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`wn ae y
`Major Breakthroughs
`eleTebreta Novarti
`Immuy o)Keyeats
`eBNES
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`nology
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`Kuropean Journal of Immunology (SSN 0014-2980) is published monthly by
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`©) 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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`www.eji-journal.eu
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`

`

`Eur. J. Immunol. 2007.
`
`37: 53-4
`
`S3,
`
`Pati ce)el LM lltts lis)J
`
`m S1
`
`Editorial
`
`m SS
`
`Meet the authors
`
`Immunology
`Breakthroughs in Immunology
`
`m S9
`
`The macrophage: Past and present and future
`Siamon Gordon
`
`m S18
`
`Seeing is believing: A focus on the contribution of microscopic
`imaging to our understanding of immune system function
`Mare Bajénoff and Ronald N. Germain
`
`m S34
`
`Historical insights into cytokines
`Charles A. Dinarello
`
`m S46
`
`Lymphoid organogenesisin brief
`:
`.
`:
`"
`i
`eG
`r
`Mark F. R. Vondenhoff, Georg Kraal and Reina E. Mebius
`-
`
`m S53
`
`m S61
`
`m S71
`
`«es
`.
`2
`3
`Dendritic cells: Understanding immunogenicity
`Ralph M. Steinman
`
`How apoptosis got the immune system in shape
`Christine Feig and Marcus E. Peter
`
`:
`:
`DNA repair and the immunesystem:
`From V(D)J recombination to aging lymphocytes
`Paola Rivera-Munoz, Laurent Malivert, Sonia Derdouch, Chantal Azerrad,
`Vincent Abramowski, Patrick Revy and Jean-Pierre de Villartay
`
`m S83
`
`The T cell antigen receptor: “The Hunting of the Snark”
`Tak W. Mak
`
`m S94
`
`A history of AIDS: Looking back to see ahead
`Warner C. Greene
`
`representation
`picture is a
`This
`a represe
`ae
`This picture is
`of the Cernunnos god superim
`posed on a nucleus showing
`GIA repair fogl revealed’ by
`immunostaining, Cernunnos1s
`the namegiven to a DNA repair
`factor identified in 2001. This
`picture was designedby Patrick
`and Jean-Claude Revy and
`is provided by Jean-Pierre de
`Villartay.
`
`m $103Abrief history of CD8 T cells
`David Masopust, Vaiva Vezys, E. John Wherry and Rafi Ahmed
`
`m S111
`
`NKTcells: In the beginning...
`H. Robson MacDonald
`
`™ S116 Regulatory T cells - a brief history and perspective
`Shimon Sakaguchi, Kajsa Wing and Makoto Miyara
`
`© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`www.eji-journal.eu
`
`

`

`m S4
`
`Eur. J. Immunol.
`
`I:
`
`2007.
`
`7,37: S3-4
`3
`
`Fritz Melchers
`
`™ S134 From a Dream to Reality
`Klaus Rajewsky
`
`™ S138 From gene amplification to V(D)J recombinationand back:
`A personalaccountof myearly years in B cell biology
`Frederick W. Alt
`
`Novartis Essays ™ $125 Starting at the end
`
`© Source: PhotoDisc, Inc./Getty
`images
`
`™® S148 Prevention of cancer through immunization:
`Prospects and challenges for the 21*' century
`lan H. Frazer, Doug R. Lowy and John T. Schiller
`
`™ 5156
`
`Impressum
`
`The cover picture is a montage illustrating the key breakthroughs in immunology featured
`in this EJI supplemental issue. The montage depicts the two major themes: discovery and
`immunology. Discovery is symbolised by the hands of a researcher holding oneofthe Petri
`dishes. Immunological research is highlighted by the immunecell images (Tcells, Treg cells,
`DC, macrophagesetc.), immunostained or observed with an electronic microscope. We thank
`Ron Germain, Siamon Gordon, Reina Mebius, Shimon Sakaguchi and Ralph Steinman for
`kindly providing us with these images.
`
`Newfeature: EJI Podcast
`
`|
`
`Hear Ralph Steinmantalk about the discovery of dendritic cells, current developments in the field, science funding,
`translational research and more in EJI's first podcast. Visit www.eji-journal.eu to download the podcast whichwill be
`available early November.
`
`tly NOVARTIS
`
`© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`www.eji-journal.eu
`
`

