- Email: [email protected]
Cytokines in autoimmunity
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Cytokines in autoimmunity Fionula M Brennan* and Marc Feldrnannt The past few years have witnessed exciting developments regarding the role of cytokines in autoimmune diseases, particularly in rheumatoid arthritis and Crohn's disease, with the demonstration that anti-TNF(x therapy is clinically beneficial and provides reproducible results. Recent contributions to this field, derived from in vivo studies in animal models of autoimmunity, and increasingly from clinical trials, have greatly enhanced our understanding of this field.
areas in which there have been major advances over the past few years, and in particular will focus on the role of cytokines in RA. T h e role of cytokines in other autoimmune diseases, in addition to RA, including insulin-dependent diabetes mellitus, multiple sclerosis (MS), thyroid diseases, Sj6gren's syndrome, systemic lupus erythematosus, scleroderma and psoriasis is dealt with comprehensively in a book published recently [1].
Addresses Kennedy Institute of Rheumatology, 1 Aspenley Road, Hammersmith, London W6 8LH, UK *e-mail: [email protected] ~e-mail: [email protected]
Proinflammatory c y t o k i n e s : T N F a n d IL-1 There is now considerable evidence that cytokines such as T N F ~ and IL-1 contribute to the pathogenesis of inflammatory autoimmune diseases such as RA (recently reviewed in [2]). This is based both on their direct proinflammatory effects on target tissues in the synovial joint, including cartilage and bone, and on their indirect effects, which include the induction of other cytokines which can perpetuate the inflammation in RA. T N F ~ has a pivotal position in this network since its removal from RA synovial joint cell cultures leads to the downregulation of IL-1 and granulocyte macrophage colony-stimulating factor (reviewed in [2]) and also, as shown recently, to the inhibition of IL-6 and IL-8 [3]. T h e production of IL-6 and IL-8 is also partly dependent upon IL-1, because the inclusion of the IL-1 receptor antagonist (IL-lra) diminishes IL-6 and IL-8 levels, but not levels of T N F ~ or IL-1 [3]. Taken together, these results suggest that the proinflammatory cytokines are linked together in a cascade and that TNFc~ is a good target for therapy because neutralizing it will concomitantly reduce the levels of other proinflammatory mediators. Evidence of a cytokine cascade is also evident in the human TNFo~ 3' 13 globin U T R mouse, which spontaneously develops arthritis, as blockade of IL-1 activity using a lytic IL-1 receptor type antibody ameliorates disease in these animals [4].
Current Opinion in Immunology 1996, 8:8'72-87? © Current Biology Ltd ISSN 0952-7915 Abbreviations cA2 TNF antibody ClA type II collagen-induced arthritis CNS central nervous system EAE experimental autoimmune encephalomyelitis IFN interferon IL interleukin MIP macrophage inflammatory protein MS multiple sclerosis R receptor re receptor antagonist RA rheumatoid arthritis s soluble TCR T cell receptor TNF tumor necrosis factor TGF transforming growth factor
Introduction T h e investigation of the role of cytokines in autoimmune diseases has expanded rapidly over the past few years. Although the upregulation of certain cytokines in tissues affected by autoimmune disease had been demonstrated previously, the importance of these cytokines in the disease pathogenesis had still to be proven. Since then a number of clinical trials have been carried out, particularly directed at blocking the activity of T N F ~ in rheumatoid arthritis (RA) and Crohn's disease. These trials have confirmed hypotheses that this cytokine plays a pivotal role in the inflammatory processes in these conditions. Our understanding of cytokines in autoimmunity has been greatly facilitated by studies of animal models of autoimmunity, of transgenic mice aberrantly expressing these cytokine genes and more recently of cytokine 'knockout' mice, particularly if backcrossed onto the appropriate genetic background.
This review cannot be fully comprehensive as the subject area is now vast, but rather will concentrate on those
Clinical trials T h e role of T N F ~ in contributing to the pathogenesis of RA was verified in clinical trials in which T N F a activity was blocked by the addition of a neutralizing antibody. This was demonstrated first in an open phase trial using a chimeric T N F antibody (cA2) and then in a placebo-controlled trial [5] and retreatment study [6]. T h e cA2 antibody rapidly induced a high degree of clinical benefit noted in all clinical parameters tested, which was substantiated by rapid and marked changes in biochemical markers of inflammation. Subsequent studies from other groups with a different antibody [7 °] or an I g G - T N F receptor (R) fusion protein [8] have confirmed the benefit of TNFcc blockade. As T N F a is a major inducer of endothelial adhesion molecules and an inducer of chemokines, it might be predicted that TNFc~ could have a major effect on the recruitment of leucocytes to
Cytokines in autoimmunity Brennan and Feldmann
the joints. It was of interest, therefore, that following a n t i - T N F a therapy, leucocyte trafficking was diminished. This effect was reflected in a rapid augmentation in lymphocyte counts and in diminution of serum soluble E-selectin and soluble intercellular adhesion molecule-I [9"]. Supporting evidence comes from immunohistologicai analysis of joint biopsies before and after a n t i - T N F ~ infusion [10]. One concern with anti-TNFot therapy is whether the patients may become more susceptible to infection. Although this did not appear to be the case in the limited scope of the clinical trials, one interesting observation was that, following a n t i - T N F a treatment with cA2, the peripheral blood T cell proliferative response to recall antigens in the patients normalized [11]. Thus, the phenomenon of suboptimal T cell responses to recall antigen or mitogen in RA patients appears to be due in part to their chronic exposure to T N F a in vivo. Indeed, T N F a downregulated the activity of synovial T cells taken from RA patients [12]. T a k e n together, these data suggest that chronic exposure of T lymphocytes to T N F a , rather than enhancing the T cell response, actually impairs activation via the T C R - C D 3 receptor complex. T h e effect of monoclonal TNFo~ antibodies when used as a probe for pathogenesis in RA is considered in more detail in a recent review [13].
T h e success of a n t i - T N F ~ therapy in RA has also prompted equally successful clinical trials in Crohn's disease [14"], an inflammatory" condition in which the involvement of T N F ~ as a 'pivotal' cytokine had not been established from in vitro analysis. There arc likely to be a number of other diseases in which anti-TNF~ therapy may be beneficial, such as MS, for which there is good evidence that T N F ~ is pathologically involved (reviewed in [15]). Support for this has recently come from the observation that a spontaneous demyelination disease, in which T N F transgene expression occurs exclusively in the central nervous system (CNS) developed in one founder transgenic line which expresses murine T N F ~ human 13 globin 3' U T R under T N F ' s constitutive promoter [16"']. It is unclear, however, if T N F a antibody therapy will be useful in MS, as it may not penetrate the blood-brain barrier effectively once inflammation in the CNS is reduced. In light of this, other TNFcc blockers which can cross the blood-brain barrier, such as the type IV phosphodiesterase inhibitors, may be more effective. One of these, rolipram, has recently been used to prevent experimentally-induced autoimmune encephalomyelitis (EAE) in mice [17], and also to prevent autoimmune demyelination in nonhuman primates [18]. A similar inhibitor, pentoxifylline, was used recently in a small open study of severe refractory" RA in humans [19]. In this study a small, but significant, diminution in the number of tender and swollen joints as well as in erythrocyte sedimentation rate was noted after three months, warranting further investigation of this type of therapy.
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An alternative strategy, currently exciting the pharmaceutical industry, is to block the processing of membrane p r o - T N F a by inhibiting the T N F a convertase enzyme. Interest in this enzyme was generated after the discovery by three different independent groups that a metalloproteinase-like enzyme cleaved p r o - T N F a (26kDa) to yield the secreted (17kDa) form [20-22]. Because metalloproteinase-like enzymes also cleave the surface p55 and p75 T N F - R [23,24"'], however, a broadspectrum inhibitor of matrix metalloproteinase activity, such as hydroxamic acid derivatives, which do not distinguish between these events, could enhance T N F ~ signalling. This is because membrane T N F ~ and surface T N F - R s would accumulate, and the production of soluble T N F - R s (sTNF-Rs), which function as inhibitors of T N F ~ activity [25], would be blocked. This appeared to be the case if a hydroxamate compound was added to RA synovial membrane cell cultures, as no effect on the cytokine cascade (IL-1, IL-6 or IL-8) was observed, although T N F a production was abrogated [24"']. Also, arthritis still developed in human T N F ~ T g 3' 13 globin mice in which the T N F c ~ a ~ n s g e n e lacked the T N F ~ convertase enzyme cleavage site, and as such was not cleaved by T N F a convertase enzyme [26]. Despite evidence for the role of IL-1 in RA (reviewed in [2]), clinical trials blocking IL-1 activity have not been as successful as might have been predicted. T h e results of a multidose nonplacebo-controlled trial of the IL-lra in RA patients (n = 175) were recently published [27]. Although the IL-lra was well tolerated, the results were inconclusive because of the multiple small treatment groups and the lack of a placebo arm. In a different double-blind study in a smaller group of patients (n=25), the recombinant soluble human IL-1R type I was tested [28]. Only one out of eight patients treated with the highest concentration of recombinant human slL-1R type employed demonstrated clinically relevant improvement [28]. It is not clear why in the human disease blockade of IL-1 is not as effective as T N F a blockade. It may reflect the short half-life and, therefore, the efficacy of the inhibitory proteins used (IL-lra or slL-1R) compared with those of a chimeric or humanized antibody, as blockade of IL-1 (particularly IL-113) with a neutralizing antibody is effective in type II collagen-induced arthritis (CIA) in DBA/1 mice [29], as is an inhibitor of the IL-113 convertase [30].
