2007 Conference (Very Long and Heavy on Science!)

[Guest guest]

Dear All;

At the 2007 Conference in Denver this last weekend it was a great

pleasure to meet up with old friends and make so many new ones. It

was a wonderful, uplifting experience, as always. Thank you Don and

Ricky for all your efforts in making this such a great event. I hope

that other conference attendees came away from the conference as

energized as I was. I very much look forward to the next conference

in 2008, but I will leave the honor of announcing where and when this

will be to Ricky!

At the Denver conference I tried to convey my enthusiasm for recent

research being done on Th17 cells. These are a new set of T cells

that are distinct from the well known Th1 and Th2 cells. Production

of Th17 cells is stimulated by interleukin-23 (IL-23), and the Th17

cells themselves produce a pro-inflammatory cytokine, interleukin-17

(IL-17). These newly discovered Th17 cells, and their inflammatory

mediators (IL-23 and IL-17), are now being implicated in a number of

autoimmune and autoinflammatory diseases. For example, the IL-23

receptor (IL-23R) is a receptor on Th17 cells that has recently been

identified as a gene involved in human inflammatory bowel disease and

psoriasis.

Some conference attendees asked me to provide further background

information on these Th17 cells, and why there is so much excitement

about them in the field of autoimmune/autoinflammatory diseases. So

here's a list of recent references that have perked my interest and

which prompted me to discuss them at the conference. I sincerely

apologize that this message is very long and heavy on science.

Best regards,

Dave

(father of (21); PSC 07/03; UC 08/03)

_______________________________________

Curr Opin Rheumatol. 2007 May;19(3):284-8.

The role of T cells in rheumatoid arthritis: new subsets and new

targets.

Toh ML, Miossec P

Department of Immunology and Rheumatology, Hopital Edouard Herriot,

Lyon, France.

PURPOSE OF REVIEW: To update the knowledge on the contribution of T

cells in rheumatoid arthritis, a selection of publications between

the end of 2005 and 2006 were reviewed. RECENT FINDINGS: Th17 cells

driven by TGF-beta, IL-1, IL-6 and IL-23 challenge previous concepts

of 'Th1'-induced rheumatoid arthritis. Other advancements in IL-17

studies include novel concepts on the IL-17 receptor and additional

information on the mechanism of IL-17-induced effects. Regulatory T

cells fail to control disease due to defective function secondary to

the synovial inflammatory milieu. The predominance of pathogenic

effector T cells in the presence of impaired T-cell regulatory

mechanisms may therefore contribute to rheumatoid arthritis

chronicity. Cellular therapies attempt to restore the balance that

includes production of immunoregulatory cytokines such as IL-4 or IL-

10. Better T-cell-targeted therapies controlling costimulation are in

place with purported increased efficacy and durability, including

anti-tumour necrosis factor nonresponders. Additional direct and

indirect T-cell approaches include antagonism of T-cell-derived

cytokines, T-cell activation or B-cell ablation. SUMMARY: A renewed

interest in T cells comes from the discovery of Th17 in rheumatoid

arthritis and from novel findings on the role of T cells in

rheumatoid arthritis induction, chronicity and relapse. PMID:

17414957.

_______________________________________

Nat Immunol. 2007 Apr;8(4):345-50.

T(H)-17 cells in the circle of immunity and autoimmunity.

Bettelli E, Oukka M, Kuchroo VK

Estelle Bettelli and Vijay K. Kuchroo are in the Center for

Neurologic Diseases, Brigham and Women's

Hospital, Boston, Massachusetts 02115, USA.

CD4(+) effector T cells have been categorized into two subsets: T

helper type 1 (T(H)1) and T(H)2. Another subset of T cells that

produce interleukin 17 (IL-17; 'T(H)-17 cells') has been identified

that is highly proinflammatory and induces severe autoimmunity.

Whereas IL-23 serves to expand previously differentiated T(H)-17 cell

populations, IL-6 and transforming growth factor-beta (TGF-beta)

induce the differentiation of T(H)-17 cells from naive precursors.