`

`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Charles A. Dinarello
`
`Eur. J. Immunol. 2007, 37; $3445
`
`Breakthroughs in Immunology
`
`
`
`Historical insights into cytokines
`
`Charles A. Dinarello
`
`University of Colorado Health Sciences Center, Denver, USA
`
`Cytokines affect nearly every biological process; these include embryonic development,
`disease pathogenesis, non-specific response to infection, specific response to antigen,
`changes in cognitive functions and progression of the degenerative processes of aging.
`In addition, cytokines are part of stemcell differentiation, vaccineefficacy andallograft
`rejection. This short insight focuses on the milestones in cytokine biology and how the
`various and often contradictory activities of these small, non-structural proteins
`affected the fields of inflammation and immunology. Multiple biological properties or
`pleiotropism is the hallmark of a cytokine. Today, the term “cytokine” encompasses
`interferons, the interleukins, the chemokine family, mesenchymal growth factors, the
`tumor necrosis factor family and adipokines. As of this writing, 33 cytokines are called
`interleukins, but many are part of families of related but distinct gene products. There
`are certainly over 100 separate genes coding for cytokine-like activities, many with
`overlapping functions and manystill unexplored. Also discussed in this overview arethe
`failures and successes of cytokines as therapeutic targets. A recent advance in the field
`has been that of differential cytokine production, which can be used toclassify human
`disease as being “autoimmune”or“autoinflammatory” thus impacting on therapeutic
`interventions.
`
`Received 21/8/07
`Revised
`6/9/07
`Accepted 18/9/07
`
`[DOI 10,1002/eji.200737772|
`
`™ Key words:
`Autoimmune - Host
`response- Infection
`- Inflammation
`- Leukocytes
`
`Introduction
`
`Cytokines can be divided into functional classes. For
`example,
`some cytokines are primarily lymphocyte
`growth factors, others function as pro-inflammatory
`or anti-inflammatory molecules whereas other cyto-
`kines polarize the immuneresponseto antigen. During
`the past 25 years, cytokines have become an important
`frontier in medicine in a vital place as diagnostic,
`prognostic and therapeutic agents in human disease.
`Although cytokines are studied today in nearly every
`biological discipline, cytokine-mediated effects domi-
`
`Correspondence: Charles A. Dinarello, University of Colorado
`Health Sciences Center, 4200 East Ninth Ave., B168, Denver,
`CO 80262, USA
`Fax: +1-303-315-8054
`e-mail: cdinare333@aol.com
`
`Abbreviations: CARD: caspase-1 recruitment domain -
`FGF: fibroblast growthfactors - IL-1Ra: IL-1R antagonist -
`PG: prostaglandin - VEGF: vascular endothelial growth factor
`
`© 2007 WILEY-VCH Verlag GmbH & Co, KGaA, Weinheim
`
`nate the fields of inflammation, immunology, athero-
`sclerosis and cancer. For instance, chemokines and their
`receptors have
`impacted on
`inflammation, HIV-1
`pathogenesis, lymphocyte trafficking and autoimmune
`disease. Some chronic diseases appear to be driven by
`“autoinflammatory” pathways whereas others have
`classic characteristics of “autoimmune” mechanisms.
`Mutations in the gene NALP1 are associated with
`autoimmunediseases |1] whereas mutations in NALP3
`are associated with autoinflammatory diseases
`[2].
`Although there is clinical overlap in this classification,
`distinct cytokine portfolios have emerged based on the
`functions of
`the
`caspase-1
`“inflammasome”, The
`discovery of the mammalian surface Toll-like receptors
`(TLR)
`for
`recognizing a
`large and heterogeneous
`number of microbial products is intrinsic to cytokine
`biology because the intracellular signaling domains of
`TLR are nearly identical to those of the interleukin-1
`receptor (IL-1R), both mediating host
`responses to
`infection andinjury.
`
`WILEY
`InterScience’
`
`*%,
`
`www.eji-journal.eu
`
`

