n experimental allergic encephalo-myelitis (EAE), an animal model formultiple sclerosis (MS), T helper 1(Th1)/Th2 immunological effector

pathways are altered. Neuropathologicalfindings and results from MS treatment tri-als suggest that our view of MS and otherputative autoimmune diseases and theiranimal models as Th1-mediated diseases istoo simplistic and that the Th1/Th2 para-digm is overstated.

Regulation and differentiation ofcytokine phenotypeIn a keynote address, W. Paul (Bethesda,MD) noted that the Th1/Th2 paradigm hasremained remarkably robust for 15 yearsand has had a fundamental impact on ourunderstanding of a broad variety of disor-ders including autoimmunity. He statedthat Th1-driven autoimmune disease maybe the ‘price one has to pay’ for having abroad T-cell-based immune response thateliminates viral and other infections viaTh1-cell mechanisms. By contrast, allergicdiseases such as asthma may be the ‘price’for strong Th2-type responses necessary tofight parasitic diseases.

The cytokine environment in whichnaive T cells differentiate is key to the entireTh1/Th2 paradigm. Priming without inter-leukin 4 (IL-4) leads to interferon g (IFN-g)production, which is enhanced by IL-12. Bycontrast, IL-4 is the primary inducer of Th2-cell differentiation. Paul noted that IL-4binds with high affinity to the IL-4 receptor(IL-4R) a-chain, which then recruits thecommon g-chain to which the Janus familykinases JAK2 and -3 bind after phosphoryl-ation of five conserved tyrosine residues.The latter regulates not only IL-4-mediatedgrowth, but also the binding of the signaltransducer and activator of transcriptionSTAT6 and subsequent gene activation. Mu-tations of these domains may result in atopy

and asthma. Knockout experiments demon-strated the importance of STAT6 for Th2-celldevelopment.

An important question raised by Pauland subsequent speakers was whether Tcells, once differentiated into Th1 or Th2cells, can change their Th1/Th2 polariz-ation. In vitro polarized T cells transferred tocongenic animals were remarkably stablebeyond 18 months. Restimulation of Th2cells in the presence of IL-12 resulted in cellssecreting IL-4 and IFN-g or even only IFN-g,due to reduced expression and phosphoryl-ation of JAK3 and STAT6, and inactivationof the IL-4R. Paul suggested that further dis-section of the intracellular pathways allowstherapeutic manipulations of Th1 and Th2cells in autoimmune diseases.

K. Murphy (St Louis, MO) noted that inT-cell differentiation STAT4-mediated-IFN-g gene activation is positively regulated byERM (a member of the Ets family of tran-scription factors) and negatively regulatedby the intermediate repressor GATA3, whichis probably independent of IL-4 and deacti-vated by STAT4. The STAT4 pathway isunique for Th1-cell development and alsoactivates IL-12. Proof of the activating prop-erties of GATA3 for the Th2-cell pathwaycame from antisense transfection experi-ments (R. Flavell, New Haven, CT) and frommutagenesis studies of the GATA3 site of theIL-5 promoter (A. Ray, New Haven, CT).Commitment to the Th1 or Th2 lineage wasrelated to the differential expression of theIL-12R b2-chain: expressed in Th1 cells,

which can thus respond to IL-12, but not inTh2 cells. Th2-cell priming in the presence ofIFN-g maintains IL-12R b2-chain expression,which is abrogated by IL-4 alone. This ex-plains why early Th2-cell cultures, which donot express the IL-12R b2-chain, are resistantto IL-12. Thus, the initial priming conditionsare crucial in determining whether theTh1/Th2 differentiation is reversible or not.

Knocking out both STAT4 and -6 resultsin mice that develop Th1 but no Th2 cellssuggesting that IFN-g secretion is the de-fault pathway (M. Grusby, Boston, MA). IfSTAT6 is not bound to the IL-4R, cells willproduce IFN-g, which is further enhancedby STAT4 activation. Flavell stressed thatsimilar principles are operative in both armsof the cytokine differentiation pathways, i.e.factors that act directly and factors that in-hibit or induce others that operate in thesame or opposite direction. Ray showed thatthese pathways can be followed in vivo byenhanced GATA3 expression and related IL-5 secretion in biopsies and bronchoalveolarfluids from asthma patients. Infections mayinfluence the Th1 or Th2 bias in positive ornegative ways, and the absence of infectionsrather than the exposure to allergens may beresponsible for the rise in allergic diseases.