These data suggest a dichotomy between CD4(+) regulatory T cells

positive for the transcription factor Foxp3 and T(H)-17 cells: TGF-

beta induces Foxp3 and generates induced regulatory T cells, whereas

IL-6 inhibits TGF-beta-driven Foxp3 expression and together with TGF-

beta induces T(H)-17 cells. Emerging data regarding T(H)-17 cells

suggest a very important function for this T cell subset in immunity

and disease. PMID: 17375096.

_______________________________________

Clin Exp Immunol. 2007 Feb 27; [Epub ahead of print]

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human

organ transplantation and autoimmune disease.

Afzali B, Lombardi G, Lechler RI, Lord GM

Department of Nephrology and Transplantation, King's College London,

Guy's and St ' Hospital, UK.

Uncommitted (naive) murine CD4(+) T helper cells (Thp) can be induced

to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (T

(reg)) phenotypes according to the local cytokine milieu. This can be

demonstrated most readily both in vitro and in vivo in murine CD4(+)

T cells. The presence of interleukin (IL)-12 [signalling through

signal transduction and activator of transcription (STAT)-4] skews

towards Th1, IL-4 (signalling through STAT-6) towards Th2,

transforming growth factor (TGF)-beta towards T(reg) and IL-6 and TGF-

beta towards Th17. The committed cells are characterized by

expression of specific transcription factors, T-bet for Th1, GATA-3

for Th2, forkhead box P3 (FoxP3) for T(regs) and RORgammat for Th17

cells. Recently, it has been demonstrated that the skewing of murine

Thp towards Th17 and T(reg) is mutually exclusive. Although human Thp

can also be skewed towards Th1 and Th2 phenotypes there is as yet no

direct evidence for the existence of discrete Th17 cells in humans

nor of mutually antagonistic development of Th17 cells and T(regs).

There is considerable evidence, however, both in humans and in mice

for the importance of interferon (IFN)-gamma and IL-17 in the

development and progression of inflammatory and autoimmune diseases

(AD). Unexpectedly, some models of autoimmunity thought traditionally

to be solely Th1-dependent have been demonstrated subsequently to

have a non-redundant requirement for Th17 cells, notably experimental

allergic encephalomyelitis and collagen-induced arthritis. In

contrast, T(regs) have anti-inflammatory properties and can cause

quiescence of autoimmune diseases and prolongation of transplant

function. As a result, it can be proposed that skewing of responses

towards Th17 or Th1 and away from T(reg) may be responsible for the

development and/or progression of AD or acute transplant rejection in

humans. Blocking critical cytokines in vivo, notably IL-6, may result

in a shift from a Th17 towards a regulatory phenotype and induce

quiescence of AD or prevent transplant rejection. In this paper we

review Th17/IL-17 and T(reg) biology and expand on this hypothesis.

PMID: 17328715.

_______________________________________

Int Immunopharmacol. 2007 Apr;7(4):409-16.

After interleukin-12p40, are interleukin-23 and interleukin-17 the

next therapeutic targets for inflammatory bowel disease?

Zhang Z, Hinrichs DJ, Lu H, Chen H, Zhong W, Kolls JK

Department of Pediatrics, Oregon Health and Science University,

Portland, OR 97239, USA.

Inflammatory bowel disease (IBD), typified by Crohn's disease and

ulcerative colitis, is a common disorder characterized by recurrent

and serious inflammation of the gastrointestinal tract. Recent

immunologic advances have established that T cells and inflammatory

cytokines play a pivotal role in the gastrointestinal inflammation of

IBD. However, many cytokines not only elicit inflammation but also

protect host against microbial invasion. Hence, suppression of these

dual-purpose cytokines often exposes the patients to significant risk

of infection. Recent research on Interleukin (IL)-23, IL-17, and IL-

17 producing T cells has become the vanguard of further understanding

the contribution of cytokines to autoimmune and inflammatory

diseases. IL-23 is a newly discovered member of the IL-12-related

cytokine family, and is primarily involved in the differentiation of

pathogenic T cells characterized by their production of IL-17. IL-17

is a potent inflammatory mediator implicated in a number of

autoimmune diseases. The discovery of this IL-23/IL-17-mediated

inflammatory axis is having a profound impact on the elucidation of T

cell-mediated pathogenesis as well as development of novel

therapeutic targets. In this review, we discuss the current

literature and present our recent studies on the role of IL-23 and IL-

17 in the pathogenesis of IBD. Controlling the expression/production

of IL-23 and IL-17 is an approach that would allow the development of

a novel treatment strategy with more anti-inflammatory efficacy and

potentially with less suppressive effects on host defenses. PMID:

17321463.