`

`Eur. J. Immunol. 2007. 37: 534-45
`
`Cytokines in evolution
`
`Cytokines evolved from the earliest forms as intracell-
`ular molecules before the appearance of receptors and
`signaling cascades. Cytokine-like activities have been
`demonstrated in invertebrates such as star fish and
`Drosophilia, where they played an essential role in host
`defense and repair. A cytokine-mediated rise in body
`temperature as survival mechanism was demonstrated
`in poikilothermiclizards [3]. Some cytokines function as
`transcription factors (likely their initial functions) as
`well as extracellular
`ligands
`for specific receptors
`(evolvedlater). Recordedhistory is full of examples of
`the devastating effect of infection on societies and one
`can argue that cytokine-mediated events underlie the
`pathological processes of these epidemics.
`Cytokine biology springs fromthe host production of
`“pus”. Long before the microscope, exudates containing
`pus andthe presenceoffever and local swelling and pain
`were well-documented by writers in the ancient world,
`Pus was visible and later could be studied in the
`laboratory. The field had its earliest advance with
`interest in soluble “factors”, as they were thencalled,
`which were studied in the mid-1940s as products of
`white blood cells (pus). Indeed, most cytokines are best
`definedas soluble factors producedby one cell that acts
`on another cell. Today, however, we recognize that
`cytokines can also function as
`integral membrane
`proteins and some are never released from the cell.
`Initially, cytokines werecalled “lymphokines”to distin-
`guish them from “monokines” in an attempt to classify
`these soluble factors by their primary sources, but that
`nomenclature was short-lived and yielded to “cyto-
`kines”. With the exception of the red blood cell, every
`cell can produceas well as respond toa cytokine,
`
`The pioneering days
`
`Soluble factors released from neutrophils from the
`peritoneal cavity of rabbits were thefirst to establish a
`link between adisease (in most cases infection) and the
`responseofthe host (fever). The biological properties of
`these soluble factors includedfever, resistance to viral
`infections, elevated white bloodcell count, the synthesis
`of acute-phase proteins, death of cancer cells and
`migration of
`inflammatory cells, Soluble factors as
`regulators of lymphocyte functions were not studied
`until
`the mid-1970s, with the first description of
`“lymphocyte activating factor” by Igal Gery and Byron
`Waksman[4] and later as T cell growth factor [5].
`A paradigmdevelopedthat a disease process induces
`the production of these soluble factors (cytokines) from
`cells and it
`is the property(s) of these “factors” that
`accounts for the manifestations of the disease. The
`
`Breakthrough
`
`$35
`
`is best appreciated with the non-specific
`concept
`physiological and immunological upheaval that the host
`initiates with infection. The “innate immuneresponse”is
`nothing more than a cytokine stormtoinfectionorto cell
`damage triggered by TLR. The hallmark of the innate
`immune response is
`its non-specific nature as
`the
`response occurs repeatedly,
`regardless of triggering
`event. The effect of the response on the specific or
`adaptive immune responseis actually collateral.
`
`The good and badof cytokines
`
`Here lies the conundrum in cytokine biology, particu-
`larly for
`the immunologist. The innate responseis
`required for host survival but is also causative indisease.
`For example, interferon (IFN)-y, essential for defense
`against several
`intracellular microorganisms such as
`Mycobacterium tuberculosis,
`is also a major cytokine in
`the pathogenesis of several autoimmunediseases. The
`issue of the “good cytokine versus the bad cytokine” has
`its greatest impact in therapeutic arena. IL-2 is needed
`for the generation of cytotoxic T cells (CTL) and forms
`the basis for several vaccines but
`the same cytokine
`drives graft-versus-host disease andlimits the success of
`bone marrow transplantation.
`
`Cytokine as hormonesof the immunesystem
`
`For sure, the definition of a cytokine as a soluble factor
`producedby onecell and acting on anothercell, in order
`to bring about a changein the functionof thetarget cell,
`was based on the endocrine system of hormones.
`In a
`way, one can consider cytokines as the “hormones”of
`immuneand inflammatory responses. However, several
`properties of cytokines escape this definition. For
`example,
`in lymphoid organs the role of cytokines in
`the humoral and cell-mediated immune response to
`antigen,
`is mainly local
`for paracrine and juxtacrine
`activities.
`In addition, hormones are the primary
`products of a specific tissue or cell whereas cytokines
`are products of most cells. But during a systemic
`inflammatory response, cytokines do exhibit endocrine-
`like activities, such as the synthesis of hepatic acute
`phase proteins and release of leukocytes from the bone
`marrow, both distant
`from a
`site of
`infection or
`inflammation. On a molar basis, cytokines are far more
`potent than hormones. For example, the concentration
`of the cytokine interleukin-1 (IL-1) that induces gene
`expression and synthesis of cyclooxygenase-2 (COX-2) is
`10 pM and the ability of IL-12 to induce IFN-y is 20 pM.
`In fact, because of their potency, during purification of
`some cytokines fromcell culture supernatents, it was not
`
`©) 2007 WILEY-VCH Verlag GmbH & Co, KGaA, Weinheim
`
`www.eji-journal.eu
`
`