A series of talks examined how thestrength of the T-cell receptor (TCR) signalinfluences cytokine secretion. K. Bottomly(New Haven, CT) reported that Th1/Th2differentiation depends on the dose of thepriming peptide and its affinity to major his-tocompatibility complex (MHC) moleculesas well as the TCR. As a rule, Th2-type cyto-kines are induced as a result of weak TCRsignals. With respect to co-receptor interac-tions, binding of CD4 to MHC class II wasless important for IFN-g secretion, but cru-cial for Th2-cell development. By contrast,A. Abbas (Boston, MA) reported data ob-tained in a transgenic mouse system that in-dicated that a higher antigen dose led to Th2bias. IL-2 is important for maintaining

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T helper cell differentiation in multiple sclerosis andautoimmunity

Roland Martin, Nancy H. Ruddle, Stephen Reingold and David A. Hafler

Researchers from the fields of basic

immunology and autoimmune

disease, largely but not exclusively

focused on multiple sclerosis, came

together at a recent workshop* to

develop a better understanding of

T helper cell responses in

autoimmune disease.

I

*The International Workshop on Th1/Th2: T-Cell Differentiation in MSand Autoimmunity was held at Savannah, GA, USA, on 1–5 April 1998.

and/or shutting down Th1 or Th2 cells, andcrucial for Fas–Fas-ligand (FasL)-mediatedcell death via activation of FLICE (caspase8), whereas IL-4 does not have this effect.

R. Germain (Bethesda, MD) outlinedhow changes of antigen structure and doseimpact on functional T-cell activation andTCR signaling. He demonstrated the influ-ences of various ligands on TCR activationand introduced a kinetic model of signalingin which partially phosphorylated forms ofTCR z chain (p21 in mice, p32/35 in hu-mans), which do not or only poorly recruitZAP-70, do not lead to agonist function. Thepartial phosphorylation state results in de-layed and transient mitogen-activated pro-tein (MAP) kinase activity, which also al-lows SHP-1 phosphatase activity. Bycontrast, the agonist ligand induces full TCRz phosphorylation (p23 in mice, p38 in hu-mans), early and sustained MAP kinase ac-tivity and little SHP-1. This in turn leads toefficient ZAP-70 recruitment and down-stream signaling. Thus TCR activation relieson positive feedback pathways to assurethat a certain threshold is reached. Time andstrength of the signal are both critical to per-mit selective TCR amplification.

Functional aspects of TCR activation werepresented by B. Hemmer (Bethesda, MD),who demonstrated that different cytokinesare not activated all at once but according toa clone-specific hierarchy. This can bebrought about by varying either the dose(quantity of the stimulus) or potency (struc-ture) of the ligand. For defined levels of func-tional activation, it is important to achieve acertain degree of TCR downmodulation and,with human CD41 clones, each TCR ligandshowed a characteristic pattern of z-chainphosphorylation and ZAP-70 recruitment,which could not be altered by changing anti-gen dose. Depending on the cytokine acti-vation hierarchies of individual T cells inmixed populations, the response to differentantigen doses will result in a Th1 or Th2 bias.

The biological relevance of altered pep-tide ligands (APLs) was addressed by V.Kuchroo (Boston, MA) in an EAE modelusing the encephalitogenic proteolipid pro-tein (PLP) 139–151 peptide modified in theTCR contact position Q144. When the pri-mary TCR contact was shifted to the N-ter-minus, this peptide induced Th2 clones.

Since the latter cells are protective in vivo,the data suggested that the APL expands aprotective Th2-cell repertoire that is distinctfrom the pathogenic Th1 cells.

