The application of molecular immunology techniques in the study of rheumatoid arthritis has resulted in an explosion of knowledge on the risk factors for the disease, predictors of disease severity, the molecular mechanisms of inflammatory responses, and mechanisms of tissue destruction. We know, for example, that inheriting certain genes in the major histocompatibility complex partly dictates susceptibility and severity of rheumatoid arthritis. These genes and others in the major histocompatibility complex are critical for the occurrence of immune responses both constructive (prevention of infection, surveillance for malignant cells) and destructive (development of autoimmune diseases). We also now understand mechanisms of cell communication, regulation of immune responses, how the cells that mediate immune responses and tissue injury accumulate in tissues, and how the injury occurs. The knowledge itself is satisfying, but more important, based on this knowledge, effective and reasonably safe treatments that address basic mechanisms of the disease process have been developed and are now widely used. In fact, the newer treatments represent the “tip of the iceberg,” and as our basic knowledge increases, so too will the armamentarium with which we can fight rheumatoid arthritis and other similar autoimmune diseases.
For definitions of terms, see Glossary at end of text.
References
- 1.
Decker JL ,Malone DG ,Haraoui B ,Wahl SM ,Schrieber L ,Klippel JH ,et al . NIH conference. Rheumatoid arthritis: evolving concepts of pathogenesis and treatment. Ann Intern Med. 1984;101:810-24. [PMID:6093663 ] LinkGoogle Scholar - 2.
Firestein GS . The immunopathogenesis of rheumatoid arthritis. Curr Opin Rheumatol. 1991;3:398-406. [PMID:1883694 ] CrossrefMedlineGoogle Scholar - 3.
Wordsworth BP ,Bell JI . The immunogenetics of rheumatoid arthritis. Springer Semin Immunopathol. 1992;14:59-78. [PMID:1440198 ] CrossrefMedlineGoogle Scholar - 4.
Stastny P . Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978;298:869-71. [PMID:147420 ] CrossrefMedlineGoogle Scholar - 5.
Nepom GT ,Hansen JA ,Nepom BS . The molecular basis for HLA class II associations with rheumatoid arthritis. J Clin Immunol. 1987;7:1-7. [PMID:3558732 ] CrossrefMedlineGoogle Scholar - 6.
Nelson JL ,Mickelson E ,Masewicz S ,Barrington R ,Dugowson C ,Koepsell T ,et al . Dw14(DRB1*0404) is a Dw4-dependent risk factor for rheumatoid arthritis. Rethinking the “shared epitope” hypothesis. Tissue Antigens. 1991;38:145-51. [PMID:1724805 ] CrossrefMedlineGoogle Scholar - 7.
Weyand CM ,Xie C ,Goronzy JJ . Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis. J Clin Invest. 1992;89:2033-9. [PMID:1602009 ] CrossrefMedlineGoogle Scholar - 8.
Poulter LW ,Duke O ,Hobbs S ,Janossy G ,Panayi G . Histochemical discrimination of HLA-DR positive cell populations in the normal and arthritic synovial lining. Clin Exp Immunol. 1982;48:381-8. [PMID:6213328 ] MedlineGoogle Scholar - 9.
Klareskog L ,Forsum U ,Malmnäs Tjernlund UK ,Kabelitz D ,Wigren A . Appearance of anti-HLA-DR-reactive cells in normal and rheumatoid synovial tissue. Scand J Immunol. 1981;14:183-92. [PMID:6458880 ] CrossrefMedlineGoogle Scholar - 10.
Burmester GR ,Dimitriu-Bona A ,Waters SJ ,Winchester RJ . Identification of three major synovial lining cell populations by monoclonal antibodies directed to Ia antigens and antigens associated with monocytes/macrophages and fibroblasts. Scand J Immunol. 1983;17:69-82. [PMID:6573767 ] CrossrefMedlineGoogle Scholar - 11.
Weyand CM ,Oppitz U ,Hicok K ,Goronzy JJ . Selection of T cell receptor V β elements by HLA-DR determinants predisposing to rheumatoid arthritis. Arthritis Rheum. 1992;35:990-8. [PMID:1384516 ] CrossrefMedlineGoogle Scholar - 12.
Smith JB ,Bocchieri MH ,Sherbin-Allen L ,Borofsky M ,Abruzzo JL . Occurrence of interleukin-1 in human synovial fluid: detection by RIA, bioassay and presence of bioassay-inhibiting factors. Rheumatol Int. 1989;9:53-8. [PMID:2814208 ] CrossrefMedlineGoogle Scholar - 13.