Cytokine inhibitors and anti-inflammatory cytokines Over the past few years it has become apparent that in inflammatory" disease in which there is increased production of cytokines with proinflammatory potential, there is an accompaniment of increased production of cytokine inhibitors including s T N F - R and IL-lra, and also of cytokines with immunoregulatory potential, such as IL-10 (reviewed in [2]). Soluble T N F - R s are produced by
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proteolytic cleavage of the membrane receptors, neutralize T N F bioactivity, are upregulated in RA and other diseases, and function as T N F ~ inhibitors (as antibodies to s T N F - R can unmask T N F a lytic activity in RA synovial cell cultures [25]). IL-lra levels are also upregulated in both the joints and serum of RA patients, but not enough to abrogate IL-l's pro-inflammatory effects, because IL-1 is still biologically active [31]. Cytokines which are considered to possess anti-inflammatory effects include IL-10 and IL-4. IL-10 has been documented in RA peripheral blood [32] and synovial joint tissue [33,34]. In RA synovial cell cultures, the endogenous IL-10 produced is functional, as shown by the fact that inhibition of its activity using a neutralizing monoclonal antibody enhanced T N F a and IL-1 production, and addition of recombinant IL-10 to these cultures inhibited production of these cytokines [33]. In a similar study but using synovial tissue organ cultures [35], it was observed that exogenous IL-10 also inhibited IL-l[3, although IL-4 was more potent. Interestingly, IL-4 (but not IL-10) induces the production of the IL-1 inhibitor IL-lra, and IL-10 (but not IL-4) induces the production of the endogenous T N F inhibitors, sTNF-Rs (reviewed in [2]). Thus IL-10 and IL-4 downregulate inflammatory effects, such as cartilage degradation [36], by inhibiting the production of the proinflammatory cytokines whilst upregulating the production of their inhibitors. Not all the properties of IL-10 or IL-4 are immunosuppresive, however. For example, the B-cell-stimulatory effects of IL-10 may be important in the production of rheumatoid factors, and in a recent publication [37] it was demonstrated that the terminal differentiation of B cells spontaneously secreting rheumatoid factor and that had been taken from rheumatoid arthritis patients was dependent upon endogenous IL-10. T h e involvement of IL-10 as an immunoregulatory cytokine has also been borne out in animal models of arthritis. Thus, IL-10 production is observed in synovial tissue of DBA/1 mice with CIA, and mice receiving neutralizing IL-10 antibodies develop an accelerated disease onset and more severe arthritis [38°°]. Furthermore, progression of established disease in DBA/1 mice can be ameliorated by daily treatment with recombinant IL-10 [39]. Similarly, in EAE, relapses could be prevented by IL-10 or transforming growth factor (TGF)-[3 administration [40 °] and mice with experimental autoimmune thyroiditis disease severity was significantly reduced when the mice were treated with high doses of recombinant human IL-10, an effect reflected in an increase of T cells undergoing apoptosis compared with controls [41°]. Clearly IL-10 has potent immunoregulatory properties and as such it is not surprising that mice homozygous for IL-10 deletion spontaneously develop a chronic enterocolitis with features characteristic of human ulcerative colitis and Crohn's disease [42].
There is also evidence that IL-10 is unregulated in other autoimmune diseases, such as SLE [32]; however, it is likely that the role of IL-10 in SLE, unlike in RA, is associated with disease development. A recent report demonstrated that an increase in the ratio of IL-10 : IFNyproducing cells in peripheral blood was correlated with disease severity [43], and in NZB/W mice, anti-IL-10 treatment inhibits disease onset [44]. It is also unclear whether IL-10 has a protective or disease-potentiating role in insulin-dependent diabetes mellitus. For example, transgenic mice expressing IL-10 in islet cells develop an insulinitis with leucocyte extravasation, and in nonobese diabetic mice transgene expression of IL-10 in the islets accelerates autoimmune insulin-dependent diabetes mellitus [45,46]. T h e s e results suggest that IL-10 may promote inflammatory events by enhancing leucocyte trafficking and extravasation. T h e above results, taken together, make it clear that in autoimmune disease there is upregulation of both inhibitory cytokines and cytokine inhibitors. There is a relative imbalance, however, in favour of the proinflammatory mediators, and therefore therapy aimed at tipping the balance in favour of the anti-inflammatory arm may be beneficial. Interestingly, it has been reported that IFN[3 therapy of MS patients in whom there has been a modest reduction of the relapse rate results in an increase in serum IL-lra levels [47]. Of interest too is the report that IFNl3-stimulated monocytes produce IL-10 [48]. Thus it is tempting to speculate that IFNI3 therapy reduces the relapse rate in MS by reversing the pro- versus anti-inflammatory cytokine balance, but this hypothesis needs further testing.
Cytokines and cell trafficking From the clinical studies using T N F antibodies in RA patients, it has become apparent that some of the benefit is a consequence of reduced cell trafficking to the inflamed synovial joints [9"], due to a reduction in adhesion molecule facilitated extravasation across endothelium in synovial tissue but also possibly due to a reduction in chemokine production. T h e human chemokines are a superfamily of low molecular weight peptides and consist of three subfamilies which are chemotactic for neutrophils, mononuclear cells or lymphocytes (reviewed in [49]). T h e production of many chemokines in RA synovial tissue and in inflammatory joint disease has been described (reviewed recently in [2,50°]). More recently, however, the expression of chemokines in murine CIA has been investigated [38"]. This study demonstrated the expression of monocyte chemotactic peptide-1, macrophage inflammatory protein (MIP)I~, epithelial neutrophil activating peptide 78 (ENA)-78 and MIP-2 (the murine functional homology of IL-8), furthermore, passive immunization of CIA mice with antibodies against either MIP-lot or MIP-2 resulted in both a delay in disease onset and a decrease of disease
Cytokines in autoimmunity Brennan and Feldmann
severity. Interestingly, anti-IL-10 treatment increased the expression of MIP-1 ot and MIP-2, an effect associated with enhanced leucocyte infiltration in the joints, suggesting a homeostatic role for IL-10 in chemokine regulation [38"'], in addition to its previously reported role [33] in regulating TNFo~ and IL-113. T h e role of chemokines in other animal models of autoimmune disease has also been demonstrated recently. For example, macrophage chemotactic peptide [51] and MIP-lc~ [52] are found in the CNS of rats with EAE. Furthermore, the administration of anti-MIP-lc~ prevented the development of both acute and relapsing paralytic disease as well as the infiltration of mononuclear cells into the CNS initiated by the transfer of neuroantigen peptide activated T cells [52].
Thl versus Th2 cytokines and involvement of IL-12 Over the past few years studies of cytokines in autoimmune disease have pursued the hypothesis that local autoimmunity results as a preponderance of T h l over Th2 subsets. As this topic is considered in detail in a separate review in this section (Nicholson and Kuchroo, pp 837-842) only those key papers relating to the involvement of IL-12 will be considered here. IL-12 is a heterodimeric cytokine which is thought to play a key role in promoting T h l immune responses and, as such, in skewing the T h l :Th2 ratio in autoimmune diseases. Support for this idea comes from the observation, in CIA [53"], that IL-12 may replace the need for mycobacteria after being shown to markedly augment the incidence of arthritis in DBA/1 mice injected with Freund's incomplete adjuvant and type II collagen. Somewhat surprisingly, it was also demonstrated by the same group [54] that high doses of IL-12 injected systemically inhibited the development of joint disease in the same mouse model of disease. It is not clear why IL-12 exhibits these apparently contradictory effects, but it is conceivable that, in common with IL-10, it has both pro- and anti-inflammatory properties (discussed in [55]). Despite its potential to exhibit bimodal function, antibodies to IL-12 have been used successfully to treat other experimental autoimmune diseases such as EAE [56] and a murine model for human inflammatory bowel disease [57]. Furthermore, IL-12 expression has been described in a number of organ-specific autoimmune disease models (reviewed in [58"]), and in diseased islets and thyroids of BB rats [59], and is associated with rapid development of diabetes mellitus in nonobese diabetic mice [60]. There arc fewer studies of IL-12 expression and its effects in human inflammatory tissue, but a recent report [61"'] described increased expression of B7-1 and IL-12 p40 in acute MS plaques, a finding that is potentially indicative of stimuli that could stimulate T cell activation and the induction of T h l - t y p e immune
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responses. It is thought that one of the major roles of IL-12 in autoimmune disease is to induce IFN~' production, as mice homozygous for deletion of the IL-12 gene display defective IFN~'and type 1 cytokine responses [62]. I F N y knockout mice back-crossed onto the susceptible background, however, still develop EAE at the expected frequency and severity [63"']. Clearly, in the next few years the mechanism by which IL-12 and other cytokines stimulate the emergence of T h l or Th2 subsets will be central to many investigations into autoimmune diseases.
