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Concluding remarks

additional references can be accessed on the

(1995) J. Immunol. 154, 5637–5648

Advances in our knowledge of the molecular events underlying tumour development and of the cellular and molecular basis of the immune response continue apace. To date, our ability to exploit this knowledge in the prevention and treatment of malignant disease has met with limited success. Nevertheless, some of the advances reported at this meeting should encourage further endeavours in this area.

Internet (http://www.ed.ac.uk/~anton/reviews/

7 Kiener, P.A., Moran-Davis, P., Rankin, B.M.

TIAG97_dec.html).

et al. (1995) J. Immunol. 155, 4917–4925 8 Eliopoulos, A.G., Stack, M., Dawson, C.W.

Anton Alexandroff (Anton.Alexandroff@ed. ac.uk) and Keith James are at the University Dept of Surgery, Royal Infirmary, Lauriston Place, Edinburgh, UK EH3 9YW; Richard Robins is at the Dept of Immunology, Queen’s Medical Centre, Nottingham, UK; Anna Murray is at the Institute for Cancer Studies, University of Sheffield Medical School, Sheffield, UK.

et al. (1997) Oncogene 14, 2899–2916 9 Mackey, M.F., Gunn, J.R., Ting, P.P. et al. (1997) Cancer Res. 57, 2569–2574 10 Alexandroff, A.B., McIntyre, C.A., Porter, J. et al. Br. J. Cancer (in press) 11 Guo, Y., Wu, M., Chen, H. et al. (1994) Science 263, 518–520 12 Evans, E.M., Man, S., Evans, A.S. et al. (1997) Cancer Res. 57, 2943–2950 13 Sadovnikova, S. and Stauss, H.J. (1997) Proc.

We are grateful to R. Dunbar, J. Gordon, M. Glennie,

References

Natl. Acad. Sci. U. S. A. 93, 13114–13118

A.M. Jackson, R. Kiessling, S. Man, G. Pawelec,

1 Türeci, O., Sahin, U. and Pfreundschuh, M.

14 Lamm, D.L. (1996) Semin. Oncol. 23,

R. Rees, J. Suttles, O. Türeci and R.H. Wiltrout for

(1997) Mol. Med. Today 3, 342–349

598–604

either critical reading of the manuscript or useful

2 Coulie, P.G. (1997) Mol. Med. Today 3, 261–268

15 Kono, K., Salazar-Onfray, F., Petersson, M.

comments. This report is based primarily on oral

3 Riethmuller, G., Schneider-Gadicke, E.,

et al. (1996) Eur. J. Immunol. 26, 1308–1313

and poster presentations of the Tumour Im-

Schlimok, G. et al. (1994) Lancet 343, 1177–1183

16 Stout, R.D. and Suttles, J. (1996) Immunol.

munology session with references to other ses-

4 French, R.R., Bell, A.J., Hamblin, T.J. et al.

Today 17, 487–492

sions where appropriate. We regret that space

(1996) Leuk. Res. 20, 607–617

17 Grewal, I.S. and Flavell, R.A. (1996) Immunol.

limitations prevent us from citing all presen-

5 Koho, H., Paulie, S., Ben-Aissa, H. et al. (1984)

Today 17, 410–414

tations and appropriate references. However, an

Cancer Immunol. Immunother. 17, 165–172

18 van Kooten, C. and Banchereau, J. (1997)

extended version of this report incorporating

6 Gajewski, T.F., Renauld, J-C., Pel, A.V. et al.

Curr. Opin. Immunol. 9, 330–337

Pediatric rheumatology: autoimmune mechanisms and therapeutic strategies Jasmin B. Kümmerle-Deschner, Michael K. Hoffmann, Dietrich Niethammer and Günther E. Dannecker Increased basic immunological knowledge has greatly advanced our understanding of autoimmunity, but

R

heumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints and progressive destruction of cartilage and bone. RA is associated with expression of certain HLA-DR haplotypes. CD4⫹ T cells are a pathogenic force at least in the initial stage of the disease, whereas monocytes have been implicated in the progression of RA (Fig. 1). Similar autoimmunological principles may apply to the pathogenesis of juvenile chronic arthritis (JCA), although the term JCA comprises at least four distinct disease subsets that may involve different pathogenetic mechanisms.