_______________________________________

J Cell Physiol. 2007 May;211(2):273-8.

Th17 cell induction and immune regulatory effects.

Bi Y, Liu G, Yang R

State Key laboratory of Pathogen and Biosecurity, National Center for

Biomedical Analysis, Army Center for Microbial Detection and

Research, Institute of Microbiology and Epidemiology, Academy of

Military Medical Sciences (AMMS), Beijing, China.

The T help 1 (Th1) and Th2 cell classification have provided the

framework for understanding CD4(+) T cell biology and the interplay

between innate and adaptive immunity for almost two decades. Recent

studies have defined a previously unknown arm of the CD4(+) T cell

effector response, the Th17 lineage, which promises to change our

understanding of immune regulation, immune pathogenesis and host

defense. The factors that specify differentiation of IL-17 producing

effector T cells from naive T cell precursors are being rapidly

discovered and are providing insights into mechanisms by which

signals from cells of the innate immune system guide alternative

pathways of Th1, Th2, or Th17 development. In this review, we will

focus on recent studies that have identified new subsets of Th cells,

new insights regarding the induced generation and differentiation

mechanisms of Th17 cells and immune regulatory effects. PMID:

17311299.

_______________________________________

Nat Med. 2007 Feb;13(2):139-45.

A brief history of T(H)17, the first major revision in the T(H)1/T(H)

2 hypothesis of T cell-mediated tissue damage.

Steinman L

Interdepartmental Program in Immunology, Department of Neurology and

Neurological Sciences, Beckman Center for Molecular Medicine,

Stanford University, Stanford, California 94305, USA.

steinman@...

For over 35 years, immunologists have divided T-helper (T(H)) cells

into functional subsets. T-helper type 1 (T(H)1) cells-long thought

to mediate tissue damage-might be involved in the initiation of

damage, but they do not sustain or play a decisive role in many

commonly studied models of autoimmunity, allergy and microbial

immunity. A major role for the cytokine interleukin-17 (IL-17) has

now been described in various models of immune-mediated tissue

injury, including organ-specific autoimmunity in the brain, heart,

synovium and intestines, allergic disorders of the lung and skin, and

microbial infections of the intestines and the nervous system. A

pathway named T(H)17 is now credited for causing and sustaining

tissue damage in these diverse situations. The T(H)1 pathway

antagonizes the T(H)17 pathway in an intricate fashion. The evolution

of our understanding of the T(H)17 pathway illuminates a shift in

immunologists' perspectives regarding the basis of tissue damage,

where for over 20 years the role of T(H)1 cells was considered

paramount. PMID: 17290272.

_______________________________________

Autoimmun Rev. 2007 Jan;6(3):169-75.

Autoimmune inflammation from the Th17 perspective.

Furuzawa-Carballeda J, Vargas-Rojas MI, Cabral AR

Department of Immunology and Rheumatology, Instituto Nacional de

Ciencias Medicas y Nutricion Salvador Zubiran, Vasco de Quiroga 15

Tlalpan, Mexico City 14000, Mexico.

Recent studies demonstrated an IL-17-producer CD4+ T cell

subpopulation, termed Th17, distinct from Th1 and Th2. It represents

a different pro-inflammatory Th-cell lineage. This notion is

supported by gene-targeted mice studies. Mice lacking IL-23 (p19-/-)

do not develop experimental autoimmune encephalomyelitis (EAE) or

collagen-induced arthritis (CIA), while knockout mice for the Th1

cytokine IL-12 (p35-/-) strongly develop both autoimmune diseases.