Conclusion With our increasing knowledge of the importance of cytokines in the pathogenesis of autoimmune disease, it is likely that a n t i - T N F a will not remain the sole effective anticytokine therapy in autoimmunity. We eagerly await the use of cytokine therapeutic 'cocktails' in different diseases, an approach which may get much closer to a real long-term cure than do the current forms of treatment.
References and recommended reading Due to editorial constraints there were two additional references that we felt should have been highlighted hut could not be because they were published more than twelve months ago. Reference [5] describes the first successful randomized double-blind trial of an anti-TNFec antibody in RA patients, confirming an open-phase study that a single infusion of 1 or 10 mg kg-1 chimeric monoclonal antibody to TNFcc (cA2) resulted in highly significant (p=0.0083; low dose cA2 and p==O.0001 ; high dose cA2) improvements in both clinical and biochemical measures of disease activity at four weeks compared with placebo treatment in seventy-three patients with active RA. Reference [31] explores the interaction between IL-1 activity and the IL-1 inhibitor IL-lra in RA synovial tissue and makes the important observation that it is the ratio of IL-lra:lL-1 rather than the absolute level of each protein which determines the bioactivity of IL-t, which in RA synovial joint tissue cells is well below the 10 000-fold excess of IL-lra needed to inhibit IL-1 bioactivity. Thus, although the inhibitor of IL-1 is upregulated in inflammatory conditions, this increase is insufficient to abrogate the proinflammatory effects of IL-1. Papers of particular interest, published within the annual period of review, have been highlighted as: . o.
of special interest of outstanding interest Brennan FM, Feldmann MF: Cytokines in Autoimmunity. Austin, Texas: RG Landes Company; 1996. Feldmann M, Brennan FM, Maini RN: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996, 14:397-440. Butler DM, Maini RN, Feldmann M, Brennan FM: Modulation of proinflammatery cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti-TNF(x antibody with the IL-1 receptor antagonist. Eur Cytokine Network 1995, 6:225-230.
4.
Probert L, Plows D, Kontogeorgos G, Kollias G: The type 1 interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF- transgenic mice. Eur J Immuno11995, 25:1794-1797.
5.
EUiott M J, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H et aL: Randomised double blind comparison of a chimaeric monoclonal antibody to tumour necrosis factor (x (cA2) versus placebo in rheumatoid arthritis. Lancet 1994, 344:1105-1110.
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Elliott M J, Maini RN, Feldmann M, Long-Fox A, Charles P, Bill H, Woody JN: Repeated therapy with monoclonal antibody to tumour necrosis factor cc (cA2) in patients with rheumatoid arthritis. Lancet 1994, 344:1125-1127. Rankin ECC, Choy EHS, Kassimos D, Kingsley GH, Sopwith SM, Isenberg DA, Panayi GS: The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody
7.
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(CDP571) in rheumatoid arthritis. Br J Rheumatol 1995, 34:334-342. This paper describes a double-blind trial in which the humanized TNF antibody CDP571 administered intravenously in single doses of 0.1, 1.0 or 10 mg kg-1 to patients with active RA (n =24), was compared with placebo (n=12). CDP571 at the higher dose (10mgkg -1) caused a significant reduction in erythrocyte sedimentation rate, C-reactive protein and the number of tender joints, maximally after one or two weeks.
Moreland LW, Margolies GR, Heck LW, Saway PA, Jacobs C, Beck C, Blosch C, Koopman WJ : Soluble tumor necrosis factor receptor (sTNFR):- results of a phase ! dose-escalation study in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 1994, 32 (suppl):295. 9. Paleolog EM, Hunt M, Elliott MJ, Feldmann M, Maini RN, Woody • JN: Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor c( antibody in rheumatoid arthritis. Arthritis Rheum 1996, 7:1082-1091. This paper examines the effect of chimeric cA2 treatment in RA patients on endothelial activation, and demonstrates that serum levels of E-selectin and intercellular adhesion molecule-1 (but not vascular cell adhesion molecule-I) were reduced after infusion of cA2 (1 or lOmgkg-1). In parallel, a rapid and sustained increase in circulating lymphocyte counts was observed, with largest changes observed in patients in whom a clinical benefit (>_20% Paulus response at week four) was observed. 10. Tak PP, Taylor PC, Breedveld FC, Smeets TJM, Kluin PM, Meinders AE, Maini RN: Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor c< monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996, 39:1092-1101. 11. Cope AP, Londei M, Chu NR, Cohen SBA, Elliott MJ, Maini RN, Brennan FM, Feldmann M: Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis. J C/in Invest 1994, 94:749-760. 12. Lai NS, Lan JL, Yu CL, Lin RH: Role of tumor necrosis factoralpha in the regulation of activated synovial T cell growth: down-regulation of synovial T cells in rheumatoid arthritis patients. Eur J/mmunol 1995, 25:3243-3248. 13. MainiRN, Elliott MJ, Brennan FM, Williams RO, Chu CQ, Paleolog E, Charles PJ, Taylor PC, Feldmann M: Monoclonal anti-TNFc¢ antibody as a probe of pathogenesis and therapy of rheumatoid disease./mmuno/Rev 1995, 144:195-223. 14. Van Dullemen HM, Van Deventer SJH, Hommes DW, Bijl HA, • Jansen J, Tytgat GNJ, Woody J: Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995, 109:129-135. This paper describes for the first time the efficacy of cA2 therapy in an openlabel treatment protocol of ten patients with active Crohn's disease who were previously unresponsive to steroid treatment. Eight patients showed normalization of Crohn's disease activity index scores and healing of ulcerations as judged by colonoscopy within four weeks of treatment with a single infusion of cA2, with an average duration of response of four months. 15. RaineCS: Multiple sclerosis: TNF revisited, with promise [comment]. Nat Med 1995, 1:211-214. 16. Probert L, Akassoglou K, Pasparakis M, Kontogeorgos G, Kollias •. G: Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. Proc Nat/Acad Sci USA 1995, 92:11294-11298. This interesting study describes the spontaneous development of a chronic inflammatory demyelinating disease in transgenic mice that constitutively express a dysregulated murine TNF transgene under the control of its own promoter. Transgene expression was restricted to the CNS, with high-level expression in neurons distributed throughout the brain. The direct involvement of TNF in the pathogenesis of this disease was confirmed by peripheral administration of neutralizing routine mTNF(x antibodies. 17. Sommer N, Loschmann P-A, Northoff GH, Weller M, Steinbrecher A, Steinbach JP, Lichtenfels R, Meyermann R, Riethmuller A, Fontana A et a/.: The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med 1995, 1:244-248. 18. Genain CP, Roberts T, Davis RL, Nguyen M-H, Uccelli A, Faulds D, Li Y, Hedgpeth J, Hauser SL: Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterese inhibitor. Proc Nat/Acad Sci USA 1g95, 92:3601-3605. 19. MaksymowychWP, Avina-Zubieta A, Luong MH, Russell AS: An open study of pentoxifyUine in the treatment of severe refractory rheumatoid arthritis. J Rheumatol 1995, 22:625-629.
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McGeehan GM, Becherer JD, Bast Jr RC, Boyer CM, Champion B, Connolly KM, Conway JG, Furdon P, Karp S, Kidao S et al.: Regulation of tumour necrosis factor a processing by a metalloprotainase inhibitor. Nature 1994, 370:558-561. Mohler K, Sleath PR, Fitzner JN, Cerretti DP, Alderson M, Kerwar SS, Torrance DS, Otten-Evans C, Greenstreet 1", Weerawama K et al.: Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature 1994, 370:218-220.
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Gearing AJH, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon J L e t a/.: Processing of tumour necrosis factor-(x precursor by metalloproteinases. Nature 1994, 370:555-557,
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Williams L, Gibbons DL, Gearing A, Feldmann M, Brennan FM: Paradoxical effects of a synthetic metalloprotainase inhibitor which blocks both p55 and p75 TNF receptor shedding and TNF~ processing. J C/in Invest 1996, 97:2833-2841. The results described in this paper raise the interesting possibility that a close relationship exists between the enzyme(s) which process membranebound TNF(x, and those involved in surface TNF-R cleavage, and suggest that hydroxamate inhibitors of MMP activity which block TNFc¢ secretion and TNF-R cleavage may not modulate downstream effects of TNFa. The precise specificity of these compounds, therefore, will be highly relevant to their clinical efficacy in inflammatory diseases. 25. BrennanFM, Gibbons DL, Cope AP, Katsikis P, Maini RN, Feldmann M: TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand J Immuno/ 1995, 42:158-165. 26. Georgopoulos S, Plows D, Kollias G: Trensmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. J Inf/amm 1996, 46:86-97. 27.