has had little impact on the treatment of autoimmune diseases so far. Immunologists and pediatric rheumatologists met recently* to assess the autoimmune process, review current treatment strategies and explore options for future therapy. Protein processing, antigen presentation and MHC association Presentation of peptides by major histocompatibility complex (MHC) class I or II mol-

Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0167-5699/98/$19.00

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ecules follows rules that are different for each allelic product, and the requirements of allele-specific peptide–MHC interaction can be summarized as motifs defined by number, spacing and specificities of anchors. The anchoring peptide side-chains bind to complementary pockets in the MHC groove, and the pockets of MHC class II molecules are in general less specific than the pockets of MHC class I molecules, resulting in a functional polymorphism. Elution of peptides from four closely related HLA-DR4 molecules, associated or not associated with RA, did yield allele-specific motifs with anchors at the relative positions P1 and P4 and, with more degenerate binding, P6 and PII: S0167-5699(98)01263-8

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*The meeting ‘From Basic Immunology to Pediatric Rheumatology: Closing the Cleft?’ was held at Tübingen, Germany, on 13–14 October 1997.

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Peptide Synoviocyte TCR

Regulation of the immune response

MHC

T cell Adhesion molecules

Metalloproteinases

Cytokines

Monocyte

Chondrocytes

Fig. 1. Pathogenesis of rheumatoid arthritis/juvenile chronic arthritis: a model. A T cell activated by an antigen (or superantigen) has reached the joint and interacts with synoviocytes and monocytes, resulting in the production of proinflammatory cytokines. This leads to production of metalloproteinases from synoviocytes, with subsequent destruction of chondrocytes. In this model, T cells would be necessary only for induction of the disease, and not for maintaining the ongoing inflammatory process. P7. On the basis of these results, a sequence of putative RA-inducing peptides was predicted to be LXXEXSEXX, and peptide fragments from mycobacterial heat shock protein 65 (hsp65) or from the human collagen ␣1 (II) precursor do contain such a motif1 (H-J. Schild, H-G. Rammensee, Tübingen). Recently, these results have been confirmed by X-ray crystal structure studies of HLA-DR4 complexed with a peptide from human collagen II; RA susceptibility correlated with the electrostatic charge of the P4 pocket2. RA is strongly associated with the expression of HLA-DR4 (DRB1*0401, DRB1*0404) or HLA-DR1 (DRB1*0101). In contrast, the early-onset pauciarticular subset of JCA (EOPA-JCA) is positively associated with the expression of HLA-A2, HLADR5 and HLA-DR8, as well as DPB1*0201, but negatively with HLA-DR4 and HLADR7. The different DR alleles have a certain hierarchy of disease association, where most alleles are either positively or negatively associated and few are neutral with respect to disease susceptibility. This hierarchy can also be identified at the HLA-DQ, but not at the HLA-A and HLA-DPB, region and can be found in other autoimmune diseases with a different pattern. The concept

of hierarchy is in accordance with the reported degenerate binding specificity of HLA class II molecules: for example, one or more hypothetical JCA-‘arthritogenic’ peptide(s) would bind with high affinity to HLA-DR8 and HLA-DR5, less so to HLA-DR4 and not at all to HLA-DR7. EOPA-JCA is also associated with the expression of certain DQ alleles. The DQA alleles DQA1*0401, DQA1*0501 and DQA1*0601 are expressed in 86% of patients with EOPA-JCA, and these alleles have a unique sequence of six amino acids suggesting that these DQ molecules determine the binding specificity for a given peptide3. But the DQ locus lies immediately next to the DR locus, resulting in strong linkage disequilibrium. It is therefore not possible to decide which of the two loci may represent the primary disease association. It was found that DRB1*1104, but not DRB1*1101, is strongly associated with EOPA-JCA. This could mean that both DR and DQ HLA molecules are necessary for disease induction. It has been proposed that HLA-A2- and/or DPB1*0201-derived self-peptides are presented by DRB1*1104 and/or DQA1*0401, DQA1*0501 and DQA1*0601 (E. Albert, Munich).