The role of costimulationA. Sharpe (Boston, MA) emphasized thatCTLA-4 is important for turning off acti-vated cells, as indicated by widespread lym-phoproliferation in CTLA-4-deficient mice.She described the crucial homeostatic bal-ance between CD28-mediated activationand downregulation by CTLA-4. Mice lack-ing both B7-1 and B7-2 are severely im-munocompromised, and studies withsplenic antigen-presenting cells lacking ei-ther receptor demonstrate that both con-tribute to IFN-g and IL-4 production, particu-larly during priming under suboptimalconditions. When EAE was induced in B7-1/2-deficient mice with myelin oligoden-drocyte glycoprotein (MOG), which triggersmyelin-specific T cells as well as antibodies,these developed only mild disease. Interest-ingly, IFN-g secretion was similar to that inwild-type animals, whereas IL-10 secretionwas markedly reduced.

The role of B7 costimulation was furtherdiscussed by S. Miller (Evanston, IL), whohad previously demonstrated that CD28–B7interactions by CTLA-4–Ig inhibited the in-duction of EAE. Expression of certain cyto-kine mRNAs, i.e. IFN-g and tumor necrosisfactor a (TNF-a), correlates with diseaseonset, whereas IL-4 expression correlateswith remission. By contrast, in Theiler’svirus-induced encephalomyelitis, TNF-aappeared before onset, IFN-g steadily rose,and IL-4 and IL-10 did not seem to play aregulatory role. In EAE, B7-1 is preferen-tially upregulated on T cells, macrophagesand B cells in the central nervous system(CNS) and periphery, and anti-B7-1 F(ab)2,but not anti-B7-2 therapy, during disease re-mission blocked epitope spreading and re-sulted in long-term inhibition of relapses.Increased B7-1 expression has also beendemonstrated in MS brain tissue (D. Hafler,Boston, MA; J. Antel, Montreal, CA). In vitrodata from Hafler’s and M. Racke’s (St Louis,MO) laboratories showed that myelin-spe-cific T cells from healthy individuals requireB7 costimulation, whereas T cells from MS

patients are costimulation-independent.Abbas and Sharpe both presented datashowing that CD28–B7 interaction is impor-tant for IL-4 secretion.

Innate immune system effects onT-cell differentiationThe role of the innate immune system inshaping the cytokine milieu was addressedby A. Bendelac (Princeton, NJ). CD1d spe-cializes in presenting lipids to a subset of Tcells expressing invariant TCRs (Va24 andVb11 in humans; Va14 and Vb8 in mice).There is evidence for two functionally dis-tinct subsets of CD1d-restricted autoreactiveT cells. These natural killer (NK)/T cellsmay secrete either IL-4 or IFN-g and thusshape an evolving immune response. Thepotential role of CD1d NK1.1 T cells in ani-mal models of autoimmune disease waspresented by J-F. Bach (Paris), who showedthat nonobese diabetic (NOD) mice have anumerical and functional defect of thispopulation. Overexpression of IL-4-produc-ing NK1.1 T cells prevents diabetes onsetand inhibits disease transfer. This cell popu-lation may be important in orchestrating aregulatory CD41 T-cell population. A simi-lar defect (i.e. lack of IL-4 production) hasbeen demonstrated by Hafler in diabetes pa-tients, and NK1.1 T cells are probably rel-evant in EAE as well.

Experimental models of cytokinesecretionN. Ruddle (New Haven, CT) reviewed theconflicting conclusions derived from experi-ments with cytokine knockout and transgenicmice examining Th1-type cytokines, particu-larly IFN-g and the TNF/lymphotoxin(TNF/LT) family. Their roles as Th1 medi-ators are confused by the fact that, althoughall three members of the TNF/LT family (LT-a3, LT-a1 b2, and TNF-a3) are produced byactivated CD41 Th1 and CD81 cells, TNF-a isalso secreted by many other cell types andmay even serve physiological functions in theCNS. TNFs are involved in the migration ofautoreactive T cells across the blood–brainbarrier, the recruitment of other inflammatorycells, the damage of oligodendrocytes andmyelin and reactive gliosis. Ruddle speculated