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Campion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M, The IL-lra Arthritis Study Group: Dose-range and dose frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 1996, 39:1092-1101. Drevlow BE, Lovis R, Haag MA, Sinacore JM, Jacobs C, Blosche C, Landay A, Moreland LW, Pope RM: Recombinant human interleukin-1 receptor type I in the treatment of patients with active rheumatoid arthritis. Arthritis Rheum 1996, 39:257-265. Joosten LAB, Helsen MMA, Vandeloo FAJ, Vandenberg WB: Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: a comparative study using anti-TNF alpha, anti-lL-1 alpha/beta, and IL-1Ra. Arthritis Rheum 1996, 39:797-809. Ku G, Faust 1", Lauffer LL, Livingston DJ, Harding MW: Interleukin1 beta converting enzyme inhibition blocks progression of type II collagen-induced arthritis in mice. Cytokine 1996, 8:377-386. FiresteinGS, Boyle DL, Yu C, Paine MM, Whisenand TD, Zvaifler NJ, Arend WP: Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum 1994, 37:644-652. Llorente L, Richaud-Patin ¥, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier B, Galanaud P, Emilie D: In vivo production of interleukin-lO by non-T cells in rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Arthritis Rheum 1994, 37:1647-1655. Katsikis P, Chu CQ, Brennan FM, Maini RN, Feldmann M: Immunoregulatory role of interleukin 10 (IL-IO) in rheumatoid arthritis. J Exp Med 1994, 179:1517-1527. Cush JJ, Splawski JB, Thomas R, McFarlin JE, Schulze-Koops H, Davis LS, Fujita K, Lipsky PE: Elevated interleukin-lO levels in patients with rheumatoid arthritis. Arthritis Rheum 1995, 38:96-104. Chomarat P, Banchereau J, Miossec P: Differential effects of interleukins 10 and 4 on the production of interleukin-6 by blood and synovium monocytes in rheumatoid arthritis. Arthritis Rheum 1995, 38:1046-54. Vanroon JAG, Vanroy J, Gmeligmeyling FHJ, Lafeber F, Bijlsma JWJ : Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-lO and interleukin-4. Arthritis Rheum 1996, 39:829-835.
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37.
Perez L, Orte J, Brieva JA: Terminal differentiation of spontaneous rheumatoid factor-secreting B cells from rheumatoid arthritis patients depends on endogenous interleukin-lO. Arthritis Rheum 1995, 38:1771-1776. 38. Kasama T, Strieter RM, Lukacs NW, Lincoln PM, Burdick MD, *• KunkelSL: Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J Clin Invest 1995, 95:2868-2876. This interesting study demonstrates for the first time expression of chemokines during the evolution of CIA, the onset of which was delayed if administered with antibodies directed against either MIP-1¢¢ or MIP-2. On the contrary, CIA mice receiving neutralizing IL-IO antibodies demonstrated an acceleration of the onset and an increase in the severity of arthritis. 39. Walmsley M, Katsikis PD, Abney E, Parry S, Williams RO, Maini RN, Feldmann M: Interleukin-1O inhibition of the progression of established collagen-induced arthritis. Arthritis Rheum 1996, 39:495-503. 40. Crisi GM, Santambrogio L, Hochwald GM, Smith SR, Carlino * JA, Thorbecke GJ: Staphylococcal enterotoxin B and tumornecrosis factor-alpha-induced relapses of experimental allergic encephalomyelitis: protection by transforming growth factorbeta end interleukin-10. Eur J Immuno/1995, 25:3035-3040. This paper describes the ability of staphylococcal enterotoxin B or TNF to induce relapses of EAE in SJL mice. Adminstration of IL-10 and TGF-~2 reduced these relapses, whilst anti-lL-lO increased both the incidence and the severity. The authors conclude that TNF production is probably important in causing EAE relapses, and that endogenous IL-10 rather than TGF-~ production appears to limit the susceptibility to relapses in this model. 41. Mignon-Godefroy K, Rott O, Brazillet MP, Charreire J: Curative * end protective effects of IL-10 in experimental autoimmune thyroiditis (EAT). Evidence for IL-10-enhanced cell death in EAT. J/mmuno/1995, 154:6634-6643. This paper examines the effect of recombinant human IL-10 administration in two models of experimental autoimmune thyroiditis. Administration results in a significant reduction in severity of disease but no change in level of anti-mTg (mouse thyroglobulin) autoantibody levels. Activation-induced cell death of autoreactive T lymphocytes was increased. 42. KuhnR, Lohler J, Rennick D, Rajewsky K, Muller W: InterleukinlO-deficient mice develop chronic enterocolitis. Ce//1993, 75:263-274. 43. Hagiwara E, Gourley MF, Lee S, Klinman DM: Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: interferon-gammasecreting cells in the peripheral blood. Arthritis Rheum 1996, 39:379-385. 44. Ishida H, Muchamuel T, Sakaguchi S, Andrade S, Menon S, Howard M: Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med 1994, 179:305-310. 45. Wogensen L, Huang X, Sarvetnick N: Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans. J Exp Med 1993, 178:175-185.
46.
Wogensen L, Myung-Shik L, Sarvetnick N: Production of interleukin-10 by islet cells accelerates immune-mediated destruction of 13cells in nonobese diabetic mica. J Exp Med 1994, 179:t 379-1384. 47. Nicoletti F, Patti F, Dimarco R, Zaccone P, Nicoletti A, Meroni PL, Reggio A: Circulating serum levels of IL-lra in patients with relapsing remitting multiple sclerosis are normal during remission phases but significantly increased either during exacerbations or in response to IFN-beta treatment. Cytokine 1996, 8:395-400. 48. PorriniAM, Gambi D, Reder AT: Interferon effects on interleukin10 secretion. Mononuclear cell response to interleukin-10 is normal in multiple sclerosis patients. J Neuroimmuno/1995, 61:27-34. 49. Strieter RM, Standiford TJ, Huffnagle GB, Colletti LM, Lukacs NW, Kunkel SL: "The good, the bad, and the ugly": the role of chemokines in models of human disease - commentary. J /mmuno/1996, 156:3583-3586. 50. KunkelSL, Lukacs N, Kasama T, Stfieter RM: The role of • chemokines in inflammatory joint disease. J Leukocyte Biol 1996, 59:6-12. A well written review describing the association of chemokines with RA, and information from animal models regarding the kinetics of production
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and contribution of specific mediators to the development of experimental arthritis. 51.
Barman JW, Guida MP, Warren J, Amat J, Brosnan CF: Localization of monocyte chemoattrectant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat. J /mmuno/1996, 156:3017-3023.
52.
Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD: An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T call-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 1995, 155:5003-5010.
53. •
Germann T, Szeliga J, Hess H, Storkel S, Podlaski FJ, Gately MK, Schmitt E, Rude E: Administration of interleukin 12 in combination with type II collagen induces severe arthritis in DBA/1 mice. Proc Natl Acad Sci USA 1995, 92:4823-4827. This paper makes the interesting observation that IL-12 can replace the mycobacterial component of CIA and cause severe arthritis of DBA/1 mice when administered in combination with type II collagen. IL-12 administration resulted in an increase in collagen type II specific IFNy synthesis and collagen-specific IgG2a and tgG2b antibodies. 54.
Hess H, Gately MK, Rude E, Schmitt E, Szeliga J, Germann T: High doses of Interleukin-12 inhibit the development of joint disease in DBA/1 mice immunized with type II collagen in complete Freund's adjuvant. Eur J Immunol 1996, 26:187-191.
55.
Lamont AG, Adorini L: IL-12: a key cytokine in immune regulation./mmunol Today 1996, 17:214-217.
56.
Leonard JP, Waldburger KE, Goldman SJ: Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 1995, 181:381-386.
57.
Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W: Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 1995, 182:1261-1290.
58. •
TrembleauS, Germann T, Gately MK, Adorini L: The role of IL12 in the induction of organ-specific autoimmune diseases. Immunol Today 1995, 16:383-386. This review examines the role of IL-12, a key cytokine guiding the development of Thl cells, in the induction of autoimmune diseases, and discusses potential immunointervention strategies based on administration of IL-12 antagonists. 59.
Zipris D, Greiner DL, Malkani S, Whalen B, Mordes JR Rossini hA: Cytokine gene expression in islets and thyroids of BB rats-IFN-gamma and IL-121040 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats. J Immunol 1996, 156:1315-1321.
60.
Rothe H, Burkart V, Faust A, Kolb H: Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice. Diabetologia 1996, 39:119-122.
61. **
Windhagen A, Newcombe J, Dangond F, Strand C, Woodroofe MN, Cuzner ML, Hafler DA: Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), end interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med 1995, 182:1985-1996. This interesting paper describes increased expression of B7-1 and IL-12 p40 in acute MS plaques, particularly from early disease cases, but not in inflammatory infarcts, and speculates that an early event in the initiation of MS involves upregulation of B7-1 and IL-t2, and results in conditions that maximally stimulate T cell activation and induction of Thl-type immune responses. 62.
63. -*
Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu C, Ferrante J, Stewart C, Sarmiento U, Faherty DA, Gately MK: IL-12 deficient mice are defective in IFNy production and type 1 cytokine responses. Immunity 1996, 4:471-481.
Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG: Mice with a disrupted IFNgamma gene are susceptible to the induction of experimental autoimmune encephalolmyelitis (EAD. J Immunol 1996, 156:5-7. This short report makes the interesting but unexpected finding that IFN7 is not crucial for the induction or perpetuation of EAE. This is based on their observation that mice homozygous for deletion in the IFN7 gene, back-crossed onto an EAE-susceptible strain, develop disease following immunization with MBP, with massive mononuclear ceil infiltrates in the CNS.