Xu WD ,Firestein GS ,Taetle R ,Kaushansky K ,Zvaifler NJ . Cytokines in chronic inflammatory arthritis. II. Granulocyte-macrophage colony-stimulating factor in rheumatoid synovial effusions. J Clin Invest. 1989;83:876-82. [PMID:2646320 ] CrossrefMedlineGoogle Scholar - 14.
Brennan FM ,Chantry D ,Turner M ,Foxwell B ,Maini R ,Feldmann M . Detection of transforming growth factor-β in rheumatoid arthritis synovial tissue: lack of effect on spontaneous cytokine production in joint cell cultures. Clin Exp Immunol. 1990;81:278-85. [PMID:2201470 ] CrossrefMedlineGoogle Scholar - 15.
Buchan G ,Barrett K ,Turner M ,Chantry D ,Maini RN ,Feldmann M . Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1 α. Clin Exp Immunol. 1988;73:449-55. [PMID:3264773 ] MedlineGoogle Scholar - 16.
Chu CQ ,Field M ,Abney E ,Zheng RQ ,Allard S ,Feldmann M ,et al . Transforming growth factor-β 1 in rheumatoid synovial membrane and cartilage/pannus junction. Clin Exp Immunol. 1991;86:380-6. [PMID:1747946 ] CrossrefMedlineGoogle Scholar - 17.
Suzuki N ,Nakajima A ,Yoshino S ,Matsushima K ,Yagita H ,Okumura K . Selective accumulation of CCR5+ T lymphocytes into inflamed joints of rheumatoid arthritis. Int Immunol. 1999;11:553-9. [PMID:10323208 ] CrossrefMedlineGoogle Scholar - 18.
Borzi RM ,Mazzetti I ,Macor S ,Silvestri T ,Bassi A ,Cattini L ,et al . Flow cytometric analysis of intracellular chemokines in chondrocytes in vivo: constitutive expression and enhancement in osteoarthritis and rheumatoid arthritis. FEBS Lett. 1999;455:238-42. [PMID:10437780 ] CrossrefMedlineGoogle Scholar - 19.
Mack M ,Brühl H ,Gruber R ,Jaeger C ,Cihak J ,Eiter V ,et al . Predominance of mononuclear cells expressing the chemokine receptor CCR5 in synovial effusions of patients with different forms of arthritis. Arthritis Rheum. 1999;42:981-8. [PMID:10323454 ] CrossrefMedlineGoogle Scholar - 20.
Breedveld FC ,Kalden JR ,Smolen JS . Advances in targeted therapies: TNFalpha blockade in clinical practice. Ann Rheum Dis. 1999;58Suppl 1 I1. [PMID:0010577966 ] CrossrefMedlineGoogle Scholar - 21.
Panayi GS . Targeting of cells involved in the pathogenesis of rheumatoid arthritis. Rheumatology Oxford. 1999;38Suppl 2 8-10. [PMID:10646482 ] MedlineGoogle Scholar - 22.
Schulze-Koops H ,Davis LS ,Haverty TP ,Wacholtz MC ,Lipsky PE . Reduction of Th1 cell activity in the peripheral circulation of patients with rheumatoid arthritis after treatment with a non-depleting humanized monoclonal antibody to CD4. J Rheumatol. 1998;25:2065-76. [PMID:9818646 ] MedlineGoogle Scholar - 23.
Bresnihan B ,Alvaro-Gracia JM ,Cobby M ,Doherty M ,Domljan Z ,Emery P ,et al . Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998;41:2196-204. [PMID:9870876 ] CrossrefMedlineGoogle Scholar - 24.
Moreland LW ,Schiff MH ,Baumgartner SW ,Tindall EA ,Fleischmann RM ,Bulpitt KJ ,et al . Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med. 1999;130:478-86. [PMID:10075615 ] LinkGoogle Scholar - 25.
Harriman G ,Harper LK ,Schaible TF . Summary of clinical trials in rheumatoid arthritis using infliximab, an anti-TNFalpha treatment. Ann Rheum Dis. 1999;58Suppl 1 I61-4. [PMID:10577975 ] CrossrefMedlineGoogle Scholar - 26.
Kavanaugh AF ,Davis LS ,Nichols LA ,Norris SH ,Rothlein R ,Scharschmidt LA ,et al . Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum. 1994;37:992-9. [PMID:7912930 ] CrossrefMedlineGoogle Scholar - 27.
Kavanaugh AF ,Schulze-Koops H ,Davis LS ,Lipsky PE . Repeat treatment of rheumatoid arthritis patients with a murine anti-intercellular adhesion molecule 1 monoclonal antibody. Arthritis Rheum. 1997;40:849-53. [PMID:9153545 ] CrossrefMedlineGoogle Scholar - 28.