`

`S36
`
`Charles A. Dinarello
`
`Eur. J. Immunol, 2007. 37: 534—45
`
`uncommonto have abiological response in the absence
`of a visible band on gel electrophoresis.
`
`Genes and more genes
`
`The nomenclature of interleukins
`
`Being non-structural proteins, biological properties
`were andstill are the gold standards for defining a
`cytokine, The interleukin nomenclature was inventedto
`deal with the issue of multiple biological properties of
`cytokines. At the time of the naming these molecules
`with an interleukin number, primary amino acid
`sequences of the active molecules were not known.
`The term IL-1 was used to define a monocyte product
`and the term IL-2 was used to define a lymphocyte
`product. But the nomenclature did nothing to resolve
`the broader
`issue of multiple biological properties
`ascribed to a single molecule.
`IL-1 was reported to
`cause fever,
`induce acute-phase protein synthesis,
`activate B cells and act
`as a co-factor
`for
`T cell
`proliferation in the presence of antigens or mitogens.
`IL-2 was reported to expand T cell proliferation and also
`activate B cells. IL-2 was initially termed Tcell growth
`factor and expanded human Tcells in vitro [5]. T cell
`growth factor producedin thelaboratory of Robert Gallo
`at the NIH allowed for the isolation of HIV-1,
`
`The skeptics are rained in
`
`a single molecule could possess
`that
`The concept
`multiple and diverse biological activities was viewed
`with considerable skepticismby cell biologists but it was
`the immunological community that provided increas-
`ingly convincing data that indeedthis was the case. The
`issue was particularly problematic for those working
`with IL-1, as its properties ranged fromeffects on control
`of body temperatureto liver protein synthesis to T cell
`responses to antigens and mitogens.
`Despitehighly purified preparations of IL-1 andIL-2,
`it was the molecular cloning of the cDNA and the
`expression of recombinant forms ofthese cytokines that
`broke the impasse. All doubts were pushedaside using
`recombinant
`forms of cytokines [6]. A great deal of
`biology was accomplished using recombinant cytokines
`and immunological
`research advanced greatly with
`receptor identification. Recombinant cytokines were
`usednotonly to confirm the biological properties of the
`natural molecule derived from cell cultures but more
`importantly used to discover new properties. Recombi-
`nant cytokines also provided antigens for monoclonal
`antibody production and the ELISA kit. The ELISA kit
`liberated the immunologist from the tediumof bioassays
`and provided for a rapid method for determining the
`quantity of a cytokine.
`
`Today wespeak not only of a cytokine as a single gene
`product but also of cytokine families. The family of TNF
`includes over 20 members, each a separate gene product
`but with a considerable overlap in biological properties
`such
`cell
`death. Although
`there
`are
`presently
`33 interleukins,
`the IL-1 family has 11 members and
`include IL-la, IL-1, IL-18 and IL-33. Although each
`member of the IL-1 family is a separate gene,
`their
`products overlap in functions as pro-inflammatory
`cytokines. The family of IL-6 includes several members
`such as IL-6, leukemia inhibitory factor,
`IL-11, oncos-
`tatin, ciliary neurotropic factor and cardiotropin-1, Each
`memberinduces hepatic acute-phase proteins in addi-
`tion to other unrelated biological properties. The IL-10
`family includes
`IL-22 and represents
`a
`family of
`cytokines
`that
`inhibit
`inflammation and immune
`responses. IL-15 accomplishes nearly the samefunctions
`as does IL-2. Colony-stimulating factors such as IL-3,
`G-CSF, GM-CSF, M-CSF, have overlapping functions but
`remain distinct gene products with specific receptors.
`The most
`impressive families are the chemokine
`families.
`In total, there are over 30 individual human
`genes for chemokines. Althoughthere are twostructural
`classes, the CC chemokines and the CXC chemokines,
`regardless of structure, chemokines orchestrate cell
`migration from the blood compartment into thetissues.
`Whythis duplication of function? Such duplication in
`function is not
`found in the endocrine system of
`hormones.
`
`Duplication of function
`
`The duplication in cytokine function is best explained
`from the viewpoint of host defense and immune
`function. Challenged with death from microbial
`inva-
`sion, the host turns on most cytokine genes. There are
`probably few persons reading this feature who havenot
`cleared a pneumococcal bacteremia without antibiotics.
`In doing so, cytokines mobilize several mechanisms for
`defeating microbial invaders. For example, cells migrate
`to the site of infection,
`reactive oxygen species are
`producedto aid in phagocyte-mediatedkilling, and pro-
`coagulant activities are initiated to wall-off the invader
`and limit spread of the infection. At
`the same time,
`several cytokines assist dendritic cells in the process of
`antigen (microbial) presentation, which results in the
`generation of CTL and production of neutralizing
`antibodies.
`It
`is unlikely that evolution could depend on a few
`cytokines to rescue the host from alethal infection. The
`large numberof cytokines induced during an infection
`also includes cytokines that aid in repair. For example,
`
`©2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`www.eji-journal.eu
`
`

