ARTICLE
Auteur(s) :, Robert P
Numerof1,*, Charles A Dinarello2, Khusru
Asadullah3
1RBA Dermatology USA, Berlex Biosciences, 2600
Hilltop Drive, PO Box 4099, Richmond, CA 94804-0099, USA
2University of Colorado School of Medicine, Denver, CO,
USA
3CRBA Dermatology, Schering AG, Berlin, Germany
A unifying model for the pathophysiology of psoriasis, with
cytokines as the central mediators, was described by Nickoloff in
1991 [1]. While this cytokine network theory of psoriasis proposed
the pathological involvement of multiple cytokines, including
TNF-α, the relative importance of TNF-α only became apparent with
subsequent experimental investigations [2]. The hypothesized key
role for TNF-α in psoriasis and other inflammatory diseases led to
the development of therapeutic strategies targeting TNF-α
specifically. A number of soluble TNF receptors and anti-TNF
antibodies have now been either approved by the FDA for the
treatment of psoriasis or are in the late stages of development.The
pendulum though, has now swung back towards a greater interest, not
only in TNF-α, but also the other cytokines responsible for the
initiation, maintenance, or resolution of psoriatic skin
inflammation (table 1)( Table 1 )
and other inflammatory dermatoses that may be considered as
“visible immunological diseases”. A workshop sponsored by Berlex
Biosciences held in the Napa Valley, California, November 17-19,
2004 focused on cytokines (including, but not limited to, TNF-α) as
potential therapeutic targets for inflammatory skin diseases. The
current report summarizes key findings presented at the workshop.
These proceedings will be published by Springer-Verlag
(Berlin/Heidelberg, Germany).
Pro-inflammatory cytokines apart from TNF-α, as novel targets –
lessons from clinical trials
Gerald Krueger (University of Utah, Salt Lake City, UT, USA) set
the stage for the workshop by summarizing the current state of
clinical investigations involving anti-cytokine strategies. The
soluble TNF receptor etanercept, the first anti-TNF therapeutic
approved by the FDA for psoriasis, represents a major advancement,
and appears to be safe and effective for many patients. The
antibodies directed against TNF-α, infliximab and adalimumab, are
likely to be approved by the FDA for psoriasis in the near future.
Biologics in development, targeting other cytokines, include
IL-18-binding protein, and anti-IL-12, anti-IL-18 receptor, and
anti-IFN-γ monoclonal antibodies (table 2)( Table 2 ). Gottfried Alber (University of Leipzig,
Germany) discussed the IL-12 family including IL-12 and IL-23,
which share a p40 subunit, and IL-27. He reminded the audience that
current clinical studies targeting the p40 subunit, commonly
referred to as “anti-IL-12 therapy”, will not be able to
differentiate between pathogenic effects derived from IL-12
(p35/p40) or IL-23 (p19/p40), and suggested that p19- and
p35-knockout mice may be more useful for this purpose.
Boris Skurkovich (Brown University, Providence, RI, USA)
presented clinical results using polyclonal anti-IFN-γ therapy in a
variety of TH1-mediated skin diseases including psoriasis, alopecia
areata, and vitiligo. Studies with a humanized monoclonal antibody
directed against IFN-γ are also being pursued in clinical trials,
but no data are presently available.
A rationale for anti-IL-15 clinical trials in psoriasis was
presented by Ian McInnes (University of Glasgow, Scotland). IL-15
is elevated in psoriatic skin and a humanized anti-IL-15 antibody,
AMG714, reduced inflammation and typical psoriatic skin features in
human psoriatic skin grafted onto SCID mice. Anti-IL-15 antibodies
are currently in Phase II trials for rheumatoid arthritis. However,
all of these anti-cytokine strategies for treating psoriasis must
also be compared to the new biologics targeting T cells directly,
such as alefacept and efalizumab, which block T cell/antigen
presenting cell interactions, as well as the non-biologics still in
use [3].
A major impact of cytokines has also been demonstrated in
several other inflammatory skin diseases such as allergic and
atopic dermatitis. However, clinical intervention involving the
cutaneous cytokine network has so far been focused mainly on
psoriasis.
Table 1 Cytokines in psoriasis
|
Cytokines
|
Function
|
Presence in psoriatic plaquesa
|
|
TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-12p40, IL-15, IL-17, IL-18,
IL-1F6, IL-1F8
|
Pro-inflammatory
|
Elevated
|
|
IL-4, IL-10, IL-1RA
|
Anti-inflammatory
|
Reduced
|
amRNA or protein.
