IFN-γ

Bioengi-

Actimmune Chronic granuloma- tous disease Osteoporosis Idiopathic pulmo- nary fibrosis Ovarian cancer

Approved

Inter-

12

neered IFN-γ−

mune

1b

Approved

Pharma

40

 

Phase III

Phase III

IFN-α

IFN-α−con-1

Infergen

Hepatitis C

Approved Intermune

9

 

Pharma

IFN-α

IFN-α−n3 leu-

Alferon-N

HPV gental warts Hepatitis C West Nile virus HIV

Approved

Hemi

10

kocyte derived

Phase II/III

sperx

 

Phase II/III

Bio-

Phase I/II

pharma

IFN-α

Pegylated

Pegasys

Chronic hepatitis C Hepatitis B

Approved

Roche

IFN-α−2a

Phase III/

8

 

Filed

IFN-α

Recombinant

Roferon-A

Hairy cell leukemia Kaposi’s sarcoma Chronic myleloid leukemia Chronic hepatitis C

Approved

Roche

7

IFN-α−2a

Approved

 

Approved

Approved

IFN-α

Recombinant

Intron-A

Hairy cell leukemia Kaposi’s sarcoma

Approved

Schering-

7

IFN-α−2b

Approved

Plough

 

Chronic hepatitis B/

Approved

C

Malignant mela-

Approved

noma

Follicular lymphoma

Approved

Condylomata acumi-

Approved

nata

IFN-α

PEG recombi-

PEG Intron

Hepatitis C

Approved

Schering-

nant IFN-α−

Malignant mela-

Phase III

Plough

2b

noma

IFN-β

IFN-β−1a

Avonex

Relapsing multiple

Approved

Biogen

13

 

sclerosis

Idec

IFN-β

IFN-β−1a

Rebiferon

Relapsing multiple sclerosis Chronic hepatitis C

Approved

Serono

13

 

Phase III

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ANNALS NEW YORK ACADEMY OF SCIENCES

TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial

 

Clinical

 

Trade name/

trial phase/

Ref/

Cytokine

Drug

code

Application

outcome

Company

Link

IFN-β

IFN-β−1b

Betaseron

Early/relapsing

Approved

Berlex

13

 

multiple sclerosis

GM-CSF

Recombinant

Leukine/Sar-

Leukemia

Approved

Schering-

GM-CSF

gramostim

Bone marrow/stem

Approved

AG

 

cell transplants

Crohn’s disease

Phase III

[1]http://www.clinicaltrials.gov/show/NCT00053976 (GvHD). [2] http://www.clinicaltrials.gov/ct/show/NCT00080431?order=5. [3] http://www.clinicaltrials.gov/ct/show/NCT00050661?order=10. [4] http://www.pdl.com/applications/press_releases.cfm?newsId=241.

receptors, such as IL-6, IL-8, IL-18, and gamma interferon (IFN-γ) (TABLE 1b) in a variety of clinical conditions. Another approach to cytokine therapy that has been applied successfully is treat- ment using recombinant cytokines. IL-2 has been used in cancer, 6,7 various deriva- tives of IFN-α in viral infection and cancer, 810 IL-11 in the treatment of post- chemotherapy induced thrombocytopenia, 11 IFN-γ in cancer and osteoporosis, 12 and IFN-β in multiple sclerosis 13 (TABLE 1a). Therapy using recombinant cytokines has also been unsuccessful in some cases. Recombinant IL-10 provided no beneficial therapy over side effects in a number of settings (TABLE 1b). However, this potent immunosuppressive cytokine may yet have some therapeutic application. 14 Recom- binant IL-12 can also induce adverse side effects. 15