`

`Eur. J. Immunol, 2007, 37: $3445
`
`Breakthrough
`
`$37
`
`fibroblast growth factors (FGF) and vascular endothelial
`growth factor (VEGF) should be considered cytokines
`that participatein the healing process. But again, weare
`faced with the duality in cytokine biology as FGFis a
`pathological molecule in lung and liver fibrosis and
`VEGE is a pathological molecule in cancer.
`
`Dysregulation of cytokine production
`
`Cytokines wreak havoe with the immune system turning
`against itself in autoimmune diseases. During infection,
`the cytokine “storm” subsides as
`the infection is
`eliminated and the genes return to their normal state
`of being repressed by histone deacetylases. When
`cytokines genes fail to shut down, their products drive
`the host into a state of chronically activated cells, which
`now dominate an otherwise resting immune system.
`Auto-reactive Tcells are cells that persist andfail to die.
`There are likely other mechanismsof“failure to die” that
`account
`for
`the persistence which are influenced
`genetically. Most anti-cytokine therapies for autoim-
`mune disease
`target
`the
`effects of cytokines on
`inflammatory andtissue remodeling processes but seem
`unable to shut down the persistently activated auto-
`reactive T cell.
`
`develop normally and for the most part age normally
`without a spontaneous disease. Only when challenged
`with disease-inducing events does the deficiency reveal
`a role for the cytokine.
`In contrast, mice deficient in IL-10, IL-1R antagonist
`(IL-IRa) or IL-2 develop spontaneous diseases. The
`diseases are inflammatory such as inflammatory bowel
`disease and arthritis. In the case ofIL-18-deficient mice,
`spontaneousdisease develops only as the mice age when
`they begin to eat excessively, becomeobese, diabetic and
`atherosclerotic [10]. Thus IL-18 deficiency reveals a
`property of the cytokine neveranticipated as a mediator
`of Thl and Th2 responses.
`Another advance in cytokine biology came as the
`genomic make-up of a species was sequencedyielding
`thousands of genes without known function. The cDNA
`for human IL-32 was deposited in the gene bank
`13 years ago but remained without function until the
`recombinant cytokine was tested and anti-IL-32 anti-
`bodies usedto detect its presence in disease [11]. IL-32 is
`a pro-inflammatory cytokine inducing TNF-u, IL-1and
`several chemokines, and is
`found in tissues
`from
`rheumatoid arthritis and Crohn's disease [12]. One
`can asked the question: how manyothergenes presently
`with unknownfunction are actually cytokines and may
`have a role in immunological functions or disease?
`
`Gene deletions and gene screenings advance
`the field
`
`Thefailures and benefits of cytokines for
`treating human disease
`
`for cytokine studies remains mole-
`The major impact
`cular cloning of biologically active molecules,the testing
`of recombinantcytokines, and the identification oftheir
`specific receptors [7]. The most recent example of this
`area is the identification of IL-33. IL-33 is the specific
`ligand for the orphan receptor ST2 [8]. A great deal
`about the functionofthis receptor for the Th2 response
`and allergic diseases was gained over the past 12 years
`without knowing the ligand [9]. With the cloning of
`IL-33,
`the recombinant cytokine fulfills each of the
`biological properties attributed to the receptor and
`closes the circle.
`Although neutralizing antibodies greatly advanced
`cytokine studies, deleting a specific cytokine gene or
`receptor in a mouse wasalso a major advance. However,
`in the gene deletion studies, the unexpected finding was
`that most cytokine or cytokine receptordeletions did not
`affect the mouse unless the mouse was challenged with
`infection or an immunological challenge. The lack of a
`phenotype in cytokine-deficient mice supports
`the
`concept that most cytokines are not needed for health
`but
`rather for
`infections,
`trauma or
`immunological
`challenge. For example, mice deficient in IL-la, IL-1,
`caspase-1, ‘TNF-a orIL-6 are fertile, and their off-spring
`
`With progress in the late 1970s on the biological
`activities of “soluble factors” came increasing interest
`from the pharmaceutical industry. In fact, the develop-
`ment of
`the biotech industry can be
`linked to
`developments in cytokine biology, particularly as cDNA
`and recombinant cytokines validated the field. The
`molecular cloning of the first cytokines in the early
`1980s (IFN-a, IL-1, IL-2 and TNF-«) coincided in 1984
`withthe discovery of HIV-1 as the causative agent in the
`acquired immunodeficiency syndrome (AIDS). Thera-
`peutic use ofIL-1 andIL-2 held great promiseas natural
`immuno-stimulant to combat the immunedeficiency of
`AIDS. At
`the same time,
`it was thought
`that
`the
`immunosuppression of cancer could be reversed by
`injecting patients with immuno-stimulating cytokines.
`There was no dearth of animal and in vitro studies to
`support trials for treating cancer patients or patients
`with AIDS with these cytokines. At the same time TNF-a
`held promise for treating patients with cancer. The fact
`remains, however, that injecting humans withIL-1, IL-2,
`IL-3,
`IL-4, IL-6, IL-12 or TNF-a induces unacceptable
`systemic inflammationandthe use of these cytokinesas
`therapies was abandoned.
`
`© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`www.eji-journal.eu
`
`