Table 2 Anti-cytokine therapies in clinical development
for psoriasis
|
Therapeutic
|
Mechanism
|
Stage of development
|
|
Etanercept
|
Soluble TNF receptor
|
Approved in US 04/04
|
|
Infliximab
|
Anti-TNF monoclonal ab
|
Phase III
|
|
Adalimumab
|
Anti-TNF monoclonal ab
|
Phase II completed
|
|
Onercept
|
Soluble TNF binding protein
|
Phase III
|
|
CNTO-1275
|
Anti-IL-12p40 monoclonal ab
|
Phase I/II
|
|
IL-18 bp
|
IL-18 binding protein
|
Phase II
|
|
Fontolizumab
|
Anti-IFN-γ monoclonal ab
|
Phase I completed
|
Which cytokines are on the horizon as potential targets?
A number of presenters reviewed the use of transgenic and knockout
mice for identifying pro-inflammatory or anti-inflammatory
activities of particular cytokines. Yochiro Iwakura (University of
Tokyo, Japan) described the inflammatory disease-like conditions
that develop spontaneously in mice deficient in IL-1-receptor
antagonist. The development of a destructive, rheumatoid
arthritis-like disease and aortitis was significantly suppressed by
the additional deficiency of TNF-α or IL-17, whereas the
development of dermatitis was inhibited by the simultaneous
deficiency of TNF-α. These studies suggest a role for IL-1-induced
TNF +/- IL-17 at particular sites of inflammation. John Sims (Amgen
and University of Washington, Seattle, WA, USA) summarized findings
using overexpression of IL-1 and IL-1R family members specifically
in the skin. Skin-specific expression of IL-1α or IL-18, under the
control of the keratin 14 promoter, leads to an inflammatory
condition, and in the case of IL-18 it exacerbates the dermatitis
elicited by contact hypersensitivity [4]. Transgenic skin-specific
expression of two newer members of the IL-1 family, IL-1F6 or
IL-1F8, or their putative common receptor IL-1R rp2 induces an
inflammatory skin condition, which histologically bears some degree
of resemblance to human psoriasis. Consistent with these findings,
elevated levels of both IL-1F6 and IL-1F8 are found in psoriatic
skin.
Dendritic cells, regulatory T cells, and roles for
anti-inflammatory cytokines
Upon activation by microbes or cytokines, immature dendritic cells
(DC) acquire the ability to present processed antigen and secrete
cytokines, thus influencing the immune response and, via cytokines
such as IL-12, the critical Th1/Th2 balance.
Alexander Rudensky (University of Washington, Seattle, WA, USA)
discussed the regulation of antigen presentation by lysosomal
cysteine proteases and pointed out the preferential use of
cathepsin S by dendritic cells. While numerous cytokines are
produced by activated DC, Paola Ricciardi-Castagnoli (University of
Milano-Bicocca, Milan, Italy) identified IL-2 as an unexpected
dendritic cell-derived cytokine that acts upon NK cells, thus
linking DC to the innate immune response as well. Grant Gallagher
(University of Medicine and Dentistry of New Jersey, Newark, NJ,
USA) discussed a role for IL-19, a member of the IL-10 family, in
inducing increased IL-10 in DC and shifting the Th1/Th2 balance
towards the Th2 phenotype. As recently reported [5], elevated
levels of IL-10 in a subset of DC may be important for the
induction of type 1 regulatory T (Tr1) cells, a regulatory T cell
subset characterized by the ability to secrete IL-10 and TGF-β,
cytokines with well documented anti-inflammatory activities.
Unlike Tr1 cells, conventional CD4+CD25+
regulatory T cells do not secrete TGF-β, but exert their
immunosuppressive function in a cell contact-dependent manner.
Alexander Enk (University of Heidelberg, Heidelberg, Germany)
demonstrated the generation of antigen-specific
CD4+CD25+ regulatory T cells by targeting
CD11c+ DC with antigen, and Kevin Cooper (Case Western
Reserve University, Cleveland, OH, USA) described a functional
defect in CD4+CD25+ regulatory T cells in
psoriatic patients. Richard Flavell (Yale University, New Haven,
CT, USA) presented evidence that overexpression of TGF-β in T-cells
expands the pool of CD4+CD25+ regulatory T
cells, thus providing an additional mechanism for the
immunosuppressive function of this cytokine.
