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 pathways 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 produced upon stimulation and are secreted by a variety of cell types, and distinct cytokines often have redundant or overlapping functions. They are extremely potent
biomolecules acting at a picomolar, sometimes femtomolar range and may have multiple (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 providing 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 receptors 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 heterotrimers. Interestingly, many of the multiple chain receptors form subfamilies with one
chain shared by all members of the subfamily. Due to their multiple functions, including regulatory and effector function in many diseases, these molecules, their receptors, and their signal transduction pathways are promising candidates for
therapeutic interference.
Advances in the understanding of the role of cytokines in immune and inflammatory disorders have led to the development of cytokine-based therapies. Therapies
Address for correspondence: Frank Brombacher, Institute for Infectious Disease and Molecular 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: 1629 (2005). 2005 New York Academy of Sciences.
doi: 10.1196/annals.1352.002
16

CUTLER & BROMBACHER: CYTOKINE THERAPY

17

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 therapeutics 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 treatment are also being assessed. Currently, the most utilized approach to cytokine therapy 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), are among the most successful therapeutics approved for clinical use.13 Of patients with rheumatoid arthritis (RA), 6070% exhibit amelioration of disease upon
treatment with anti-TNF-. Fusion proteins of sTNF receptor4 and interleukin (IL)1R antagonist5 are also routinely used in the treatment of RA. It has become apparent that TNF blockers are more efficient than therapies aimed at IL-1 antagonism or
blocking. The scope of therapy using TNF- 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 success has led to the development of mAbs targeting a number of cytokines/cytokine

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TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial
Clinical
trial phase/
Ref/
Trade name/
outcome Company Link
Cytokine
Drug
code
Application
IL-1R
Recombinant Kineret / Rheumatoid arthri- Approved Amgen
5
IL-1R
Anakinra
tis (RA)
antagonist
Sepsis
Approved
Osteoarthritis
Phase II
IL-2
Recombinant Proleukin Metastatic renal cell Approved Chiron
6
IL-2
carcinoma
Metastatic mela- Approved
noma
Non-Hodgkins lym- Phase II
phoma
IL-2
Humanized Daclizamab Renal transplanta- Licensed
PDL/
IL-2R-chain
tion
Roche
blocking mAb
Asthma
Phase II
[1]
GvHD
Phase III
38
Multiple sclerosis Phase II
[2]
HIV
Phase I
[3]
Psoriasis
Phase I/II
[4]
Ulcerative uveitis
Halted
Humanized Simulect / Renal transplanta- Licensed Novartis 39
IL-2R-chain Basiliximab
tion
blocking mAb
IL-11
Recombinant Oprelvekin / ChemotherapyApproved Genetics 34
IL-11
Neumega
induced thromboInstitute,
cytopenia
Inc/
Crohns disease
Phase III Wyeth
RA
Phase II
Psoriasis
Phase II
Colitis
Phase I
TNF-
Human antiAdaliRA
Approved CAT/
3
TNF- mAb
mumab/
Juvenile RA
Phase II Abbott
Humira/
Ankylosing
Phase III
D2E7
spondylitis
Psoriatic arthritis Phase III
Crohns disease
Phase III
Chronic plaque pso- Phase II
riasis
TNF-
Humanized
Remicade
RA
Approved Centocor 1, 2
anti-TNF /Infliximab
Crohns disease Approved
mAb
Ulcerative colitis
Phase II
Psoriasis
Phase II
Psoriatic arthritis
Phase II
Ankylosing
Phase II
spondylitis
Juvenile idiopathic Phase II
arthritis
Pediatric Crohns
Phase II
disease

CUTLER & BROMBACHER: CYTOKINE THERAPY

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TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial
Clinical
trial phase/
Ref/
Trade name/
outcome Company Link
Cytokine
Drug
code
Application
TNF-
Soluble p75
Etanercept/
RA
Approved Amgen
4
TNF recepEnbrel
Juvenile RA
Approved
tor-Fc
Ankylosing
Approved
fusion
spondylitis
Psoriatic arthritis Approved
Psoriasis
Approved
Severe plaque
Approved
psoriasis
IFN-
BioengiActimmune Chronic granuloma- Approved Inter12
neered IFN-
tous disease
mune
1b
Osteoporosis
Approved Pharma
40
Idiopathic pulmo- Phase III
nary fibrosis
Ovarian cancer
Phase III
IFN-
IFN-con-1 Infergen
Hepatitis C
Approved Intermune 9
Pharma
IFN-
IFN-n3 leu- Alferon-N HPV gental warts Approved Hemi
10
kocyte derived
Hepatitis C
Phase II/III sperx
West Nile virus Phase II/III BioHIV
Phase I/II pharma
IFN-
Pegylated
Pegasys
Chronic hepatitis C Approved Roche
8
IFN-2a
Hepatitis B
Phase III/
Filed
IFN-
Recombinant Roferon-A Hairy cell leukemia Approved Roche
7
IFN-2a
Kaposis sarcoma Approved
Chronic myleloid Approved
leukemia
Chronic hepatitis C Approved
IFN-
Recombinant Intron-A Hairy cell leukemia Approved Schering7
IFN-2b
Kaposis sarcoma Approved Plough
Chronic hepatitis B/ Approved
C
Malignant mela- Approved
noma
Follicular lymphoma Approved
Condylomata acumi- Approved
nata
IFN-
PEG recombi- PEG Intron
Hepatitis C
Approved Scheringnant IFN-
Malignant melaPhase III Plough
2b
noma
IFN-
IFN-1a
Avonex
Relapsing multiple Approved Biogen
13
sclerosis
Idec
IFN-
IFN-1a
Rebiferon Relapsing multiple Approved Serono
13
sclerosis
Chronic hepatitis C Phase III