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that LT, because of its crucial role in lymphoiddevelopment, may also be involved in theperpetuation of disease by establishing ter-tiary lymphoid organs in the target tissue. Invarious knockout strains in which IFN-g, theIFN-gR, TNF-a, LT-a or LT-b, or TNF-a andLT-a, had been targeted, IFN-g had either noeffect or appeared to be protective in animalswith different backgrounds. TNF/LT knock-out mice demonstrated more variable effects,with a slight reduction in disease severity (LT-b knockout) in a MOG-induced EAE modelbut stronger effects, i.e. no disease, in the LT-a knockout. LT-a was thus clearly establishedas a major Th1-type cytokine in EAE. Inter-estingly, K. Frei (Zürich) observed that EAEinduction in double-knockout mice (TNF-aand LT-a, H2-S) with mixed spinal cord hom-ogenate, PLP or MOG showed more severedisease (mortality up to 100%). It becameclear that both background genes and the en-cephalitogen are important modulators ofdisease course and severity. TNF expressionin the brain of transgenic mice under the con-trol of the myelin basic protein (MBP) pro-moter, and thus targeted to oligodendrocytes(T. Owens, Montreal), did not result in spon-taneous disease, but more severe inducedEAE. Recent data suggested Fas–FasL inter-actions as an important effector pathway formyelin damage, but Frei demonstrated thatoligodendrocytes in contrast to astrocytes areresistant to Fas-mediated lysis, and mice withnatural mutations of Fas (lpr) or FasL (gld)showed monophasic disease. By contrast,perforin knockout mice exhibited very severeand chronic-relapsing disease (Frei). The in-volvement of Fas–FasL-mediated apoptosisin nonobese diabetes (L. Matis, New Haven,CT) indicates that different damaging mecha-nisms may be operative in different putativeTh1-mediated autoimmune diseases.

Chemokine receptors as markersfor Th1 and Th2 cellsA. Lanzavecchia (Basel) summarized recentobservations on the preferential expressionof certain chemokine receptors in commit-ted Th1 (CXCR3, CCR5) or Th2 (CCR3,CCR4) clones. Although an understandingof the role of chemokines and their receptorsin defined T-cell subsets is just evolving, S. Romagnani (Florence) has already demon-

strated the differential expression of theTh2-associated chemokine receptor CCR4 intissue of patients with systemic sclerosisand in Kaposi’s sarcoma. Furthermore, encephalitogenic T cells in EAE express distinct chemokine profiles (S. Brocke,Bethesda, MD), which are apparently im-portant for the selective migration to CNStissue. Thus, the complexity of the cytokinesecretion patterns, i.e. simultaneous secre-tion of Th1- and Th2-type cytokines, is fur-ther complicated by the expression of differ-ent chemokines as well as their receptors.

Cytokine profiles in MS and otherdiseases, and treatmentapproachesB. Arnason (Chicago, IL) reported puzzlingdata from a Phase II multicenter trial in MSwith three doses of recombinant fusion pro-tein of the p55 TNFR IgG1 Fc fusion proteinwith the rationale to capture TNF-a/LT-a.Both the number and the duration of exac-erbation rates increased in treated patientswithout a significant change in magneticresonance imaging (MRI) activity. Whetherthese results indicate that TNF has benefi-cial rather than damaging effects in MS, con-trary to prior belief, or whether they suggestthat the TNFR fusion protein first capturesand then slowly releases TNF, serving as adepot and prolonging inflammation, is cur-rently not clear. M. Feldmann (London)compared this observation with studies ofanti-TNF antibodies in rheumatoid arthritis(RA) where TNF-a is well established as theprimary disease effector and anti-TNF im-proves all parameters of disease. He specu-lated that MS may be more heterogeneousthan RA with respect to the cellular versushumoral inflammatory mechanisms andthat the target tissue in MS is much less ac-cessible than the joint in RA, in particularfor large molecules.

H. Lassmann (Vienna) showed that thehistopathological patterns of inflammationand demyelination in MS are homogeneousin a given patient, but differ between pa-tients. Careful staging of MS plaques, withrespect to inflammatory cells, complementand antibody deposition, expression ofmyelin proteins and signs of oligodendro-cyte dystrophy or axonal changes, indicated