Cytokines in autoimmunity Fionula M Brennan* and Marc Feldrnannt The past few years have witnessed exciting developments regarding the role of cytokines in autoimmune diseases, particularly in rheumatoid arthritis and Crohn's disease, with the demonstration that anti-TNF(x therapy is clinically beneficial and provides reproducible results. Recent contributions to this field, derived from in vivo studies in animal models of autoimmunity, and increasingly from clinical trials, have greatly enhanced our understanding of this field.
areas in which there have been major advances over the past few years, and in particular will focus on the role of cytokines in RA. T h e role of cytokines in other autoimmune diseases, in addition to RA, including insulin-dependent diabetes mellitus, multiple sclerosis (MS), thyroid diseases, Sj6gren's syndrome, systemic lupus erythematosus, scleroderma and psoriasis is dealt with comprehensively in a book published recently [1].
Addresses Kennedy Institute of Rheumatology, 1 Aspenley Road, Hammersmith, London W6 8LH, UK *e-mail: [email protected] ~e-mail: [email protected]
Proinflammatory c y t o k i n e s : T N F a n d IL-1 There is now considerable evidence that cytokines such as T N F ~ and IL-1 contribute to the pathogenesis of inflammatory autoimmune diseases such as RA (recently reviewed in [2]). This is based both on their direct proinflammatory effects on target tissues in the synovial joint, including cartilage and bone, and on their indirect effects, which include the induction of other cytokines which can perpetuate the inflammation in RA. T N F ~ has a pivotal position in this network since its removal from RA synovial joint cell cultures leads to the downregulation of IL-1 and granulocyte macrophage colony-stimulating factor (reviewed in [2]) and also, as shown recently, to the inhibition of IL-6 and IL-8 [3]. T h e production of IL-6 and IL-8 is also partly dependent upon IL-1, because the inclusion of the IL-1 receptor antagonist (IL-lra) diminishes IL-6 and IL-8 levels, but not levels of T N F ~ or IL-1 [3]. Taken together, these results suggest that the proinflammatory cytokines are linked together in a cascade and that TNFc~ is a good target for therapy because neutralizing it will concomitantly reduce the levels of other proinflammatory mediators. Evidence of a cytokine cascade is also evident in the human TNFo~ 3' 13 globin U T R mouse, which spontaneously develops arthritis, as blockade of IL-1 activity using a lytic IL-1 receptor type antibody ameliorates disease in these animals [4].
Current Opinion in Immunology 1996, 8:8'72-87? © Current Biology Ltd ISSN 0952-7915 Abbreviations cA2 TNF antibody ClA type II collagen-induced arthritis CNS central nervous system EAE experimental autoimmune encephalomyelitis IFN interferon IL interleukin MIP macrophage inflammatory protein MS multiple sclerosis R receptor re receptor antagonist RA rheumatoid arthritis s soluble TCR T cell receptor TNF tumor necrosis factor TGF transforming growth factor
Introduction T h e investigation of the role of cytokines in autoimmune diseases has expanded rapidly over the past few years. Although the upregulation of certain cytokines in tissues affected by autoimmune disease had been demonstrated previously, the importance of these cytokines in the disease pathogenesis had still to be proven. Since then a number of clinical trials have been carried out, particularly directed at blocking the activity of T N F ~ in rheumatoid arthritis (RA) and Crohn's disease. These trials have confirmed hypotheses that this cytokine plays a pivotal role in the inflammatory processes in these conditions. Our understanding of cytokines in autoimmunity has been greatly facilitated by studies of animal models of autoimmunity, of transgenic mice aberrantly expressing these cytokine genes and more recently of cytokine 'knockout' mice, particularly if backcrossed onto the appropriate genetic background.
This review cannot be fully comprehensive as the subject area is now vast, but rather will concentrate on those
Clinical trials T h e role of T N F ~ in contributing to the pathogenesis of RA was verified in clinical trials in which T N F a activity was blocked by the addition of a neutralizing antibody. This was demonstrated first in an open phase trial using a chimeric T N F antibody (cA2) and then in a placebo-controlled trial [5] and retreatment study [6]. T h e cA2 antibody rapidly induced a high degree of clinical benefit noted in all clinical parameters tested, which was substantiated by rapid and marked changes in biochemical markers of inflammation. Subsequent studies from other groups with a different antibody [7 °] or an I g G - T N F receptor (R) fusion protein [8] have confirmed the benefit of TNFcc blockade. As T N F a is a major inducer of endothelial adhesion molecules and an inducer of chemokines, it might be predicted that TNFc~ could have a major effect on the recruitment of leucocytes to
Cytokines in autoimmunity Brennan and Feldmann
the joints. It was of interest, therefore, that following a n t i - T N F a therapy, leucocyte trafficking was diminished. This effect was reflected in a rapid augmentation in lymphocyte counts and in diminution of serum soluble E-selectin and soluble intercellular adhesion molecule-I [9"]. Supporting evidence comes from immunohistologicai analysis of joint biopsies before and after a n t i - T N F ~ infusion [10]. One concern with anti-TNFot therapy is whether the patients may become more susceptible to infection. Although this did not appear to be the case in the limited scope of the clinical trials, one interesting observation was that, following a n t i - T N F a treatment with cA2, the peripheral blood T cell proliferative response to recall antigens in the patients normalized [11]. Thus, the phenomenon of suboptimal T cell responses to recall antigen or mitogen in RA patients appears to be due in part to their chronic exposure to T N F a in vivo. Indeed, T N F a downregulated the activity of synovial T cells taken from RA patients [12]. T a k e n together, these data suggest that chronic exposure of T lymphocytes to T N F a , rather than enhancing the T cell response, actually impairs activation via the T C R - C D 3 receptor complex. T h e effect of monoclonal TNFo~ antibodies when used as a probe for pathogenesis in RA is considered in more detail in a recent review [13].
T h e success of a n t i - T N F ~ therapy in RA has also prompted equally successful clinical trials in Crohn's disease [14"], an inflammatory" condition in which the involvement of T N F ~ as a 'pivotal' cytokine had not been established from in vitro analysis. There arc likely to be a number of other diseases in which anti-TNF~ therapy may be beneficial, such as MS, for which there is good evidence that T N F ~ is pathologically involved (reviewed in [15]). Support for this has recently come from the observation that a spontaneous demyelination disease, in which T N F transgene expression occurs exclusively in the central nervous system (CNS) developed in one founder transgenic line which expresses murine T N F ~ human 13 globin 3' U T R under T N F ' s constitutive promoter [16"']. It is unclear, however, if T N F a antibody therapy will be useful in MS, as it may not penetrate the blood-brain barrier effectively once inflammation in the CNS is reduced. In light of this, other TNFcc blockers which can cross the blood-brain barrier, such as the type IV phosphodiesterase inhibitors, may be more effective. One of these, rolipram, has recently been used to prevent experimentally-induced autoimmune encephalomyelitis (EAE) in mice [17], and also to prevent autoimmune demyelination in nonhuman primates [18]. A similar inhibitor, pentoxifylline, was used recently in a small open study of severe refractory" RA in humans [19]. In this study a small, but significant, diminution in the number of tender and swollen joints as well as in erythrocyte sedimentation rate was noted after three months, warranting further investigation of this type of therapy.
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An alternative strategy, currently exciting the pharmaceutical industry, is to block the processing of membrane p r o - T N F a by inhibiting the T N F a convertase enzyme. Interest in this enzyme was generated after the discovery by three different independent groups that a metalloproteinase-like enzyme cleaved p r o - T N F a (26kDa) to yield the secreted (17kDa) form [20-22]. Because metalloproteinase-like enzymes also cleave the surface p55 and p75 T N F - R [23,24"'], however, a broadspectrum inhibitor of matrix metalloproteinase activity, such as hydroxamic acid derivatives, which do not distinguish between these events, could enhance T N F ~ signalling. This is because membrane T N F ~ and surface T N F - R s would accumulate, and the production of soluble T N F - R s (sTNF-Rs), which function as inhibitors of T N F ~ activity [25], would be blocked. This appeared to be the case if a hydroxamate compound was added to RA synovial membrane cell cultures, as no effect on the cytokine cascade (IL-1, IL-6 or IL-8) was observed, although T N F a production was abrogated [24"']. Also, arthritis still developed in human T N F ~ T g 3' 13 globin mice in which the T N F c ~ a ~ n s g e n e lacked the T N F ~ convertase enzyme cleavage site, and as such was not cleaved by T N F a convertase enzyme [26]. Despite evidence for the role of IL-1 in RA (reviewed in [2]), clinical trials blocking IL-1 activity have not been as successful as might have been predicted. T h e results of a multidose nonplacebo-controlled trial of the IL-lra in RA patients (n = 175) were recently published [27]. Although the IL-lra was well tolerated, the results were inconclusive because of the multiple small treatment groups and the lack of a placebo arm. In a different double-blind study in a smaller group of patients (n=25), the recombinant soluble human IL-1R type I was tested [28]. Only one out of eight patients treated with the highest concentration of recombinant human slL-1R type employed demonstrated clinically relevant improvement [28]. It is not clear why in the human disease blockade of IL-1 is not as effective as T N F a blockade. It may reflect the short half-life and, therefore, the efficacy of the inhibitory proteins used (IL-lra or slL-1R) compared with those of a chimeric or humanized antibody, as blockade of IL-1 (particularly IL-113) with a neutralizing antibody is effective in type II collagen-induced arthritis (CIA) in DBA/1 mice [29], as is an inhibitor of the IL-113 convertase [30].