Multiple sclerosis (MS) has been considered as ‘rheumatoid arthritis of the brain’. MS is histologically characterized by inflammation of the central nervous system (CNS) and a selective loss of myelin. Experimental allergic encephalomyelitis (EAE) is commonly accepted as an animal model for MS, but generally signs only of inflammation and not of demyelinization are found. EAE can be induced by certain proteins, such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) or S100␤, or by the adoptive transfer of CD4⫹ T helper 1 (Th1)-cell lines specific for these proteins. Although these antigens are not expressed only in the CNS, autoreactive T cells can be generated against all of them. However, these autoreactive T cells differ with regard to their pathogenic effect4. For example, both MBP- and S100␤-reactive T cells result in T-cell infiltrates in the brain to the same extent, but only MBP- and not S100␤-reactive T cells recruit macrophages to the brain, resulting in disease. This finding has been taken to suggest that CNS auto-antigens and T cells that react with them are heterogeneous and that neurological dysfunction is mediated by macrophages and not by T cells. Immunization with the MOG antigen induces a relapsing–remitting course of EAE. This resembles more closely the clinical course of MS since it also results in demyelinization. T cells cause only very limited disease after adoptive transfer. Transfer of MOG antibodies alone produces no disease, but combined transfer of T cells and antibodies results in the induction of severe disease with demyelinization, suggesting a role for Th2 cells (C. Linington, Munich). Monocytes are not only a major source of proinflammatory [interleukin 1 (IL-1) and tumour necrosis factor ␣ (TNF-␣)] and anti-inflammatory [interleukin 10 (IL-10)] cytokines, they are also involved in antigen presentation and mediate antibodydependent cell-mediated cytotoxicity (ADCC). Recent experiments demonstrated that monocytes in human immunodeficiency virus-infected individuals lose their capacity to present antigen and to exert a costimulatory effect, but acquire instead the capacity

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+

−

IFN-γ

Stimulus

Stimulus

Th1 IL-12 M1

B7 MHC class II IL-1, TNF-␣

M2

Th0

CD16

IL-10 Th2

−

IL-10

ADCC

+ IL-4, IL-6 IL-10 B cell

Fig. 2. Two distinct macrophage populations regulate the function of CD4⫹ T cells. In this model, M1 cells represent the prototypical antigen-presenting cells. They express MHC class II for the presentation of antigenic peptides and express B7 molecules for the costimulation of T cells. M2 cells lack the tools for antigen-specific T-cell activation but express FcRs, which enable them to destroy antibody-reactive target cells. M1 and M2 cells exert opposite effects on Th-cell development. M1 cells generate IL-12, which facilitates the development of Th1 cells, whereas M2 cells generate IL-10, which facilitates the generation of Th2 cells. Th1 cells release IFN-␥ which stimulates M1 cells and inhibits M2 cells, whereas Th2-produced IL-10 inhibits M1 cells and promotes the generation of M2 cells. Through the release of IL-1 and TNF-␣, M1 functions as a proinflammatory macrophage, whereas M2 cells, by virtue of IL-10 production, act as anti-inflammatory macrophages (see Ref. 11 for more details). Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; IFN-␥, interferon ␥; IL-1, interleukin 1; MHC, major histocompatibility complex; Th, T helper cell; TNF-␣, tumour necrosis factor ␣. to destroy CD4⫹ T cells in an ADCC fashion5. A dichotomy in monocytes analogous to the Th1 and Th2 cell dichotomy has been proposed. Proinflammatory M1 monocytes express an MHC class IIhiB7hiCD16lo phenotype. Monocyte differentiation into M1 cells is induced by interferon ␥, but inhibited by IL-10. In contrast, anti-inflammatory M2 monocytes are induced by IL-10, express the MHC class IIloB7loCD16hi phenotype and mediate ADCC (M.K. Hoffmann, Valhalla, NY) (Fig. 2). M2 cells are generated as an immunoregulatory response to acute inflammation. The anti-inflammatory action of M2 cells suppresses inflammatory symptoms but poses the risk of enhanced ADCC activity and tissue destruction. Massive macrophage- and antibody-dependent cytotoxicity against lymphocytes has been shown in systemic lupus erythematosus patients. Involvement of antibodies has been observed in the pathogenic process of most known autoimmune