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TABLE 1a. Cytokine therapies approved for clinical use and further clinical trial
Clinical
trial phase/
Ref/
Trade name/
outcome Company Link
Cytokine
Drug
code
Application
IFN-
IFN-1b
Betaseron
Early/relapsing
Approved Berlex
13
multiple sclerosis
GM-CSF Recombinant Leukine/SarLeukemia
Approved ScheringGM-CSF
gramostim Bone marrow/stem Approved
AG
cell transplants
Crohns 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-) (TABLE 1b) in a
variety of clinical conditions.
Another approach to cytokine therapy that has been applied successfully is treatment using recombinant cytokines. IL-2 has been used in cancer,6,7 various derivatives of IFN- in viral infection and cancer,810 IL-11 in the treatment of postchemotherapy induced thrombocytopenia,11 IFN- in cancer and osteoporosis,12 and
IFN- in multiple sclerosis13 (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 Recombinant 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 luteinizing hormone16 and human chorionic gonadotropin17 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 potential cytokine therapy was our finding, in collaboration with Van Snicks group, that
IL-9vaccinated mice showed increased resistance to cutaneous leishmaniasis,22
and IL-12vaccinated 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- proteins fused to an Ova helper
sequence19 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 pathologic hallmarks of arthritis and asthma, respectively.

CUTLER & BROMBACHER: CYTOKINE THERAPY

21

TABLE 1b. Cytokine therapies in clinical trial

Application

Clinical trial
phase/
outcome

Company

Ref/
link

Cytokine

Drug

Trade name/
code

IL-1

Blocking mAb

AMG-108

Osteoarthritis

Phase II

Amgen

[1]

IL-1

IL-1 type 1R /
receptor accessory protein Fc
fusion

IL-1 TRAP

RA

Phase II

Regeneron

[2]

IL-2

Adenoviral-IL2

TG-1024

Renal cell carcinoma

Soft tissue sarcoma
Melanoma
Head + neck
cancer

Phase I/II
Phase I/II
Phase I/II
Phase I/II

Transgene

[3]

IL-2

MVA-MUC1IL-2

TG-4010

Kidney/prostate/
lung cancers

Phase II

Transgene

[4]

IL-2

MVA-HPV-IL2

TG-4001

Cerivcal cancer

Phase II

Transgene

[5]

IL-2

Humanized IL2 receptor chain blocking

mAb

MIK1

NCI

[6]

IL-4/13

Recombinant
IL-4R /
IL-13R1 Fc
fusion

IL-4/13 trap

HIV
Asthma

Phase I
Phase I

Regeneron

41

IL-4

IL-4 coupled to
Pseudomonas
exotoxin

IL-4PE
NBI-3001

Malignant
glioma
Kidney/Lung
cancers

Phase II
Phase I

Neurocrine
Bioscience

42

Asthma

Trial halted

Bayer

[7]

Asthma

Trial halted
Phase IIa

PDL/GSK

[8]

Phase II

Celltech/
ScheringPlough

43

Asthma
Hypereosinophilic syndrome
Atopic dermatitis

Phase II
Phase III

GSK

[9]
44

Peripheral neuropathy

Phase II/
halted?

IL-4/13 IL-4R antago- Bay 16-9996

nist
IL-4

Humanized
anti-IL4 mAb

IL-5

Humanized
anti-IL-5

IL-5

Humanized
Anti-IL-5

IL-6

Recombinant
IL-6

SB240683

Large granular Pre-phase I

lymphocytic
leukemia

SCH-55700 Asthma/Allergy

Mepolizumab

Atexakin

Phase II
Serono

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TABLE 1b. Cytokine therapies in clinical trial

Trade name/
code

Cytokine

Drug

IL-6

Humanized
anti-IL-6 receptor

MRA

IL-8

Anti-IL-8 mAb

ABX-IL-8

Application

Clinical trial
phase/
outcome

Company

Ref/
link

Crohns disease Phase II Chugai Phar- 45

SLE
Phase I
maceuticals/
RA
Phase III
Roche
Myeloma
Phase I/II
Systemic onset Phase II/III
juvenile idiopathic arthritis
RA
Psoriasis
COPD

Trials halted;
no therapeutic value in
Phase II

Abgenix
[10]