six different pathological patterns. He con-cluded that MS is pathologically more het-erogeneous than previously appreciated andthat this aspect merits further study. Theseobservations were supported by C. Lining-ton’s (Munich) EAE experiments, which fo-cused on MOG-induced EAE in rats. MOGhas an extracellular Ig-like domain and hadpreviously been shown by Linington to be atarget of myelin-specific antibodies. In MBP-induced disease in Lewis rats, EAE ismonophasic and purely inflammatory; how-ever, MOG-specific antibodies lead to de-myelination. In BN rats resistant to MBP-induced EAE, only 100 mg of MOG withcomplete Freund’s adjuvant (CFA) leads toacute lethal EAE with widespread demyeli-nation and eosinophil infiltration similar tothat observed in fulminant cases of MS. Healso pointed out that EAE in mice is mostlyTh1-cell- and cytokine-mediated, whereasantibodies and Th2-type mechanisms aremore important in rats and marmosets. Thisheterogeneity creates a dilemma with re-spect to the Th1/Th2 balance for diseasemechanisms and therapy.

Hafler argued for a Th1 bias in MS. Hisresults with peripheral blood T cells stimu-lated with MBP or tetanus toxoid underTh1- or Th2-biasing conditions showed nodifference in the cytokine patterns betweenpatients and controls. However, fewer MBP-reactive and IL-4-secreting cells and morecells secreting IFN-g were seen in progres-sive MS, underscoring the previously re-ported increased IL-12 secretion. Further-more, unlike the case for relapsing–remittingMS patients and controls, MBP-reactive Tcells expanded from progressive MS patientsoften secreted cytokines in the absence ofsignificant [3H]thymidine incorporation.

L. Weiner (Los Angeles, CA) reportedthat T cells from progressive MS patients arerefractory to dexamethasone-induced apop-tosis and that more IL-10-secreting, PLP-specific clones could be isolated during re-missions, suggesting a regulatory role of IL-10 in MS. This is supported by R. Rudick’s(Cleveland, OH) data on elevated serum andcerebrospinal fluid (CSF) IL-10 levels duringtherapy with recombinant IFN-b.

Several speakers addressed whether thecytokine profiles of myelin-specific T cellsdistinguish which cell population may be

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disease-related. T. Olsson (Stockholm) de-scribed higher frequencies of myelin-reac-tive Th1 and Th2 cells by ELISPOT assay inperipheral blood and CSF of MS patients.Individuals with higher numbers of TGF-b-secreting cells had milder disease, and HLA-DR21 MS patients responded strongly withIFN-g production to the immunodominantMBP peptides 84–102 and 146–165 and MOG67–87. M. Vergelli (Florence) correlated thespecificity patterns of MBP-specific T cells inthree MS patients longitudinally with MRIactivity. He demonstrated bursts duringwhich novel reactivities appeared, but it isnot clear yet whether these coincide with increased lesion activity. There was also aslight over-representation of Th2-type cellsduring increased disease activity. J. Zhang(Houston, TX) found higher numbers ofIFN-g-secreting cells in response to MBP inboth patients and controls. In summary, allthese investigations suggest that there is anincreased frequency of myelin-reactive Tcells directed against several myelin epi-topes; however, a clear correlation of certaincytokine phenotypes with disease activitydoes not exist.

R. Martin (Bethesda, MD) summarized thebroad spectrum of therapeutic approaches inuse or considered for MS, which range fromconventional chemotherapy to proven agentssuch as IFN-b1a and -1b and copolymer 1(glatiramir acetate) to more target-specific ap-proaches, such as APL, T-cell (A. Vandenbark,Portland, OR) and DNA (L. Steinman, PaloAlto, CA) vaccination. Although specific ap-proaches offer the advantage of fewer side ef-fects and target only a defined pathogeneticaspect, they also carry a higher risk of failureif we do not know the target antigen in thedisease or the damaging cytokine(s). Lessonsfrom IFN-b treatment, which efficientlyblocks early inflammatory activity in MS butmay be less active at later stages of disease, in-dicate difficulties in reaching the target tissueand/or differential efficacy with respect tothe various stages of MS.