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diseases. A striking example is the abovementioned nerve demyelinization facilitated in mice by the transfer of MOG antibodies. Experimental arthritis can be induced in rats by injection of complete Freund’s adjuvant. Early disease is mediated by T cells that recognize amino acids 180–188 of the mycobacterial hsp. Following spontaneous remission, however, T cells recognizing other, more conserved hsp determinants become sensitized and can protect against disease induction in adoptive transfer experiments. An immunoregulatory mechanism involving hsp is also suggested by data obtained from children suffering from JCA. Mononuclear cells from patients with oligoarticular JCA have shown a proliferative response to human hsp60, correlating in vitro with IL-4 and transforming growth factor ␤ production and upregulation of CD30 expression. This anti-hsp response was indicative of disease remission. It was

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not seen in the more severe, therapyresistant subtypes of JCA. In the rat model, the arthritogenic hsp 180–188 peptide was administered intranasally prior to disease induction. The peptide suppressed not only adjuvant-induced, but also nonmicrobially mediated, arthritis6, and a mutant peptide produced even stronger suppression. Induction of active immune suppression has been suggested as the most likely explanation for this phenomenon. Therefore, hsp may not function as an immunogen, but may rather trigger an immunoregulatory response that produces a protective effect. Autoimmunity may thus emerge for lack of immunoregulatory control mechanisms. The notion implies important new options for immunotherapy in JCA by mucosal tolerance induction (W. Kuis, Utrecht).

Present and future aspects of therapy in JCA Significant advances in the treatment of JCA are emerging. Concepts of combination therapy employing drugs that act at different checkpoints of pathogenesis are being developed in international study programs. Recognition of biological control mechanisms facilitates strategies of immune intervention, and stem cell support is leading to exciting new possibilities. Combination therapy shows promising results in RA patients. Analogous to chemotherapy for cancer patients, an aggressive induction phase is envisaged, as compared with milder maintenance therapy after remission has been achieved. Therapeutic strategies comparable to treatment protocols in pediatric cancer patients and precise disease classification have been delineated7 (R. Petty, Vancouver). Biological agents emerge as a most promising treatment option for autoimmune diseases8. TNF-␣ has been shown to play an important role in the pathogenesis of RA. The pathogenic action of TNF-␣ is mediated by two distinct cell-surface receptors (TNFRs), designated p55 and p75. Soluble, truncated versions (sTNFRs) of these receptors are involved in regulating TNF activity. A recombinant human TNFR p75–Fc fusion protein (TNFR:Fc) was

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constructed. Subcutaneous treatment with TNFR:Fc has been shown to be effective in the treatment of patients with RA (Ref. 9). In JCA patients, a preliminary study with TNFR:Fc resulted in improvements without serious side effects. A blinded trial will follow (D. Lovell, Cincinnati, OH). Stem cell support (i.e. intensive immunosuppression followed by autologous stem cell rescue) is emerging as an exciting new treatment concept. Thirty-five patients with autoimmune diseases have been treated and are registered at the European Bone Marrow Transplantation (EBMT) center. The results are encouraging. Patient selection for this drastic therapy is a controversial issue. Scleroderma is a consensus indication, but the timepoint for treatment must be chosen carefully. Three patients with polyarthritic JCA have been treated with autologous Tcell-depleted stem cell support by W. Kuis in Utrecht with good preliminary results. To coordinate current stem cell transfer efforts, an international consensus finding

group has been formed, and this has identified a limited number of protocols. These are available from the EBMT center in Basel10, where all patients should be registered. Furthermore, patients considered suitable for this treatment option should be seen by an independent experienced clinician to confirm the diagnosis and to agree with the proposed therapy (A. Tyndall, Basel).