Cytokine inhibitors and anti-inflammatory cytokines Over the past few years it has become apparent that in inflammatory" disease in which there is increased production of cytokines with proinflammatory potential, there is an accompaniment of increased production of cytokine inhibitors including s T N F - R and IL-lra, and also of cytokines with immunoregulatory potential, such as IL-10 (reviewed in [2]). Soluble T N F - R s are produced by
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proteolytic cleavage of the membrane receptors, neutralize T N F bioactivity, are upregulated in RA and other diseases, and function as T N F ~ inhibitors (as antibodies to s T N F - R can unmask T N F a lytic activity in RA synovial cell cultures [25]). IL-lra levels are also upregulated in both the joints and serum of RA patients, but not enough to abrogate IL-l's pro-inflammatory effects, because IL-1 is still biologically active [31]. Cytokines which are considered to possess anti-inflammatory effects include IL-10 and IL-4. IL-10 has been documented in RA peripheral blood [32] and synovial joint tissue [33,34]. In RA synovial cell cultures, the endogenous IL-10 produced is functional, as shown by the fact that inhibition of its activity using a neutralizing monoclonal antibody enhanced T N F a and IL-1 production, and addition of recombinant IL-10 to these cultures inhibited production of these cytokines [33]. In a similar study but using synovial tissue organ cultures [35], it was observed that exogenous IL-10 also inhibited IL-l[3, although IL-4 was more potent. Interestingly, IL-4 (but not IL-10) induces the production of the IL-1 inhibitor IL-lra, and IL-10 (but not IL-4) induces the production of the endogenous T N F inhibitors, sTNF-Rs (reviewed in [2]). Thus IL-10 and IL-4 downregulate inflammatory effects, such as cartilage degradation [36], by inhibiting the production of the proinflammatory cytokines whilst upregulating the production of their inhibitors. Not all the properties of IL-10 or IL-4 are immunosuppresive, however. For example, the B-cell-stimulatory effects of IL-10 may be important in the production of rheumatoid factors, and in a recent publication [37] it was demonstrated that the terminal differentiation of B cells spontaneously secreting rheumatoid factor and that had been taken from rheumatoid arthritis patients was dependent upon endogenous IL-10. T h e involvement of IL-10 as an immunoregulatory cytokine has also been borne out in animal models of arthritis. Thus, IL-10 production is observed in synovial tissue of DBA/1 mice with CIA, and mice receiving neutralizing IL-10 antibodies develop an accelerated disease onset and more severe arthritis [38°°]. Furthermore, progression of established disease in DBA/1 mice can be ameliorated by daily treatment with recombinant IL-10 [39]. Similarly, in EAE, relapses could be prevented by IL-10 or transforming growth factor (TGF)-[3 administration [40 °] and mice with experimental autoimmune thyroiditis disease severity was significantly reduced when the mice were treated with high doses of recombinant human IL-10, an effect reflected in an increase of T cells undergoing apoptosis compared with controls [41°]. Clearly IL-10 has potent immunoregulatory properties and as such it is not surprising that mice homozygous for IL-10 deletion spontaneously develop a chronic enterocolitis with features characteristic of human ulcerative colitis and Crohn's disease [42].
There is also evidence that IL-10 is unregulated in other autoimmune diseases, such as SLE [32]; however, it is likely that the role of IL-10 in SLE, unlike in RA, is associated with disease development. A recent report demonstrated that an increase in the ratio of IL-10 : IFNyproducing cells in peripheral blood was correlated with disease severity [43], and in NZB/W mice, anti-IL-10 treatment inhibits disease onset [44]. It is also unclear whether IL-10 has a protective or disease-potentiating role in insulin-dependent diabetes mellitus. For example, transgenic mice expressing IL-10 in islet cells develop an insulinitis with leucocyte extravasation, and in nonobese diabetic mice transgene expression of IL-10 in the islets accelerates autoimmune insulin-dependent diabetes mellitus [45,46]. T h e s e results suggest that IL-10 may promote inflammatory events by enhancing leucocyte trafficking and extravasation. T h e above results, taken together, make it clear that in autoimmune disease there is upregulation of both inhibitory cytokines and cytokine inhibitors. There is a relative imbalance, however, in favour of the proinflammatory mediators, and therefore therapy aimed at tipping the balance in favour of the anti-inflammatory arm may be beneficial. Interestingly, it has been reported that IFN[3 therapy of MS patients in whom there has been a modest reduction of the relapse rate results in an increase in serum IL-lra levels [47]. Of interest too is the report that IFNl3-stimulated monocytes produce IL-10 [48]. Thus it is tempting to speculate that IFNI3 therapy reduces the relapse rate in MS by reversing the pro- versus anti-inflammatory cytokine balance, but this hypothesis needs further testing.
Cytokines and cell trafficking From the clinical studies using T N F antibodies in RA patients, it has become apparent that some of the benefit is a consequence of reduced cell trafficking to the inflamed synovial joints [9"], due to a reduction in adhesion molecule facilitated extravasation across endothelium in synovial tissue but also possibly due to a reduction in chemokine production. T h e human chemokines are a superfamily of low molecular weight peptides and consist of three subfamilies which are chemotactic for neutrophils, mononuclear cells or lymphocytes (reviewed in [49]). T h e production of many chemokines in RA synovial tissue and in inflammatory joint disease has been described (reviewed recently in [2,50°]). More recently, however, the expression of chemokines in murine CIA has been investigated [38"]. This study demonstrated the expression of monocyte chemotactic peptide-1, macrophage inflammatory protein (MIP)I~, epithelial neutrophil activating peptide 78 (ENA)-78 and MIP-2 (the murine functional homology of IL-8), furthermore, passive immunization of CIA mice with antibodies against either MIP-lot or MIP-2 resulted in both a delay in disease onset and a decrease of disease
Cytokines in autoimmunity Brennan and Feldmann
severity. Interestingly, anti-IL-10 treatment increased the expression of MIP-1 ot and MIP-2, an effect associated with enhanced leucocyte infiltration in the joints, suggesting a homeostatic role for IL-10 in chemokine regulation [38"'], in addition to its previously reported role [33] in regulating TNFo~ and IL-113. T h e role of chemokines in other animal models of autoimmune disease has also been demonstrated recently. For example, macrophage chemotactic peptide [51] and MIP-lc~ [52] are found in the CNS of rats with EAE. Furthermore, the administration of anti-MIP-lc~ prevented the development of both acute and relapsing paralytic disease as well as the infiltration of mononuclear cells into the CNS initiated by the transfer of neuroantigen peptide activated T cells [52].
Thl versus Th2 cytokines and involvement of IL-12 Over the past few years studies of cytokines in autoimmune disease have pursued the hypothesis that local autoimmunity results as a preponderance of T h l over Th2 subsets. As this topic is considered in detail in a separate review in this section (Nicholson and Kuchroo, pp 837-842) only those key papers relating to the involvement of IL-12 will be considered here. IL-12 is a heterodimeric cytokine which is thought to play a key role in promoting T h l immune responses and, as such, in skewing the T h l :Th2 ratio in autoimmune diseases. Support for this idea comes from the observation, in CIA [53"], that IL-12 may replace the need for mycobacteria after being shown to markedly augment the incidence of arthritis in DBA/1 mice injected with Freund's incomplete adjuvant and type II collagen. Somewhat surprisingly, it was also demonstrated by the same group [54] that high doses of IL-12 injected systemically inhibited the development of joint disease in the same mouse model of disease. It is not clear why IL-12 exhibits these apparently contradictory effects, but it is conceivable that, in common with IL-10, it has both pro- and anti-inflammatory properties (discussed in [55]). Despite its potential to exhibit bimodal function, antibodies to IL-12 have been used successfully to treat other experimental autoimmune diseases such as EAE [56] and a murine model for human inflammatory bowel disease [57]. Furthermore, IL-12 expression has been described in a number of organ-specific autoimmune disease models (reviewed in [58"]), and in diseased islets and thyroids of BB rats [59], and is associated with rapid development of diabetes mellitus in nonobese diabetic mice [60]. There arc fewer studies of IL-12 expression and its effects in human inflammatory tissue, but a recent report [61"'] described increased expression of B7-1 and IL-12 p40 in acute MS plaques, a finding that is potentially indicative of stimuli that could stimulate T cell activation and the induction of T h l - t y p e immune
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responses. It is thought that one of the major roles of IL-12 in autoimmune disease is to induce IFN~' production, as mice homozygous for deletion of the IL-12 gene display defective IFN~'and type 1 cytokine responses [62]. I F N y knockout mice back-crossed onto the susceptible background, however, still develop EAE at the expected frequency and severity [63"']. Clearly, in the next few years the mechanism by which IL-12 and other cytokines stimulate the emergence of T h l or Th2 subsets will be central to many investigations into autoimmune diseases.
Conclusion With our increasing knowledge of the importance of cytokines in the pathogenesis of autoimmune disease, it is likely that a n t i - T N F a will not remain the sole effective anticytokine therapy in autoimmunity. We eagerly await the use of cytokine therapeutic 'cocktails' in different diseases, an approach which may get much closer to a real long-term cure than do the current forms of treatment.