AUTOVACCINATION AS A STRATEGY IN CYTOKINE THERAPY

Vaccination against autologous cytokines opens novel possibilities for therapy of chronic diseases resulting from excessive production of a particular factor. Tolerance against self-antigens can be overcome by physical association of foreign proteins to self-antigen. This concept was first validated for hormones such as bovine luteiniz- ing hormone 16 and human chorionic gonadotropin 17 and subsequently extended to cytokines. 1820 Recently, the Van Snick group chemically coupled mouse IL-9 and IL-12 to ovalbumin (Ova) that produced very immunogenic complexes, leading to complete inhibition of cytokine function in immunized mice. 21 Important for poten- tial cytokine therapy was our finding, in collaboration with Van Snick’s group, that IL-9–vaccinated mice showed increased resistance to cutaneous leishmaniasis, 22 and IL-12–vaccinated mice were protected against experimental autoimmune encephalomyelitis (EAE), 23 as summarized in TABLE 2. Similar results have also been reported after immunization with mouse TNF-α proteins fused to an Ova helper sequence 19 or with a DNA vaccine comprising a tetanus toxoid sequence inserted in IL-5 coding DNA. 24 The latter experiments showed clear inhibition of some patho- logic hallmarks of arthritis and asthma, respectively.

CUTLER & BROMBACHER: CYTOKINE THERAPY

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TABLE 1b. Cytokine therapies in clinical trial

Clinical trial

 

Trade name/

phase/

Ref/

Cytokine

Drug

code

Application

outcome

Company

link

IL-1

Blocking mAb

AMG-108

Osteoarthritis

Phase II

Amgen

[1]

IL-1

IL-1 type 1R / receptor acces- sory protein Fc fusion

IL-1 TRAP

RA

Phase II

Regeneron

[2]

IL-2

Adenoviral-IL-

TG-1024

Renal cell carci-

Phase I/II

Transgene

[3]

2

noma Soft tissue sar- coma Melanoma Head + neck cancer

Phase I/II

 

Phase I/II

Phase I/II

IL-2

MVA-MUC1-

TG-4010

Kidney/prostate/

Phase II

Transgene

[4]

IL-2

lung cancers

IL-2

MVA-HPV-IL2

TG-4001

Cerivcal cancer

Phase II

Transgene

[5]

IL-2

Humanized IL- 2 receptor β- chain blocking mAb

MIKβ1

Large granular

Pre-phase I

NCI

[6]

lymphocytic

leukemia

IL-4/13

Recombinant

IL-4/13 trap

HIV

Phase I

Regeneron

41

IL-4Rα /

Asthma

Phase I

IL-13Rα1 Fc

fusion

IL-4

IL-4 coupled to Pseudomonas exotoxin

IL-4PE

Malignant

Phase II

Neurocrine

42

NBI-3001

glioma

Phase I

Bioscience

Kidney/Lung

 

cancers

IL-4/13 IL-4Rα antago- nist

Bay 16-9996

Asthma

Trial halted

Bayer

[7]

IL-4

Humanized

SB240683

Asthma

Trial halted

PDL/GSK

[8]

anti-IL4 mAb

Phase IIa

IL-5

Humanized

SCH-55700

Asthma/Allergy

Phase II

Celltech/

43

anti-IL-5

Schering-

 

Plough

IL-5

Humanized

Mepolizumab

Asthma

Phase II

GSK

[9]

Anti-IL-5

Hypereosino-

Phase III

44

 

philic syndrome

Atopic dermati-

Phase II

tis

IL-6

Recombinant

Atexakin

Peripheral neur-

Phase II/

Serono

IL-6

opathy

halted?

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ANNALS NEW YORK ACADEMY OF SCIENCES

TABLE 1b. Cytokine therapies in clinical trial

 

Clinical trial

 

Trade name/

phase/

Ref/

Cytokine

Drug

code

Application

outcome

Company

link

IL-6

Humanized

MRA

Crohn’s disease

Phase II

Chugai Phar-

45

anti-IL-6 recep-

SLE

Phase I

maceuticals/

tor

RA

Phase III

Roche

 

Myeloma

Phase I/II

Systemic onset

Phase II/III

juvenile idio-

pathic arthritis

IL-8

Anti-IL-8 mAb

ABX-IL-8

RA

Trials halted; no therapeu- tic value in Phase II

Abgenix

 

Psoriasis

 

[10]

COPD

 

IL-8

IL-8 antagonist

656933

COPD

Phase I

GSK

IL-9

Anti-IL-9 mAb

IL-9mAb

Asthma

Phase I

Genaera /

 