Westermann J ,Engelhardt B ,Hoffmann JC . Migration of T cells in vivo: molecular mechanisms and clinical implications. Ann Intern Med. 2001;135:279-95. [PMID:11511143 ] LinkGoogle Scholar - 29.
Masi AT ,Maldonado-Cocco JA ,Kaplan SB ,Feigenbaum SL ,Chandler RW . Prospective study of the early course of rheumatoid arthritis in young adults: comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome. Semin Arthritis Rheum. 1976;4:299-326. [PMID:1273600 ] CrossrefMedlineGoogle Scholar - 30.
Jacoby RK ,Jayson MI ,Cosh JA . Onset, early stages, and prognosis of rheumatoid arthritis: a clinical study of 100 patients with 11-year follow-up. Br Med J. 1973;2:96-100. [PMID:4700332 ] CrossrefMedlineGoogle Scholar - 31.
Ollier W ,Thomson W . Population genetics of rheumatoid arthritis. Rheum Dis Clin North Am. 1992;18:741-59. [PMID:1280845 ] CrossrefMedlineGoogle Scholar - 32.
Crilly A ,Maiden N ,Capell HA ,Madhok R . Genotyping for disease associated HLA DR β 1 alleles and the need for early joint surgery in rheumatoid arthritis: a quantitative evaluation. Ann Rheum Dis. 1999;58:114-7. [PMID:10343527 ] CrossrefMedlineGoogle Scholar - 33.
Weyand CM ,Hicok KC ,Conn DL ,Goronzy JJ . The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med. 1992;117:801-6. [PMID:1416553 ] LinkGoogle Scholar - 34.
Edwards JC . The nature and origins of synovium: experimental approaches to the study of synoviocyte differentiation. J Anat. 1994;184 Pt 3 493-501. [PMID:7928638 ] MedlineGoogle Scholar - 35.
Girard JP ,Springer TA . High endothelial venules (HEVs): specialized endothelium for lymphocyte migration. Immunol Today. 1995;16:449-57. [PMID:7546210 ] CrossrefMedlineGoogle Scholar - 36.
Tak PP ,Thurkow EW ,Daha MR ,Kluin PM ,Smeets TJ ,Meinders AE ,et al . Expression of adhesion molecules in early rheumatoid synovial tissue. Clin Immunol Immunopathol. 1995;77:236-42. [PMID:7586733 ] CrossrefMedlineGoogle Scholar - 37.
Koch AE ,Burrows JC ,Haines GK ,Carlos TM ,Harlan JM ,Leibovich SJ . Immunolocalization of endothelial and leukocyte adhesion molecules in human rheumatoid and osteoarthritic synovial tissues. Lab Invest. 1991;64:313-20. [PMID:1706003 ] MedlineGoogle Scholar - 38.
Cush JJ ,Pietschmann P ,Oppenheimer-Marks N ,Lipsky PE . The intrinsic migratory capacity of memory T cells contributes to their accumulation in rheumatoid synovium. Arthritis Rheum. 1992;35:1434-44. [PMID:1282007 ] CrossrefMedlineGoogle Scholar - 39.
Thomas R ,McIlraith M ,Davis LS ,Lipsky PE . Rheumatoid synovium is enriched in CD45RBdim mature memory T cells that are potent helpers for B cell differentiation. Arthritis Rheum. 1992;35:1455-65. [PMID:1472123 ] CrossrefMedlineGoogle Scholar - 40.
Mosmann TR ,Coffman RL . TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145-73. [PMID:2523712 ] CrossrefMedlineGoogle Scholar - 41.
de Waal Malefyt R ,Abrams J ,Bennett B ,Figdor CG ,de Vries JE . Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174:1209-20. [PMID:1940799 ] CrossrefMedlineGoogle Scholar - 42.
de Waal Malefyt R ,Yssel H ,de Vries JE . Direct effects of IL-10 on subsets of human CD4 + T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993;150:4754-65. [PMID:7684412 ] MedlineGoogle Scholar - 43.
Wu J ,Cunha FQ ,Liew FY ,Weiser WY . IL-10 inhibits the synthesis of migration inhibitory factor and migration inhibitory factor-mediated macrophage activation. J Immunol. 1993;151:4325-32. [PMID:7691945 ] MedlineGoogle Scholar - 44.
Kasid A ,Bell GI ,Director EP . Effects of transforming growth factor-β on human lymphokine-activated killer cell precursors. Autocrine inhibition of cellular proliferation and differentiation to immune killer cells. J Immunol. 1988;141:690-8. [PMID:3133414 ] MedlineGoogle Scholar - 45.