Disease resistance by IL-23 knockout mice correlates well with the

absence of IL-17-producing CD4(+) T lymphocytes in target organs

despite normal presence of antigen-specific-IFN-gamma-producing Th1

cells. This finding may thus explain previous contradictory reports

showing that anti-IFN-gamma-treated mice, IFN-gamma- or IFNR-

deficient mice develop CIA or EAE. TGF-beta, IL-6 and IL-1 are the

differentiation factors of Th17 cells. IL-23 is dispensable for this

function, but necessary for Th17 expansion and survival. The master

regulator that directs the differentiation program of Th17 cells is

the orphan nuclear receptor RORgammat. IL-27, a member of the IL-

12/IL-23 family, potently inhibits Th17 development. Evidence

suggesting rheumatoid arthritis and multiple sclerosis as primarily

IL-17 autoimmune inflammatory-mediated diseases is rapidly

accumulating. The IL-17/23 axis of inflammation and related molecules

may rise as therapeutic targets for treating these and perhaps other

autoimmune diseases. PMID: 17289553.

_______________________________________

Nat Immunol. 2007 Mar;8(3):247-56.

The adaptor Act1 is required for interleukin 17-dependent signaling

associated with autoimmune and inflammatory disease.

Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D, Xiao J,

Lu Y, Giltiay N, Liu J, Kordula T, Zhang QW, Vallance B, Swaidani S,

Aronica M, Tuohy VK, Hamilton T, Li X

Department of Immunology, Cleveland Clinic, Cleveland, Ohio 44195,

USA.

T helper cells that produce interleukin 17 (IL-17) are associated

with inflammation and the control of certain bacteria. We report here

the essential involvement of the adaptor protein Act1 in IL-17

receptor (IL-17R) signaling and IL-17-dependent immune responses.

After stimulation with IL-17, recruitment of Act1 to IL-17R required

the IL-17R conserved cytoplasmic 'SEFIR' domain, followed by

recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6, which

mediate 'downstream' activation of transcription factor NF-kappaB. IL-

17-induced expression of inflammation-related genes was abolished in

Act1-deficient primary astroglial and gut epithelial cells. This

reduction was associated with much less inflammatory disease in vivo

in both autoimmune encephalomyelitis and dextran sodium sulfate-

induced colitis. Our data show that Act1 is essential in IL-17-

dependent signaling in autoimmune and inflammatory disease. PMID:

17277779.

_______________________________________

Annu Rev Immunol. 2007;25:821-52.

IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell

Lineages.

Weaver CT, Hatton RD, Mangan PR, Harrington LE

1Departments of Pathology and 2Microbiology, University of Alabama at

Birmingham, Birmingham, Alabama 35294; email: cweaver@....

Since its conception two decades ago, the Th1-Th2 paradigm has

provided a framework for understanding T cell biology and the

interplay of innate and adaptive immunity. Naive T cells

differentiate into effector T cells with enhanced functional

potential for orchestrating pathogen clearance largely under the

guidance of cytokines produced by cells of the innate immune system

that have been activated by recognition of those pathogens. This

secondary education of post-thymic T cells provides a mechanism for

appropriately matching adaptive immunity to frontline cues of the

innate immune system. Owing in part to the rapid identification of

novel cytokines of the IL-17 and IL-12 families using database

searches, the factors that specify differentiation of a new effector

T cell lineage-Th17-have now been identified, providing a new arm of

adaptive immunity and presenting a unifying model that can explain

many heretofore confusing aspects of immune regulation, immune

pathogenesis, and host defense. PMID: 17201677.

_______________________________________

J Exp Med. 2006 Dec 25;203(13):2785-91.

Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune

disease.

Lohr J, Knoechel B, Wang JJ, Villarino AV, Abbas AK

Department of Pathology, University of California, San Francisco

School of Medicine, San Francisco, CA 94143, USA.

To explore the interactions between regulatory T cells and pathogenic

effector cytokines, we have developed a model of a T cell-mediated

systemic autoimmune disorder resembling graft-versus-host disease.