Medimmune

IL-10

Recombinant

Ilodecakin /

Psoriasis Psoriatic arthri- tis Crohn’s disease Bile duct dis- eases Biliary tract diseases Gallbladder diseases Pancreatitis Pancreatic diseases HIV RA Ulcerative colitis

Phase II/

Schering-

14

IL-10

Tenovil

halted

Plough

 

Phase II/

halted

Phase II/

halted

Phase II/

halted

Phase II/

halted

Phase II/

halted

Phase II/

halted

Phase II/

halted

Phase II/

 

halted

Phase III/

halted

Phase III

IL-12

Human anti-IL-

ABT874/

Crohn’s disease

Phase II

Abbott/CAT [11]

12

J695

Multiple sclero-

Phase II

 

sis

IL-12

Recombinant

rIL-12

Asthma

Phase I/

15,

IL-12

Non-Hodgkin’s/

halted

46

 

Hodgkin’s lym-

Phase II

phoma

CUTLER & BROMBACHER: CYTOKINE THERAPY

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TABLE 1b. Cytokine therapies in clinical trial

 

Clinical trial

 

Trade name/

phase/

Ref/

Cytokine

Drug

code

Application

outcome

Company

link

IL-13

Human anti-IL-

CAT 354

Asthma

Phase I

CAT

[13]

13

IL-13

IL-13 coupled

IL-13-

Glioblastoma

Phase I/II

Neopharm

47

to truncated

PE38QQR

multiforme

Pseudomonas

endotoxin A

IL-13

Anti-IL-13

IL-13 receptor

Asthma

Preclinical

Amrad/

[14]

receptor α1

α 1

Merck

IL-15

Humanized

Humax IL-15

RA

Phase II

Genmab/

48

anti-IL-15

/AMG-714

Amgen

IL-18

Recombinant

Tadeking-α

RA

Phase IIa

Serono

[15]

IL-18 binding

Psoriasis

Phase II

protein

IL-18

Recombinant

485232 Immunologi- cally sensitive target mela- noma + renal carcinoma Lymphoma

Phase II

GSK

[16]

human IL-18

 

immuno-

modulator

 

Phase I

IL-21

Recombinant

494C10

Metastatic mela- noma Renal cell carci- noma

Phase I

NCI/

[17]

IL-21

Phase I

Zymogenet-

 

ics

TNFα

Pegylated trun- sTNFR1 / peg-

RA

Phase II

Amgen

[18]

cated soluble TNF p55 type I receptor

sunercept

TGFβ1

Oligo-

AP11014

Lung/colon/

Preclinical

Antisense

antisense

prostate cancer

Pharma

TGFβ1

Human anti-

CAT-192 /

Systemic sclero-

Phase I

CAT/Gen-

[19]

TGF-β1 mAb

metelimumab

sis

Phase II

zyme

 

Scleroderma

TGF-β2

Human anti-

CAT-152 /

Glaucoma

Phase II/III

CAT

[20]

TGFβ2 mAb

Trabio

surgery

TGF-β2 Oligo-antisense

-

Noncurable non- small cell lung cancer

Phase II

NovaRx

49

24

ANNALS NEW YORK ACADEMY OF SCIENCES

TABLE 1b. Cytokine therapies in clinical trial

 

Clinical trial

 

Trade name/

phase/

Ref/

Cytokine

Drug

code

Application

outcome

Company

link

TGF-β2 Oligo-antisense

AP12009

High grade

Phase IIb

Antisense

[20]

 

glioma

Phase I

Pharma

pancreatic can-

Phase I

cer

malignant mela-

noma

TGF-β

Human anti-

GC-1008

Idiopathic pul-

Preclinical

CAT/Gen-

TGF-β

monary fibrosis

zyme

IFN-γ

Humanized

HuZAF/fon-

Crohn’s disease

Phase I/II

PDL

50

anti-IFN-γ mAb

tolizumab

IFN-γ

Adenoviral

TG1042

Cutaneous B-

Phase I

Transgene

51

IFN-γ

cell lymphoma

 