As an alternative to the antibodies or soluble receptors
directed against pro-inflammatory cytokines discussed above, the
use of anti-inflammatory cytokines as therapeutics for inflammatory
skin diseases remains a promising approach. In this regard,
significant effects of IL-4 therapy in psoriasis have been reported
[6]. More information, however, has been generated from clinical
studies with recombinant human IL-10 [7]. After successful early
trials, a larger study involving 28 patients with
moderate-to-severe psoriasis showed that treatment with IL-10
resulted in only temporary clinical improvement despite sustained
systemic decreases in pro-inflammatory cytokines [8]. Remarkably,
IL-10 clearly failed in atopic dermatitis (Christian Reich,
Goettingen, personal communication).
Intracellular signaling pathways – an alternative means of
targeting particular cytokines
Antibodies directed against cytokines and recombinant cytokines
have been extremely effective in defining roles, or the lack
thereof, for specific cytokines in inflammation. The use of these
reagents preclinically, also allows for easy transition into the
clinic if warranted. However, protein-based therapeutics,
particularly antibodies and soluble receptors, are expensive to
produce, require sustained elevated blood levels in order to
develop significant tissue (skin) levels, and must be administered
by injection. Small-molecule, orally active therapies would be
welcomed. Thus, once a cytokine has been validated as an important
target, alternative means of suppressing (or inducing) that
cytokine by manipulation of relevant signaling pathways have been
sought. Charles Dinarello (University of Colorado, Denver, CO, USA)
discussed the ability of histone deacetylase (HDAC) inhibitors,
molecules initially identified as anti-cancer therapeutics, to
reduce gene expression of a number of cytokines involved in
inflammation. He also presented a number of animal models of
inflammation in which the administration of HDAC inhibitors
ameliorated disease. Bharat Aggarwal (University of Texas, Houston,
TX, USA) summarized the current understanding of TNF-α signaling,
and highlighted NFκB inhibitors as promising alternatives for TNF
blockers.
Conclusions and outlook
The rationale for targeting TNF-α in inflammatory skin diseases was
based on a firm understanding of the biology of TNF-α derived from
a great deal of experimentation. However, a central role for TNF-α
in psoriatic disease was only truly defined after the completion of
human clinical trials with specific neutralizing therapies.
Clinical investigation has now begun for other, cytokine-directed
therapies, such as those targeting IFN-γ, IL-12p40, and IL-18.
IFN-γ, as a T cell-derived cytokine that activates macrophages and
induces TNF-α and chemokine secretion, may be particularly
well-suited for targeting. In addition to regulating the immune
response, IFN-γ acts as a trigger for epidermal hyperplasia when
injected into the skin, and may directly affect keratinocytes by
increasing levels of Bcl-x and inhibiting apoptosis [9]. An
additional T cell-derived cytokine that appears to be a promising
target for inflammatory skin disease is IL-17, a mediator induced
by IL-15 and IL-23, two other cytokine targets of interest.
However, caution is needed since research once supported IL-8 as a
central player in the pathogenesis of psoriasis prior to
unremarkable clinical results with anti-IL-8 therapy [10]. Clinical
studies still remain the key arbiter in determining the pathogenic
relevance of a particular cytokine.
Although psoriasis is currently the primary dermatological
disease indication for these new therapeutic approaches in clinical
development, it is likely that some of them may be of value for
other cutaneous and non-cutaneous inflammatory disorders. In
addition, basic research into the molecular mechanisms of cytokine
action will undoubtedly lead to the identification of novel
targets, some of which may be more amenable for the development of
orally active, small molecules that would be more suitable for the
treatment of larger populations and more diverse types of cutaneous
disease.
Acknowledgements
This short review summarizes the scientific presentations made
during the workshop Cytokines as potential therapeutic targets for
inflammatory skin diseases, held in Napa Valley, California (17-19
November 2004) under the sponsorship of Berlex Biosciences.
Conflict of interest statement. Charles Dinarello has
received support from Berlex Biosciences. Robert Numerof is Senior
Scientist at Berlex Biosciences. Khusru Asadullah is Head, CRBA
Dermatology, at Schering AG.
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