References and recommended reading Due to editorial constraints there were two additional references that we felt should have been highlighted hut could not be because they were published more than twelve months ago. Reference [5] describes the first successful randomized double-blind trial of an anti-TNFec antibody in RA patients, confirming an open-phase study that a single infusion of 1 or 10 mg kg-1 chimeric monoclonal antibody to TNFcc (cA2) resulted in highly significant (p=0.0083; low dose cA2 and p==O.0001 ; high dose cA2) improvements in both clinical and biochemical measures of disease activity at four weeks compared with placebo treatment in seventy-three patients with active RA. Reference [31] explores the interaction between IL-1 activity and the IL-1 inhibitor IL-lra in RA synovial tissue and makes the important observation that it is the ratio of IL-lra:lL-1 rather than the absolute level of each protein which determines the bioactivity of IL-t, which in RA synovial joint tissue cells is well below the 10 000-fold excess of IL-lra needed to inhibit IL-1 bioactivity. Thus, although the inhibitor of IL-1 is upregulated in inflammatory conditions, this increase is insufficient to abrogate the proinflammatory effects of IL-1. Papers of particular interest, published within the annual period of review, have been highlighted as: . o.
of special interest of outstanding interest Brennan FM, Feldmann MF: Cytokines in Autoimmunity. Austin, Texas: RG Landes Company; 1996. Feldmann M, Brennan FM, Maini RN: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996, 14:397-440. Butler DM, Maini RN, Feldmann M, Brennan FM: Modulation of proinflammatery cytokine release in rheumatoid synovial membrane cell cultures. Comparison of monoclonal anti-TNF(x antibody with the IL-1 receptor antagonist. Eur Cytokine Network 1995, 6:225-230.
4.
Probert L, Plows D, Kontogeorgos G, Kollias G: The type 1 interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF- transgenic mice. Eur J Immuno11995, 25:1794-1797.
5.
EUiott M J, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H et aL: Randomised double blind comparison of a chimaeric monoclonal antibody to tumour necrosis factor (x (cA2) versus placebo in rheumatoid arthritis. Lancet 1994, 344:1105-1110.
6.
Elliott M J, Maini RN, Feldmann M, Long-Fox A, Charles P, Bill H, Woody JN: Repeated therapy with monoclonal antibody to tumour necrosis factor cc (cA2) in patients with rheumatoid arthritis. Lancet 1994, 344:1125-1127. Rankin ECC, Choy EHS, Kassimos D, Kingsley GH, Sopwith SM, Isenberg DA, Panayi GS: The therapeutic effects of an engineered human anti-tumour necrosis factor alpha antibody
7.
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Autoimmunity
(CDP571) in rheumatoid arthritis. Br J Rheumatol 1995, 34:334-342. This paper describes a double-blind trial in which the humanized TNF antibody CDP571 administered intravenously in single doses of 0.1, 1.0 or 10 mg kg-1 to patients with active RA (n =24), was compared with placebo (n=12). CDP571 at the higher dose (10mgkg -1) caused a significant reduction in erythrocyte sedimentation rate, C-reactive protein and the number of tender joints, maximally after one or two weeks.
Moreland LW, Margolies GR, Heck LW, Saway PA, Jacobs C, Beck C, Blosch C, Koopman WJ : Soluble tumor necrosis factor receptor (sTNFR):- results of a phase ! dose-escalation study in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 1994, 32 (suppl):295. 9. Paleolog EM, Hunt M, Elliott MJ, Feldmann M, Maini RN, Woody • JN: Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor c( antibody in rheumatoid arthritis. Arthritis Rheum 1996, 7:1082-1091. This paper examines the effect of chimeric cA2 treatment in RA patients on endothelial activation, and demonstrates that serum levels of E-selectin and intercellular adhesion molecule-1 (but not vascular cell adhesion molecule-I) were reduced after infusion of cA2 (1 or lOmgkg-1). In parallel, a rapid and sustained increase in circulating lymphocyte counts was observed, with largest changes observed in patients in whom a clinical benefit (>_20% Paulus response at week four) was observed. 10. Tak PP, Taylor PC, Breedveld FC, Smeets TJM, Kluin PM, Meinders AE, Maini RN: Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor c< monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996, 39:1092-1101. 11. Cope AP, Londei M, Chu NR, Cohen SBA, Elliott MJ, Maini RN, Brennan FM, Feldmann M: Chronic exposure to tumor necrosis factor (TNF) in vitro impairs the activation of T cells through the T cell receptor/CD3 complex; reversal in vivo by anti-TNF antibodies in patients with rheumatoid arthritis. J C/in Invest 1994, 94:749-760. 12. Lai NS, Lan JL, Yu CL, Lin RH: Role of tumor necrosis factoralpha in the regulation of activated synovial T cell growth: down-regulation of synovial T cells in rheumatoid arthritis patients. Eur J/mmunol 1995, 25:3243-3248. 13. MainiRN, Elliott MJ, Brennan FM, Williams RO, Chu CQ, Paleolog E, Charles PJ, Taylor PC, Feldmann M: Monoclonal anti-TNFc¢ antibody as a probe of pathogenesis and therapy of rheumatoid disease./mmuno/Rev 1995, 144:195-223. 14. Van Dullemen HM, Van Deventer SJH, Hommes DW, Bijl HA, • Jansen J, Tytgat GNJ, Woody J: Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995, 109:129-135. This paper describes for the first time the efficacy of cA2 therapy in an openlabel treatment protocol of ten patients with active Crohn's disease who were previously unresponsive to steroid treatment. Eight patients showed normalization of Crohn's disease activity index scores and healing of ulcerations as judged by colonoscopy within four weeks of treatment with a single infusion of cA2, with an average duration of response of four months. 15. RaineCS: Multiple sclerosis: TNF revisited, with promise [comment]. Nat Med 1995, 1:211-214. 16. Probert L, Akassoglou K, Pasparakis M, Kontogeorgos G, Kollias •. G: Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. Proc Nat/Acad Sci USA 1995, 92:11294-11298. This interesting study describes the spontaneous development of a chronic inflammatory demyelinating disease in transgenic mice that constitutively express a dysregulated murine TNF transgene under the control of its own promoter. Transgene expression was restricted to the CNS, with high-level expression in neurons distributed throughout the brain. The direct involvement of TNF in the pathogenesis of this disease was confirmed by peripheral administration of neutralizing routine mTNF(x antibodies. 17. Sommer N, Loschmann P-A, Northoff GH, Weller M, Steinbrecher A, Steinbach JP, Lichtenfels R, Meyermann R, Riethmuller A, Fontana A et a/.: The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med 1995, 1:244-248. 18. Genain CP, Roberts T, Davis RL, Nguyen M-H, Uccelli A, Faulds D, Li Y, Hedgpeth J, Hauser SL: Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterese inhibitor. Proc Nat/Acad Sci USA 1g95, 92:3601-3605. 19. MaksymowychWP, Avina-Zubieta A, Luong MH, Russell AS: An open study of pentoxifyUine in the treatment of severe refractory rheumatoid arthritis. J Rheumatol 1995, 22:625-629.
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Gearing AJH, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon J L e t a/.: Processing of tumour necrosis factor-(x precursor by metalloproteinases. Nature 1994, 370:555-557,
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Crowe PD, Walter BN, Mohler KM, Otten-Evans C, Black RA, Ware CF: A metalloprotease inhibitor blocks shedding of the 80kD TNF receptor and TNF processing in T lymphocytes. J Exp Med 1994, 181:1205-1210.
24. •-
Williams L, Gibbons DL, Gearing A, Feldmann M, Brennan FM: Paradoxical effects of a synthetic metalloprotainase inhibitor which blocks both p55 and p75 TNF receptor shedding and TNF~ processing. J C/in Invest 1996, 97:2833-2841. The results described in this paper raise the interesting possibility that a close relationship exists between the enzyme(s) which process membranebound TNF(x, and those involved in surface TNF-R cleavage, and suggest that hydroxamate inhibitors of MMP activity which block TNFc¢ secretion and TNF-R cleavage may not modulate downstream effects of TNFa. The precise specificity of these compounds, therefore, will be highly relevant to their clinical efficacy in inflammatory diseases. 25. BrennanFM, Gibbons DL, Cope AP, Katsikis P, Maini RN, Feldmann M: TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand J Immuno/ 1995, 42:158-165. 26. Georgopoulos S, Plows D, Kollias G: Trensmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. J Inf/amm 1996, 46:86-97. 27.