Cutaneous T-cell

Phase I/II

lymphoma

[1] http://www.amgen.com/rnd/pipeline.html [2] http://www.hopkins-arthritis.som.jhmi.edu/edu/eular2004/ra-treatments-il1.html [3] http://www.transgene.fr/us/product_pipeline/iframe_ad_il2.htm [4] http://www.transgene.fr/us/page.php?fam=1&rub=3&iframe=product_pipeline/

iframe_mva_muc1_il2.htm

[5] http://www.transgene.fr/us/page.php?fam=1&rub=2&iframe=product_pipeline/

iframe_mva_hpv_il2.htm

[6] http://www.clinicaltrials.gov/ct/show/NCT00076180 [7] Preclinical Evaluation of Bay 16-9996 a Dual Il-4/Il-13 Receptor Antagonist N. Fitch, M. Morton, A. Bowden, M.-C. Shanafelt, A. Shanafelt, G. Wetzel, J. Moy Biotechnology Research, Bayer Corp, Berkeley, CA. Abstract J.A.C.I 107: 2 section 209 [8] http://www.pdl.com/applications/press_releases.cfm?newsId=68 [9] http://www.gsk.com/financial/product_pipeline/docs/pipeline.pdf [10] http://www.abgenix.com/ProductDevelopment/?view=DevelopmentStrategy [11] http://www.cambridgeantibody.com/html/technology_products/product_pipeline/

abt874

inflammatory_disorders [12] http://www.nci.nih.gov/search/ViewClinicalTrials.aspx?cdrid=67489&ver-

sion=patient&protocolsearchid=1344505

[13] http://www.cambridgeantibody.com/html/technology_products/product_pipeline/cat354 [14] http://www.amrad.com.au/Files/IL-13a1%20-%20Aug%202004.pdf [15] www.serono.com/pipeline/pipeline.jsp?major=2 - 35k - 28 Dec 2004 [16] http://www.clinicaltrials.gov/ct/gui/show/NCT00085904 [17] http://www.zymogenetics.com/clinical/il-21.html [18] http://www.clinicaltrials.gov/ct/show/NCT00037700?order=1 [19] http://www.clinicaltrials.gov/ct/show/NCT00043706 [20] http://www.cambridgeantibody.com/html/technology_products/product_pipeline/trabio treatment_for_scarring_following_glaucoma_surgery [21] http://www.antisense-pharma.com/products/f_products.htm

Useful links: http://www.phrma.org/newmedicines/resources/2004-10-25.145.pdf http://imgt.cines.fr/textes/IMGTrepertoire/GenesClinical/monoclonalantibodies/other.html

CUTLER & BROMBACHER: CYTOKINE THERAPY

TABLE 2. Auto vaccination

25

Cytokine

Inhibition titer a

Disease

Effect

Interleukin-9

3–5 × 10 -4b Approx. 2 × 10 -3

Leishmaniasis

Delayed 22

Interleukin-12

EAE

Protection 23

a Fifty percent inhibition of cytokine-dependent inhibition by sera dilution. b Depending on the mouse strain used.