The cytokine responsible for tissue inflammation in this disorder is

interleukin (IL)-17, whereas interferon (IFN)-gamma produced by Th1

cells has a protective effect in this setting. Because of the

interest in potential therapeutic approaches utilizing transfer of

regulatory T cells and inhibition of the IL-2 pathway, we have

explored the roles of these in the systemic disease. We demonstrate

that the production of IL-17 and tissue infiltration by IL-17-

producing cells occur and are even enhanced in the absence of IL-2.

Regulatory T cells favor IL-17 production but prevent the disease

when administered early in the course by suppressing expansion of T

cells. Thus, the pathogenic or protective effects of cytokines and

the therapeutic capacity of regulatory T cells are crucially

dependent on the timing and the nature of the disease. PMID: 17130300.

_______________________________________

Eur J Immunol. 2006 Nov;36(11):2844-8.

Comment on:

Eur J Immunol. 2006 Nov;36(11):2849-56.

Eur J Immunol. 2006 Nov;36(11):2857-67.

Eur J Immunol. 2006 Nov;36(11):2868-74.

Anti-cytokine vaccines and the immunotherapy of autoimmune diseases.

Wraith DC

Department of Cellular and Molecular Medicine, University of Bristol,

School of Medical Sciences, Bristol, UK. d.c.wraith@...

Three papers in this issue of the European Journal of Immunology

describe the use of cytokine vaccines to prevent autoimmune disease

in experimental animals. The vaccines are based on interleukin 17 (IL-

17), a cytokine that has recently been shown to play a central role

in inflammation. PMID: 17072913.

_______________________________________

Eur J Immunol. 2006 Nov;36(11):2868-74.

Comment in:

Eur J Immunol. 2006 Nov;36(11):2844-8.

Development of an anti-IL-17A auto-vaccine that prevents experimental

auto-immune encephalomyelitis.

Uyttenhove C, Van Snick J

Ludwig Institute for Cancer Research, Brussels Branch, Brussels,

Belgium. catherine.uyttenhove@...

IL-17 has been associated with multiple inflammatory disorders such

as rheumatoid arthritis, asthma and multiple sclerosis. As these

diseases require long-term treatment we turned to an auto-vaccine

strategy for IL-17 neutralization in vivo. Mouse IL-17A was

covalently linked to ovalbumin and used to immunize C57BL/6 mice.

This vaccine induced the production of antibodies that blocked IL-17A

bioactivity in vitro but did not react with the other IL-17 isoforms,

including IL-17F. As the half-life of the Ab titers after the last

immunogen administration was approximately 4 months, the vaccine

provides for long lasting and selective inhibition of IL-17A activity

in vivo. A monoclonal Ab (mAb) derived from these mice showed the

same specificity for IL-17A. To test the ability of the vaccine to

confer protection against an IL-17-dependent disorder, SJL mice were

vaccinated with IL-17-OVA and encephalomyelitis (EAE) was induced by

proteolipid protein (PLP) peptide 139-151. Vaccinated mice were

completely protected against the disease. The above-mentioned anti-IL-

17A mAb also prevented EAE development. The absence of clinical

symptoms contrasted with unaltered PLP-induced cytokine production in

vitro and unmodified anti-PLP IgG titers and isotypes. These results

suggest that an anti-IL-17A auto-vaccine offers new perspectives for

therapy of autoimmune diseases. PMID: 17048276.

_______________________________________

Eur J Immunol. 2006 Nov;36(11):2857-67.

Comment in:

Eur J Immunol. 2006 Nov;36(11):2844-8.

Vaccination against IL-17 suppresses autoimmune arthritis and

encephalomyelitis.

Rohn TA, Jennings GT, M, Grest P, Beck M, Zou Y, Kopf M,

Bachmann MF

Cytos Biotechnology AG, Immunodrugs, Zurich, Switzerland.

Interleukin 17 is a T cell-derived cytokine that induces the release

of pro-inflammatory mediators in a wide range of cell types.

Recently, a subset of IL-17-producing T helper cells (Th17) distinct

from Th1 and Th2 cells has been described, which constitutes a new T

cell polarization state. Aberrant Th17 responses and overexpression

of IL-17 have been implicated in a number of autoimmune disorders

including rheumatoid arthritis and multiple sclerosis. Molecules

blocking IL-17 such as IL-17-specific monoclonal antibodies have

proved to be effective in ameliorating disease in animal models.