Günther M ,Haubeck HD ,van de Leur E ,Bläser J ,Bender S ,Gütgemann I ,et al . Transforming growth factor β 1 regulates tissue inhibitor of metalloproteinases-1 expression in differentiated human articular chondrocytes. Arthritis Rheum. 1994;37:395-405. [PMID:8129795 ] CrossrefMedlineGoogle Scholar - 46.
van der Veen RC ,Stohlman SA . Encephalitogenic Th1 cells are inhibited by Th2 cells with related peptide specificity: relative roles of interleukin (IL)-4 and IL-10. J Neuroimmunol. 1993;48:213-20. [PMID:8227319 ] CrossrefMedlineGoogle Scholar - 47.
Harris ED . Rheumatoid arthritis [Editorial]. Curr Opin Rheumatol. 1994;6:287-9. [PMID:8060763 ] CrossrefMedlineGoogle Scholar - 48.
Elliott MJ ,Maini RN . New directions for biological therapy in rheumatoid arthritis. Int Arch Allergy Immunol. 1994;104:112-25. [PMID:8199454 ] CrossrefMedlineGoogle Scholar - 49.
Holt I ,Cooper RG ,Hopkins SJ . Relationships between local inflammation, interleukin-6 concentration and the acute phase protein response in arthritis patients. Eur J Clin Invest. 1991;21:479-84. [PMID:1752286 ] CrossrefMedlineGoogle Scholar - 50.
Schulze-Koops H ,Davis LS ,Kavanaugh AF ,Lipsky PE . Elevated cytokine messenger RNA levels in the peripheral blood of patients with rheumatoid arthritis suggest different degrees of myeloid cell activation. Arthritis Rheum. 1997;40:639-47. [PMID:9125245 ] CrossrefMedlineGoogle Scholar - 51.
Hopkins SJ ,Humphreys M ,Jayson MI . Cytokines in synovial fluid. I. The presence of biologically active and immunoreactive IL-1. Clin Exp Immunol. 1988;72:422-7. [PMID:3262460 ] MedlineGoogle Scholar - 52.
Firestein GS ,Alvaro-Gracia JM ,Maki R ,Alvaro-Garcia JM . Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol. 1990;144:3347-53. [PMID:2109776 ] MedlineGoogle Scholar - 53.
Campbell IK ,Roughley PJ ,Mort JS . The action of human articular-cartilage metalloproteinase on proteoglycan and link protein. Similarities between products of degradation in situ and in vitro. Biochem J. 1986;237:117-22. [PMID:3541894 ] CrossrefMedlineGoogle Scholar - 54.
Brennan FM ,Zachariae CO ,Chantry D ,Larsen CG ,Turner M ,Maini RN ,et al . Detection of interleukin 8 biological activity in synovial fluids from patients with rheumatoid arthritis and production of interleukin 8 mRNA by isolated synovial cells. Eur J Immunol. 1990;20:2141-4. [PMID:2209707 ] CrossrefMedlineGoogle Scholar - 55.
Katsikis PD ,Chu CQ ,Brennan FM ,Maini RN ,Feldmann M . Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med. 1994;179:1517-27. [PMID:8163935 ] CrossrefMedlineGoogle Scholar - 56.
Roberts AB ,McCune BK ,Sporn MB . TGF-β: regulation of extracellular matrix. Kidney Int. 1992;41:557-9. [PMID:1573828 ] CrossrefMedlineGoogle Scholar - 57.
Haynes MK ,Smith JB . Can Th1-like immune responses explain the immunopathology of recurrent spontaneous miscarriage? J Reprod Immunol. 1997;35:65-71. [PMID:9373859 ] CrossrefMedlineGoogle Scholar - 58.
Paliard X ,West SG ,Lafferty JA ,Clements JR ,Kappler JW ,Marrack P ,et al . Evidence for the effects of a superantigen in rheumatoid arthritis. Science. 1991;253:325-9. [PMID:1857971 ] CrossrefMedlineGoogle Scholar - 59.
Jenkins RN ,Nikaein A ,Zimmermann A ,Meek K ,Lipsky PE . T cell receptor V β gene bias in rheumatoid arthritis. J Clin Invest. 1993;92:2688-701. [PMID:8254025 ] CrossrefMedlineGoogle Scholar - 60.