TARGETING IL-4/IL-13 IN ALLERGY AND ASTHMA

Allergies are reproducible reactions of the immune system against stimuli, which are tolerated by most people. Most allergies are mediated by Th2-dependent immune mechanisms. These are characterized by very fast responses towards the antigen, typically within minutes, with most or all of the Th2 cytokines (i.e., IL-4, IL-5, IL- 9, and IL-13) possibly involved in the disease phenotype, therefore being potential targets for cytokine therapy against allergic diseases (FIG. 2). After initial contact with the allergen (sensitization phase), symptoms are felt within minutes (effector phase) in immediate type (type 1) allergies. This type includes common reactions such as hay fever, some food allergies, and allergies against house dust mites, animal hair, and insect stings, among others. Allergic asthma is a complex disorder charac- terized by local and systemic allergic inflammation associated with a chronic pul- monary eosinophilia and elevated serum IgE levels causing mast cell activation, airway remodeling, and reversible airway obstruction. Asthma symptoms, especially shortness of breath, are primarily related to airway obstruction, and death is almost invariably due to asphyxiation. Increased airway hyperresponsiveness (AHR) and mucus hypersecretion by goblet cells are two of the principal causes of airway obstruction observed in asthmatic patients. IL-4 is known to be the central promoter of Th2 development in vivo and in vitro. However, recent studies by us and others have challenged a sole in vivo role of IL-4 in Th2 differentiation, as in the absence of IL-4 or its receptor, Th2 differentiation was still present. 25 Despite these observa- tions, the importance of IL-4 in allergic reactions has been confirmed in experimen- tal murine models, mostly using OVA as the allergen. Indeed, in the absence of IL- 4–mediated functions, either by in vivo blocking of IL-4 or its receptor or by genet- ically disrupting the gene, OVA-sensitized and challenged mice showed reduced AHR, eosinophilic inflammation, IgE production, and mastocytosis. 2630 Much conflicting data have been gathered on the role of IL-5 in allergic asthma, despite its clear role as a differentiation factor for eosinophils, 3133 with rather disappointing results in clinical studies in asthma targeting IL-5. 34 Monoclonal antibodies specific for IL-9 are now being used in phase I clinical trials in asthma. The possible role of IL-13 had remained elusive until 1998 when we and others demonstrated that IL-13 is a key factor in the asthmatic phenotype, able to directly induce goblet cell hyper- plasia and AHR in mice 35,36 (FIG. 2). These results prompted discussions about IL- 13 as a promising target for anti-asthmatic therapies, resulting in three drug leads now in clinical phase I trials (TABLE 1b). My group is currently involved in the establishment of several cell-type–specific knockout mouse models to further define the role of IL-4 and IL-13 in infectious and allergic diseases (TABLE 3).

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ANNALS NEW YORK ACADEMY OF SCIENCES

26 ANNALS NEW YORK ACADEMY OF SCIENCES FIGURE 2. Proposed allergic asthma model. Role of Th2

FIGURE 2. Proposed allergic asthma model. Role of Th2 cells, effector cells, and cytokine network in the pathogenicity of asthma. Thp, parental T helper cell; Th2, T helper 2 cell; B, B lymphocyte; E, eosinophil; G, goblet cell; M, mast cell; APC, antigen presenting cell.

TABLE 3. Interleukin-4R cell-specific knockout mice

Cell type

Strategy

Status

Macrophage/neutrophil Il- 4Rα KO

LysM Cre T × Il-4Rα flox/flox

Herbert et al. 2004

T-cell Il-4Rα KO

Ick Cre T × IL-4Rα flox/flox

Ms in preparation

T-cell Il-4Rα KO

CD4 Cre T × IL-4Rα flox/flox

In characterization

Smooth muscle cell Il-4Rα KO

SM-MHC Cre T × IL-4Rα flox/

In characterization

flox

Endothelial cell Il-4Rα KO

FABPi Cre × IL-4Rα flox/flox

In characterization

Goblet cell Il-4Rα KO

Breeding

T-cell Il-4Rα reconstitution

hIL-4RαT × IL-4Rα -/-

Seki et al. 2004

CUTLER & BROMBACHER: CYTOKINE THERAPY

FUTURE PERSPECTIVES

27

The therapeutic potential of targeting specific inflammatory cytokines with known function in RA has demonstrated the legitimacy of targeting cytokines as a means of ameliorating disease. Success in targeting cytokines in inflammation has opened a new approach to the treatment of inflammatory disease, and more mAbs specific for inflammatory cytokines such as IL-6 may be used in the clinic. Cytokine therapy has and will be successful when disease-causing mechanisms are relatively “simple” and cytokine driven. However, given the pleiotropic and redundant nature of cytokines, this will be hard to achieve in complex disease states. Perhaps a future direction in complex disorders may be the simultaneous inactivation/activation of multiple cytokines, such as simultaneous inactivation of IL-4, IL-5, IL-9, and IL- 13 in asthma. The use of interference RNA may achieve such a goal given the recent advances by Soutchek et al. 37 in delivery of iRNA.

ACKNOWLEDGMENTS

This work was supported in part by the Medical Research Council (MRC) and National Research Foundation (NRF) of South Africa. F.B. is a holder of a Wellcome Trust Research Senior Fellowship for Medical Science in South Africa (Grant

056708/Z/99).

REFERENCES

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