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
IL-10

Ilodecakin /
Tenovil

Psoriasis
Psoriatic arthritis
Crohns disease
Bile duct diseases
Biliary tract
diseases
Gallbladder
diseases
Pancreatitis
Pancreatic
diseases
HIV
RA
Ulcerative
colitis

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 II/
halted
Phase III/
halted
Phase III

ScheringPlough

ABT874/
J695

Crohns disease
Multiple sclerosis

Phase II
Phase II

Abbott/CAT [11]

rIL-12

Asthma
Non-Hodgkins/
Hodgkins lymphoma

Phase I/
halted
Phase II

15,
46

IL-12 Human anti-IL12

IL-12

Recombinant
IL-12

14

CUTLER & BROMBACHER: CYTOKINE THERAPY

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TABLE 1b. Cytokine therapies in clinical trial

Application

Clinical trial
phase/
outcome

Company

Ref/
link

CAT 354

Asthma

Phase I

CAT

[13]

IL-13 coupled
to truncated
Pseudomonas
endotoxin A

IL-13PE38QQR

Glioblastoma
multiforme

Phase I/II

Neopharm

47

IL-13

Anti-IL-13
receptor 1

IL-13 receptor
1

Asthma

Preclinical

Amrad/
Merck

[14]

IL-15

Humanized
anti-IL-15

Humax IL-15
/AMG-714

RA

Phase II

Genmab/
Amgen

48

IL-18

Recombinant
IL-18 binding
protein

Tadeking-

RA
Psoriasis

Phase IIa
Phase II

Serono

[15]

IL-18

Recombinant
human IL-18
immunomodulator

485232

Immunologically sensitive
target melanoma + renal
carcinoma
Lymphoma

Phase II

GSK

[16]

Metastatic melanoma
Renal cell carcinoma

Phase I
Phase I

RA

Phase II

Amgen

Lung/colon/
prostate cancer

Preclinical

Antisense
Pharma

Phase I
Phase II

CAT/Genzyme

[19]

Trade name/
code

IL-13 Human anti-IL13

IL-13

Cytokine

IL-21

Drug

Recombinant
IL-21

494C10

TNF Pegylated trun- sTNFR1 / pegcated

sunercept
soluble TNF
p55 type I
receptor
TGF1

Oligoantisense

AP11014

TGF1

Human antiCAT-192 / Systemic scleroTGF-1 mAb metelimumab

sis
Scleroderma

TGF-2

Human antiTGF2 mAb

TGF-2 Oligo-antisense

Phase I
NCI/
[17]
Zymogenetics
[18]

CAT-152 /
Trabio

Glaucoma
surgery

Phase II/III

CAT

[20]

Noncurable nonsmall cell lung

cancer

Phase II

NovaRx

49

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TABLE 1b. Cytokine therapies in clinical trial

Cytokine

Drug

Trade name/
code

Application

Clinical trial
phase/
outcome

Company

TGF-2 Oligo-antisense

AP12009

High grade
glioma
pancreatic cancer
malignant melanoma

Phase IIb
Phase I
Phase I

Antisense
Pharma

TGF-

GC-1008

Idiopathic pul- Preclinical

monary fibrosis

CAT/Genzyme

IFN-
IFN-

Human antiTGF-

Humanized
HuZAF/fon- Crohns disease
anti-IFN- mAb tolizumab
Adenoviral
IFN-

TG1042

Phase I/II

Cutaneous BPhase I
cell lymphoma
Cutaneous T-cell Phase I/II
lymphoma

Ref/
link
[20]

PDL

50

Transgene

51

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

25

TABLE 2. Auto vaccination

Cytokine

Inhibition titera

Interleukin-9

35

Interleukin-12

Approx. 2 10-3

10-4b

aFifty percent inhibition of cytokine-dependent

bDepending on the mouse strain used.

Disease

Effect

Leishmaniasis

Delayed22

EAE

Protection23

inhibition by sera dilution.

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, IL9, 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 characterized by local and systemic allergic inflammation associated with a chronic pulmonary 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 observations, the importance of IL-4 in allergic reactions has been confirmed in experimental murine models, mostly using OVA as the allergen. Indeed, in the absence of IL4mediated functions, either by in vivo blocking of IL-4 or its receptor or by genetically 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 hyperplasia and AHR in mice35,36 (FIG . 2). These results prompted discussions about IL13 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-typespecific 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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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
Macrophage/neutrophil Il4R KO

Strategy
LysMCreT

Il-4Rflox/flox

Status
Herbert et al. 2004

T-cell Il-4R KO

IckCreT IL-4Rflox/flox

Ms in preparation

T-cell Il-4R KO

CD4CreT IL-4Rflox/flox

In characterization

SM-MHCCreT IL-4Rflox/

In characterization

FABPiCre IL-4Rflox/flox

In characterization

hIL-4RT IL-4R-/-

Seki et al. 2004

Smooth muscle cell

Il-4R KO
Endothelial cell Il-4R KO

flox

Goblet cell Il-4R KO

T-cell Il-4R reconstitution

Breeding

CUTLER & BROMBACHER: CYTOKINE THERAPY

27

FUTURE PERSPECTIVES
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).
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