2 Dessen, A., Lawrence, C.M., Cupo, S., Zaller, D.M. and Wiley, D.C. (1997) Immunity 7, 473–481 3 Haas, J.P., Nevinny-Stickel, C., Schoenwald, U., Truckenbrodt, H., Suschke, J. and Albert, E.D. (1994) Hum. Immunol. 41, 225–233 4 Berger, T., Weerth, S., Kojima, K., Linington, C., Wekerle, H. and Lassmann, H. (1997) Lab. Invest. 76, 355–364 5 Dudhane, A., Conti, B., Orlikowsky, T. et al. (1996) AIDS Res. Hum. Retroviruses 12, 885–892 6 Prakken, B.J., van der Zee, R., Anderton, S.M.,

Jasmin Kümmerle-Deschner, Dietrich Niethammer and Günther Dannecker ([email protected]) are at the Dept of Oncology and Hematology, Children’s University Hospital, Rümelinstrasse 23, 72070 Tübingen, Germany; Michael Hoffmann is at the Dept of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA.

van Kooten, P.J., Kuis, W. and van der Eden, W. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 3284–3289 7 Petty, R.E. (1997) Rev. Rhum. Engl. Ed. 64, 161S–162S 8 Moreland, L.W., Heck, L.W. and Koopman, W.J. (1997) Arthritis Rheum. 40, 397–409 9 Moreland, L.W., Baumgartner, S.W., Schiff, M.H. et al. (1997) New Engl. J. Med. 337, 141–147 10 Tyndall, A. and Gratwohl, A. (1997) Br. J.

References

Rheumatol. 36, 390–392

1 Friede, T., Gnau, V., Jung, G., Keilholz, W.,

11 Wang, Z-Q., Horowitz, H., Orlikowsky, T.,

Stevanovic, S. and Rammensee, H-G. (1996)

Dudhane, A. and Hoffmann, M.K. J. Infect. Dis. (in

Biochim. Biophys. Acta 1316, 85–101

press)

Innate T-cell immunity to nonpeptidic antigens Fabrizio Poccia, Marie-Lise Gougeon, Marc Bonneville, Miguel Lôpez-Botet, Alessandro Moretta, Luca Battistini, Marianne Wallace, Vittorio Colizzi and Miroslav Malkovsky V␥9V␦2-encoded T-cell receptors

T

cells, which are essential components of cell-mediated immunity against invading pathogens, often recognize processed antigens in the form of short peptides bound to major histocompatibility complex (MHC) molecules on the antigenpresenting cell surface1,2. However, some T cells can recognize nonprocessed components of infectious agents3. In addition to peptides, a variety of nonpeptidic antigens stimulate T cells4–8. For example, lipid and lipoglycan antigens presented in the context of nonpolymorphic class I-like CD1 molecules stimulate certain ␣␤ T cells4,5, whereas nonpeptidic phosphoantigens induce constitutive responses in most peripheral blood V␥9V␦2 T cells6–8. The recognition of phos-

crossreact with a variety of

processing, allowing for rapid and potent responses against the invading pathogen. It is conceivable that the regulation of these responses is very tight in order to avert autoimmunity or immunopathology.

nonpeptidic phosphoantigens derived from numerous infectious agents. The reactivities of V␥9V␦2 T cells induced by different stimuli are controlled by receptors for

MHC receptors

major histocompatibility complex class I molecules. These and other important areas of natural anti-infectious immunity were discussed at a recent workshop*. phoantigens does not require the presence of classical polymorphic or nonpolymorphic MHC molecules or antigen uptake/

PII: S0167-5699(98)01266-3

One of the important regulatory mechanisms utilizes the so-called inhibitory MHC class I receptors (INMRs)9–20 that are expressed by the nonpeptidic-antigen-reactive ␣␤ and ␥␦ T cells as well as by natural killer (NK) cells. Typically, target cells lacking one or more MHC class I alleles are susceptible to NK-mediated lysis, whereas the interaction of MHC molecules with INMRs results in inhibition of NK cytotoxicity15–17. The Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0167-5699/98/$19.00

J U N E *The International Workshop on Innate Immunity in AIDS and Tuberculosis was held at Valle d’Aosta, Italy, on 1–3 December 1997.

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