L. Adorini (Milan) presented evidence thatTh2-type cytokines are protective in insulin-dependent diabetes mellitus, whereas Th1cells and IL-12 are pathogenic. In EAE, onlymicroglia produce IL-12 (p75), and this can beinhibited by IL-10 and by astrocytes. VitaminD3 derivatives that potently block IL-12 secre-

tion and EAE and lack the hypercalcemicside-effects provide an attractive novel treat-ment approach. N. Sommer (Tübingen) intro-duced the concept of preferential Th1-typecytokine inhibition by inhibitors of phospho-diesterase type IV (PDE-IV), an enzyme ex-pressed in the immune system and brain thatregulates multiple cellular processes by in-creasing the second messenger cyclic AMP (c-AMP). PDE IV inhibition abrogates acute-and chronic-relapsing EAE in mice, rats andmarmosets. Due to its preferential, but not ex-clusive, inhibition of Th1-type cytokines, it of-fers an interesting opportunity for the treat-ment of MS. H. Weiner (Boston, MA) and C. Whitacre (Columbus, OH) discussed oraltolerization and the importance of the gut-associated immune system. Low-dose oralantigen favors active suppression via Th2 orTh3 cells (TGF-b), whereas higher doses in-duce clonal deletion. It is not clear why oralbovine myelin did not show therapeutic ben-efit in a large MS trial, but the complexity anddose of the antigen were mentioned as reasons.Interestingly, cyclophosphamide, a chemo-therapeutic agent, normalized the elevatedIL-12 in chronic progressive MS patientsand, via upregulated IL-4, IL-5 and TGF-bexpression, led to cytokine deviation. Fi-nally, induction of TGF-b by 13-cis retinoicacid (L. Massacesi, Florence) and naked DNAvaccines (Steinman) were presented as effec-tive treatments for EAE, and their potentialfor MS was discussed.

ConclusionsA number of conclusions emerged from themeeting. It has been difficult to demonstratea polarized cytokine response in MS, but evi-dence favors an involvement of a Th1-typeresponse. However, the pathology of MS, aswell as data from EAE models, strongly sug-gest that MS is more heterogeneous thanpreviously appreciated. Some types of MSmay be truly ‘Th1 diseases’ but, in others,oligodendrocyte and myelin damage may beantibody- and complement-mediated or, inlater stages of disease, even driven by dys-trophic changes in oligodendrocytes andneurons. Thus, viewing MS as a Th1-medi-ated disease may still serve as a working hy-pothesis, but one must consider the impactof disease heterogeneity with respect to

genetic background and clinical phenotypes.Specific aspects of EAE models may be use-ful as a reflection of different forms andstages of MS, and continued exploration ofEAE for these purposes is warranted, evenif, overall, the animal model and human dis-eases differ. Detailed pathological exami-nation, MRI and immunological studies ofwell-stratified groups of MS patients willallow us to better assess the involvement ofTh1- or Th2-like cells. While our basic un-derstanding of cytokine regulation is rapidlydeveloping, our knowledge of the differen-tial effects of cytokines in MS is limited andthus it is difficult to predict the outcome ofimmune therapy that may depend in part onimmune deviation concepts. This is prob-ably most dramatically demonstrated by theworsening of MS after administration ofTNFR–Ig fusion protein, a result that is con-trary to what was expected. These resultsalso underscore the importance of well-designed trials not only to assess the validityof our working hypotheses about diseasepathogenesis but also to elucidate the mecha-nism of cytokine manipulation in a complexbiological disease such as MS.

The workshop was sponsored by the US National

Multiple Sclerosis Society, Anergen Inc., Athena

Neurosciences, Autoimmune Inc., Biogen, Icos Cor-

poration, International Medical Advisory Board of

the International Federation of MS Societies,

Schering AG and Serono Laboratories. We grate-

fully acknowledge the participation of all workshop

delegates and regret that space restraints do not

allow a full discussion of all the presentations.

Roland Martin (Roland_Martin@nih.gov) is atthe Neuroimmunology Branch, NINDS, NIH,Building 10, Room 5B-16, 10 Center DR MSC1400, Bethesda, MD 20892-1400, USA; NancyRuddle is at the Dept of Epidemiology and Pub-lic Health and Immunobiology, Yale UniversitySchool of Medicine, Box 208034, 815 LEPH,New Haven, CT 06520-8034, USA; StephenReingold is at the National Multiple SclerosisSociety, 733 Third Avenue, New York, NY10017-3288, USA; David Hafler is at the Cen-ter for Neurologic Diseases, Brigham andWomen’s Hospital, 77 Avenue Louis Pasteur,Harvard Institutes of Medicine Room 786,Boston, MA 02115, USA.

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