Hitherto, active immunization targeting IL-17 is an untried approach.

Herein we explore the potential of neutralizing IL-17 by active

immunization using virus-like particles conjugated with recombinant

IL-17 (IL-17-VLP). Immunization with IL-17-VLP induced high levels of

anti-IL-17 antibodies thereby overcoming natural tolerance, even in

the absence of added adjuvant. Mice immunized with IL-17-VLP had

lower incidence of disease, slower progression to disease and reduced

scores of disease severity in both collagen-induced arthritis and

experimental autoimmune encephalomyelitis. Active immunization

against IL-17 therefore represents a novel therapeutic approach for

the treatment of chronic inflammatory diseases. PMID: 17048275.

_______________________________________

Eur J Immunol. 2006 Nov;36(11):2849-56.

Comment in:

Eur J Immunol. 2006 Nov;36(11):2844-8.

Neutralization of IL-17 by active vaccination inhibits IL-23-

dependent autoimmune myocarditis.

Sonderegger I, Rohn TA, Kurrer MO, Iezzi G, Zou Y, Kastelein RA,

Bachmann MF, Kopf M

Institute of Integrative Biology, Molecular Biomedicine, ETH Zurich,

Switzerland.

The most common reason for heart failure in young adults is dilated

cardiomyopathy often resulting from myocarditis. Clinical studies and

animal models provide evidence that an autoimmune response against

heart myosin is the underlying reason for the disease. IL-12 has been

suggested to play a key role in development of experimental

autoimmune myocarditis (EAM), as IL-12p40 and IL-12Rbeta1 knockouts

are protected from disease. In this study, we have compared IL-12p40-

/- mice, IL-12p35-/- mice and mice treated with a neutralizing IL-23

antibody in EAM and found that in fact IL-23, not IL-12, is

responsible for inflammatory heart disease. However, these cytokines

appear to have redundant activity for priming and expansion of

autoreactive CD4 T cells, as specific T cell proliferation was only

defective in the absence of both cytokines. IL-23 has been suggested

to promote a pathogenic IL-17-producing T cell population. We

targeted IL-17 by capitalizing on an active vaccination approach that

effectively breaks B cell tolerance. Neutralization of IL-17 reduced

myocarditis and heart autoantibody responses, suggesting that IL-17

is the critical effector cytokine responsible for EAM. Thus,

targeting of IL-23 and IL-17 by passive and active vaccination

strategies holds promise as a therapeutic approach to treat patients

at risk for development of dilated cardiomyopathy. PMID: 17039570.

_______________________________________

Ann Rheum Dis. 2006 Nov;65 Suppl 3:iii29-33.

Potential new targets in arthritis therapy: interleukin (IL)-17 and

its relation to tumour necrosis factor and IL-1 in experimental

arthritis.

Koenders MI, Joosten LA, van den Berg WB

Radboud University Nijmegen Medical Center, Department of

Rheumatology, Rheumatology Research and Advanced Therapeutics, 272,

Geert Grooteplein 26, PO Box 9101, 6500 HB Nijmegen, the Netherlands.

m.koenders@...

Rheumatoid arthritis (RA) is a systemic autoimmune disease

characterised by chronic joint inflammation and destruction.

Interleukin (IL)-17 is a T cell cytokine expressed in the synovium

and synovial fluid of patients with RA. IL-17 is a potent inducer of

various cytokines such as tumour necrosis factor (TNF) and IL-1. IL-

17 has been shown to have additive or even synergistic effects with

TNF and IL-1 during the induction of cytokine expression and joint

damage in vitro and in vivo. TNFalpha and IL-1 are considered

powerful targets in the treatment of RA because of their leading role

in driving the enhanced production of cytokines, chemokines, and

degradative enzymes. Besides anti-TNF and anti-IL-1 therapies, whose

clinical efficacy is now established, new targets have been proposed

for RA which is not responding to conventional treatments. This paper

discusses the role of IL-17 in experimental arthritis and its

interrelationship with TNF and IL-1, currently the most targeted

cytokines in the treatment of RA. IL-17 is involved in both

initiation and progression of murine experimental arthritis. Studies

have shown that IL-17 not only synergises with TNF, but also enhances

inflammation and destruction independent of IL-1 and TNF. On the

basis of these studies, the authors propose IL-17 as an interesting

additional target in the treatment of RA. PMID: 17038468.