`

`. 538
`
`Charles A. Dinarello
`
`Eur. J. Immunol. 2007, 37: S34—45
`
`The only cytokine to receive approval for treating
`canceris IL-2, but its pro-inflammatory effects are not
`easily tolerated by most patients andits efficacy in
`treating melanomaand renal cell carcinoma is low. IL-10
`was an outstanding candidate for treating a variety of
`autoimmune diseases as IL-10 suppressed IFN-y, IL-1,
`TNF-a and IL-6 production as well as possessing other
`anti-inflammatory activities. Several trials of recombi-
`nant human IL-10 showed limited efficacy in psoriasis,
`rheumatoid arthritis and Crohn's disease, but
`the
`cytokine has never been approvedfor therapeutic use.
`Onthe other hand, colony-stimulating factors such as
`G-CSF or GM-CSF are used to treat bone marrow
`suppression associated with radiation, chemotherapy or
`transplantation, GM-CSF has also been used to treat
`Crohn's disease. Erythropoietinis routinely usedto large
`numbers of patients with anemia and bone marrow
`failure. Impressively, IFN-a is administeredto millions of
`patients to treat hepatitis B and C.
`IFN-B for
`the
`treatment of multiple sclerosis is also effective.
`
`Blocking cytokines in autoimmunedisease
`succeeds
`
`The same agents that failed in clinical trials for sepsis
`werealso tested in patients with rheumatoid arthritis,
`Crohn's disease and plaque psoriasis.
`In the case of
`blocking TNF-a, monoclonal antibodies to TNF-a or
`soluble TNF receptors
`(TNFR)
`have been highly
`successful
`in these autoimmune diseases and used in
`over 800 000 patients. As a result, nearly every anti-
`cytokine agent, whether an orally active inhibitor of a
`cytokine-regulated intracellular pathway, a neutralizing
`antibody or a soluble receptoror a receptor antagonist,
`is tested in patients with rheumatoidarthritis, Crohn's
`Disease or psoriasis. Blocking IL-1, IL-6, IL-12 or IL-23
`has been successful. Blocking IL-15 or IL-18 has been
`marginal. In general, animal models can predict which
`cytokines arelikely to improve rheumatoidarthritis as
`well as Crohn's Disease [14], but do not predict which
`anti-cytokine is efficacious for one patient but not
`another.
`
`Blocking cytokines in humans
`
`The use of agents that specifically block the activity ofa
`cytokinetruly defines the role of that cytokine in disease
`or in an immunological response, Although blocking
`cytokines in animal models with neutralizing strategies
`established the importance of
`a
`cytokine in
`the
`pathogenesis or progression of disease, approval
`for
`use in humans remains the ultimate goal,
`Thefirst studies of blocking a cytokine in humans was
`based on reducing IL-1 and TNF-u activity in animal
`models of lethal endotoxemia or live infections. The
`animal studies were impressively revealing in
`that