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Campion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M, The IL-lra Arthritis Study Group: Dose-range and dose frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 1996, 39:1092-1101. Drevlow BE, Lovis R, Haag MA, Sinacore JM, Jacobs C, Blosche C, Landay A, Moreland LW, Pope RM: Recombinant human interleukin-1 receptor type I in the treatment of patients with active rheumatoid arthritis. Arthritis Rheum 1996, 39:257-265. Joosten LAB, Helsen MMA, Vandeloo FAJ, Vandenberg WB: Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: a comparative study using anti-TNF alpha, anti-lL-1 alpha/beta, and IL-1Ra. Arthritis Rheum 1996, 39:797-809. Ku G, Faust 1", Lauffer LL, Livingston DJ, Harding MW: Interleukin1 beta converting enzyme inhibition blocks progression of type II collagen-induced arthritis in mice. Cytokine 1996, 8:377-386. FiresteinGS, Boyle DL, Yu C, Paine MM, Whisenand TD, Zvaifler NJ, Arend WP: Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum 1994, 37:644-652. Llorente L, Richaud-Patin ¥, Fior R, Alcocer-Varela J, Wijdenes J, Fourrier B, Galanaud P, Emilie D: In vivo production of interleukin-lO by non-T cells in rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Arthritis Rheum 1994, 37:1647-1655. Katsikis P, Chu CQ, Brennan FM, Maini RN, Feldmann M: Immunoregulatory role of interleukin 10 (IL-IO) in rheumatoid arthritis. J Exp Med 1994, 179:1517-1527. Cush JJ, Splawski JB, Thomas R, McFarlin JE, Schulze-Koops H, Davis LS, Fujita K, Lipsky PE: Elevated interleukin-lO levels in patients with rheumatoid arthritis. Arthritis Rheum 1995, 38:96-104. Chomarat P, Banchereau J, Miossec P: Differential effects of interleukins 10 and 4 on the production of interleukin-6 by blood and synovium monocytes in rheumatoid arthritis. Arthritis Rheum 1995, 38:1046-54. Vanroon JAG, Vanroy J, Gmeligmeyling FHJ, Lafeber F, Bijlsma JWJ : Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-lO and interleukin-4. Arthritis Rheum 1996, 39:829-835.
Cytokines in autoimmunity Brennan and Feldmann
37.
Perez L, Orte J, Brieva JA: Terminal differentiation of spontaneous rheumatoid factor-secreting B cells from rheumatoid arthritis patients depends on endogenous interleukin-lO. Arthritis Rheum 1995, 38:1771-1776. 38. Kasama T, Strieter RM, Lukacs NW, Lincoln PM, Burdick MD, *• KunkelSL: Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J Clin Invest 1995, 95:2868-2876. This interesting study demonstrates for the first time expression of chemokines during the evolution of CIA, the onset of which was delayed if administered with antibodies directed against either MIP-1¢¢ or MIP-2. On the contrary, CIA mice receiving neutralizing IL-IO antibodies demonstrated an acceleration of the onset and an increase in the severity of arthritis. 39. Walmsley M, Katsikis PD, Abney E, Parry S, Williams RO, Maini RN, Feldmann M: Interleukin-1O inhibition of the progression of established collagen-induced arthritis. Arthritis Rheum 1996, 39:495-503. 40. Crisi GM, Santambrogio L, Hochwald GM, Smith SR, Carlino * JA, Thorbecke GJ: Staphylococcal enterotoxin B and tumornecrosis factor-alpha-induced relapses of experimental allergic encephalomyelitis: protection by transforming growth factorbeta end interleukin-10. Eur J Immuno/1995, 25:3035-3040. This paper describes the ability of staphylococcal enterotoxin B or TNF to induce relapses of EAE in SJL mice. Adminstration of IL-10 and TGF-~2 reduced these relapses, whilst anti-lL-lO increased both the incidence and the severity. The authors conclude that TNF production is probably important in causing EAE relapses, and that endogenous IL-10 rather than TGF-~ production appears to limit the susceptibility to relapses in this model. 41. Mignon-Godefroy K, Rott O, Brazillet MP, Charreire J: Curative * end protective effects of IL-10 in experimental autoimmune thyroiditis (EAT). Evidence for IL-10-enhanced cell death in EAT. J/mmuno/1995, 154:6634-6643. This paper examines the effect of recombinant human IL-10 administration in two models of experimental autoimmune thyroiditis. Administration results in a significant reduction in severity of disease but no change in level of anti-mTg (mouse thyroglobulin) autoantibody levels. Activation-induced cell death of autoreactive T lymphocytes was increased. 42. KuhnR, Lohler J, Rennick D, Rajewsky K, Muller W: InterleukinlO-deficient mice develop chronic enterocolitis. Ce//1993, 75:263-274. 43. Hagiwara E, Gourley MF, Lee S, Klinman DM: Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: interferon-gammasecreting cells in the peripheral blood. Arthritis Rheum 1996, 39:379-385. 44. Ishida H, Muchamuel T, Sakaguchi S, Andrade S, Menon S, Howard M: Continuous administration of anti-interleukin 10 antibodies delays onset of autoimmunity in NZB/W F1 mice. J Exp Med 1994, 179:305-310. 45. Wogensen L, Huang X, Sarvetnick N: Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans. J Exp Med 1993, 178:175-185.
46.
Wogensen L, Myung-Shik L, Sarvetnick N: Production of interleukin-10 by islet cells accelerates immune-mediated destruction of 13cells in nonobese diabetic mica. J Exp Med 1994, 179:t 379-1384. 47. Nicoletti F, Patti F, Dimarco R, Zaccone P, Nicoletti A, Meroni PL, Reggio A: Circulating serum levels of IL-lra in patients with relapsing remitting multiple sclerosis are normal during remission phases but significantly increased either during exacerbations or in response to IFN-beta treatment. Cytokine 1996, 8:395-400. 48. PorriniAM, Gambi D, Reder AT: Interferon effects on interleukin10 secretion. Mononuclear cell response to interleukin-10 is normal in multiple sclerosis patients. J Neuroimmuno/1995, 61:27-34. 49. Strieter RM, Standiford TJ, Huffnagle GB, Colletti LM, Lukacs NW, Kunkel SL: "The good, the bad, and the ugly": the role of chemokines in models of human disease - commentary. J /mmuno/1996, 156:3583-3586. 50. KunkelSL, Lukacs N, Kasama T, Stfieter RM: The role of • chemokines in inflammatory joint disease. J Leukocyte Biol 1996, 59:6-12. A well written review describing the association of chemokines with RA, and information from animal models regarding the kinetics of production
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and contribution of specific mediators to the development of experimental arthritis. 51.
Barman JW, Guida MP, Warren J, Amat J, Brosnan CF: Localization of monocyte chemoattrectant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat. J /mmuno/1996, 156:3017-3023.
52.
Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD: An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T call-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 1995, 155:5003-5010.
53. •
Germann T, Szeliga J, Hess H, Storkel S, Podlaski FJ, Gately MK, Schmitt E, Rude E: Administration of interleukin 12 in combination with type II collagen induces severe arthritis in DBA/1 mice. Proc Natl Acad Sci USA 1995, 92:4823-4827. This paper makes the interesting observation that IL-12 can replace the mycobacterial component of CIA and cause severe arthritis of DBA/1 mice when administered in combination with type II collagen. IL-12 administration resulted in an increase in collagen type II specific IFNy synthesis and collagen-specific IgG2a and tgG2b antibodies. 54.
Hess H, Gately MK, Rude E, Schmitt E, Szeliga J, Germann T: High doses of Interleukin-12 inhibit the development of joint disease in DBA/1 mice immunized with type II collagen in complete Freund's adjuvant. Eur J Immunol 1996, 26:187-191.
55.
Lamont AG, Adorini L: IL-12: a key cytokine in immune regulation./mmunol Today 1996, 17:214-217.
56.
Leonard JP, Waldburger KE, Goldman SJ: Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 1995, 181:381-386.
57.
Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W: Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 1995, 182:1261-1290.
58. •
TrembleauS, Germann T, Gately MK, Adorini L: The role of IL12 in the induction of organ-specific autoimmune diseases. Immunol Today 1995, 16:383-386. This review examines the role of IL-12, a key cytokine guiding the development of Thl cells, in the induction of autoimmune diseases, and discusses potential immunointervention strategies based on administration of IL-12 antagonists. 59.
Zipris D, Greiner DL, Malkani S, Whalen B, Mordes JR Rossini hA: Cytokine gene expression in islets and thyroids of BB rats-IFN-gamma and IL-121040 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats. J Immunol 1996, 156:1315-1321.
60.
Rothe H, Burkart V, Faust A, Kolb H: Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice. Diabetologia 1996, 39:119-122.
61. **
Windhagen A, Newcombe J, Dangond F, Strand C, Woodroofe MN, Cuzner ML, Hafler DA: Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), end interleukin 12 cytokine in multiple sclerosis lesions. J Exp Med 1995, 182:1985-1996. This interesting paper describes increased expression of B7-1 and IL-12 p40 in acute MS plaques, particularly from early disease cases, but not in inflammatory infarcts, and speculates that an early event in the initiation of MS involves upregulation of B7-1 and IL-t2, and results in conditions that maximally stimulate T cell activation and induction of Thl-type immune responses. 62.
63. -*
Magram J, Connaughton SE, Warrier RR, Carvajal DM, Wu C, Ferrante J, Stewart C, Sarmiento U, Faherty DA, Gately MK: IL-12 deficient mice are defective in IFNy production and type 1 cytokine responses. Immunity 1996, 4:471-481.
Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG: Mice with a disrupted IFNgamma gene are susceptible to the induction of experimental autoimmune encephalolmyelitis (EAD. J Immunol 1996, 156:5-7. This short report makes the interesting but unexpected finding that IFN7 is not crucial for the induction or perpetuation of EAE. This is based on their observation that mice homozygous for deletion in the IFN7 gene, back-crossed onto an EAE-susceptible strain, develop disease following immunization with MBP, with massive mononuclear ceil infiltrates in the CNS.