_______________________________________

Curr Opin Immunol. 2006 Dec;18(6):670-5.

Erratum in: Curr Opin Immunol. 2007 Feb;19(1):111.

The IL-23/Th(17) axis: therapeutic targets for autoimmune

inflammation.

Kikly K, Liu L, Na S, Sedgwick JD

Eli Lilly and Company, Indianapolis, IN 46285, USA.

Autoimmune inflammatory responses and the diseases that develop as a

consequence are now thought to be driven through a novel non-Th(1)

pathway. IL-23, together with additional factors including TGF-beta1

and IL-6, collectively generate and sustain a distinct CD4(+) 'Th(17)

inflammation effector' T-cell subset characterized by its production

of inflammatory chemokines and cytokines, including IL-17. With this

paradigm shift in understanding of autoimmune inflammation

pathogenesis comes exciting opportunities to identify and to target

therapeutically molecules within the IL-23/Th(17) axis that are key

to disease development. PMID: 17010592.

_______________________________________

Nat Immunol. 2006 Sep;7(9):929-36.

Comment in: Nat Immunol. 2006 Sep;7(9):899-901.

Interleukin 27 limits autoimmune encephalomyelitis by suppressing the

development of interleukin 17-producing T cells.

Batten M, Li J, Yi S, Kljavin NM, Danilenko DM, Lucas S, Lee J, de

Sauvage FJ, Ghilardi N

Department of Molecular Biology, Genentech, South San Francisco,

California 94080, USA.

Interleukin 27 (IL-27) was first characterized as a proinflammatory

cytokine with T helper type 1-inducing activity. However, subsequent

work has demonstrated that mice deficient in IL-27 receptor (IL-27R

alpha) show exacerbated inflammatory responses to a variety of

challenges, suggesting that IL-27 has important immunoregulatory

functions in vivo. Here we demonstrate that IL-27R alpha-deficient

mice were hypersusceptible to experimental autoimmune

encephalomyelitis and generated more IL-17-producing T helper cells.

IL-27 acted directly on effector T cells to suppress the development

of IL-17-producing T helper cells mediated by IL-6 and transforming

growth factor-beta. This suppressive activity was dependent on the

transcription factor STAT1 and was independent of interferon-gamma.

Finally, IL-27 suppressed IL-6-mediated T cell proliferation. These

data provide a mechanistic explanation for the IL-27-mediated immune

suppression noted in several in vivo models of inflammation. PMID:

16906167.

_______________________________________

J Exp Med. 2006 Oct 30;203(11):2473-83.

Interleukin-23 drives innate and T cell-mediated intestinal

inflammation.

Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie

F, Maloy KJ

Sir Dunn School of Pathology, University of Oxford, Oxford

OX1 3RE, England, UK.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder

of the gastrointestinal tract involving aberrant activation of innate

and adaptive immune responses. We have used two complementary models

of IBD to examine the roles of interleukin (IL)-12 family cytokines

in bacterially induced intestinal inflammation. Our results clearly

show that IL-23, but not IL-12, is essential for the induction of

chronic intestinal inflammation mediated by innate or adaptive immune

mechanisms. Depletion of IL-23 was associated with decreased

proinflammatory responses in the intestine but had little impact on

systemic T cell inflammatory responses. These results newly identify

IL-23 as a driver of innate immune pathology in the intestine and

suggest that selective targeting of IL-23 represents an attractive

therapeutic approach in human IBD. PMID: 17030949.

______________________

Nat Med. 2007 Jan;13(1):26-8.

IL-23: a master regulator in Crohn disease.

Neurath MF

(no abstract available)

PMID: 17206128