`blocking either of these cytokines reduced mortality
`andthereforeit was logical to reduceIL-1 and or TNF-a in
`patients with sepsis. Despite sophisticated intensive care
`units, death fromsepsis has an unacceptable mortality
`rate with over 500 000 cases in the USA each year.
`Therefore, billions of dollars were invested in
`the
`development of blocking agents and testing in place-
`bo-controlledtrialsin over 12 000patients. Only marginal
`reductions in all-cause 28 day mortality were achieved,
`insufficient
`to gain approval. A meta-analysis of the
`clinical trials concluded that like in the animal studies, a
`mortality benefit of blocking IL-1 or TNF-a was only
`observed in patients at the highest risk of death [13].
`Blocking IL-4 or IL-5 for treating asthma was based a
`well-established animal model of airway antigen
`challenge but the results in several placebo-controlled
`trials did not show sufficient efficacy. Blocking chemo-
`kines was also thought
`to be a therapeutic strategy;
`neutralizing anti-IL-8 failed to affect psoriasis.
`
`Autoimmuneversus autoinflammatory
`disease
`
`As the properties of various cytokines were investigated,
`understanding the linkage between inflammation and
`immune responses expanded. For some cytokines, the
`ability to induce
`inflammatory mediators
`such a
`prostaglandins (PG), nitric oxide or reactive oxygen
`species impacts greatly on immuneresponses in chronic
`diseases. Autoimmune diseases have both dysfunctional
`immuneresponsesas well as a prominent inflammatory
`component. For example, in the treatment of rheuma-
`toid arthritis, psoriasis or Crohn's disease by blocking
`TNF-o or IL-12 activities, there is both a reduction in
`chronic inflammation and a_ partial
`restoration of
`suppressed immune responses. Other chronic diseases
`appear to be mostly inflammatory in nature and dueto
`dysregulation ofIL-1} processing and secretion. These
`diseases are called autoinflammatory to distinguish
`them from autoimmunediseases.
`As shownin Table 1, examples of autoinflammatory
`diseases are familial Mediterranean fever, neonatal
`onset multiple
`system inflammatory disease,
`and
`systemic onset
`juvenile idiopathic arthritis. Patients
`with these diseases suffer from chronic fevers, systemic
`inflammation andpainful joints. However, upon block-
`ing IL-1 activity there is a rapid reversal of disease
`severity. The pathological abnormality in autoinflam-
`matory diseases appears to be a failure to control the
`processing and secretion of
`IL-1f}
`in
`that
`blood
`monocytes from patients with these diseases release
`more active IL-1f} compared to cells from non-disease
`subjects. The processing and secretion of
`IL-If} is
`
`© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
`
`www.eji-journal.eu
`
`

`

`Eur. J. Immunol. 2007, 37: S34-45
`
`Breakthrough
`
`S39 4
`
`Table 1. Characteristics of autoinflammatory and autoimmunediseases
`
`Autoimmunediseases
`Autoinflammatory diseases
`
`Dominant cytokine = IL-1f}
`Secondary cytokine = IL-6
`
`Dominant cell = macrophage » T cell
`
`» B cell
`
`Examples*’
`Familial Mediterranean fever
`
`Dominant cytokine = TNF-«
`Secondary cytokines = IFN-y/IL-17/IL-23
`
`- macrophage
`
`Dominant cell = T cell
`Secondary cell = B cell
`Examples”)
`Rheumatoid arthritis
`
`Familial cold autoinflammatory syndrome
`
`Juvenile rheumatoid arthritis
`
`Muckle-Wells syndrome
`
`Neonatal onset multi-inflammatory disease
`
`Hyper-IgD syndrome
`
`Adult and juvenile Still's disease
`
`Anti-synthetase syndrome
`
`Macrophage activation syndrome
`Urticarial vasculitis
`
`Behcet's syndrome, Blau's syndrome, PAPA syndrome
`
`Schnitzler's syndrome, Sweet's syndrome
`
`Ankylosing spondylitis
`Crohn's disease
`
`Psoriasis
`
`Lupus erythematosus
`
`Pemphygus
`
`Wegener's granulomatosis
`Sarcoidosis
`
`Urate crystal arthritis (gout)
`
`Type 2 diabetes
`®) Blocking IL-1} effective therapy; blocking IL-6 effective; blocking TNF-u minimally effective or exacerbation of disease.
`») Blocking TNF-u, IL-23, CD20, CTLA-4-lg, IL-1f) effective therapy.
`
`cysteine
`an intracellular
`controlled by caspase-1,
`protease that cleaves the IL-1precursor as well as
`those