Howell MD ,Diveley JP ,Lundeen KA ,Esty A ,Winters ST ,Carlo DJ ,et al . Limited T-cell receptor β-chain heterogeneity among interleukin 2 receptor-positive synovial T cells suggests a role for superantigen in rheumatoid arthritis. Proc Natl Acad Sci U S A. 1991;88:10921-5. [PMID:1660155 ] CrossrefMedlineGoogle Scholar - 61.
Friedman SM ,Crow MK ,Tumang JR ,Tumang M ,Xu YQ ,Hodtsev AS ,et al . Characterization of human T cells reactive with the Mycoplasma arthritidis-derived superantigen (MAM): generation of a monoclonal antibody against V β 17, the T cell receptor gene product expressed by a large fraction of MAM-reactive human T cells. J Exp Med. 1991;174:891-900. [PMID:1833503 ] CrossrefMedlineGoogle Scholar - 62.
Stamenkovic I ,Stegagno M ,Wright KA ,Krane SM ,Amento EP ,Colvin RB ,et al . Clonal dominance among T-lymphocyte infiltrates in arthritis. Proc Natl Acad Sci U S A. 1988;85:1179-83. [PMID:2963340 ] CrossrefMedlineGoogle Scholar - 63.
Cooper SM ,Dier DL ,Roessner KD ,Budd RC ,Nicklas JA . Diversity of rheumatoid synovial tissue T cells by T cell receptor analysis. Oligoclonal expansion in interleukin-2-responsive cells. Arthritis Rheum. 1991;34:537-46. [PMID:2025307 ] CrossrefMedlineGoogle Scholar - 64.
Williams WV ,Fang Q ,Demarco D ,VonFeldt J ,Zurier RB ,Weiner DB . Restricted heterogeneity of T cell receptor transcripts in rheumatoid synovium. J Clin Invest. 1992;90:326-33. [PMID:1386608 ] CrossrefMedlineGoogle Scholar - 65.
Berenbaum F ,Thomas G ,Poiraudeau S ,Béréziat G ,Corvol MT ,Masliah J . Insulin-like growth factors counteract the effect of interleukin 1 β on type II phospholipase A2 expression and arachidonic acid release by rabbit articular chondrocytes. FEBS Lett. 1994;340:51-5. [PMID:8119407 ] CrossrefMedlineGoogle Scholar - 66.
Chen Q ,Daniel V ,Maher DW ,Hersey P . Production of IL-10 by melanoma cells: examination of its role in immunosuppression mediated by melanoma. Int J Cancer. 1994;56:755-60. [PMID:8314354 ] CrossrefMedlineGoogle Scholar - 67.
Gudmundsson S ,Rönnelid J ,Karlsson-Parra A ,Lysholm J ,Gudbjörnsson B ,Widenfalk B ,et al . T-cell receptor V-gene usage in synovial fluid and synovial tissue from RA patients. Scand J Immunol. 1992;36:681-8. [PMID:1439580 ] CrossrefMedlineGoogle Scholar - 68.
Yoshizaki K ,Nishimoto N ,Mihara M ,Kishimoto T . Therapy of rheumatoid arthritis by blocking IL-6 signal transduction with a humanized anti-IL-6 receptor antibody. Springer Semin Immunopathol. 1998;20:247-59. [PMID:9836380 ] CrossrefMedlineGoogle Scholar - 69.
Taylor-Robinson AW ,Liew FY ,Severn A ,Xu D ,McSorley SJ ,Garside P ,et al . Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. Eur J Immunol. 1994;24:980-4. [PMID:8149966 ] CrossrefMedlineGoogle Scholar - 70.
Lotz M . The role of nitric oxide in articular cartilage damage. Rheum Dis Clin North Am. 1999;25:269-82. [PMID:10356417 ] CrossrefMedlineGoogle Scholar - 71.
Evans CH . Nitric oxide: what role does it play in inflammation and tissue destruction? Agents Actions Suppl. 1995;47:107-16. [PMID:7540350 ] MedlineGoogle Scholar - 72.
Farrell AJ ,Blake DR ,Palmer RM ,Moncada S . Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis. 1992;51:1219-22. [PMID:1466599 ] CrossrefMedlineGoogle Scholar - 73.
Weinberg JB ,Granger DL ,Pisetsky DS ,Seldin MF ,Misukonis MA ,Mason SN ,et al . The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine. J Exp Med. 1994;179:651-60. [PMID:7507509 ] MedlineGoogle Scholar - 74.
Firestein GS ,Yeo M ,Zvaifler NJ . Apoptosis in rheumatoid arthritis synovium. J Clin Invest. 1995;96:1631-8. [PMID:7657832 ] CrossrefMedlineGoogle Scholar - 75.
Voelkel-Johnson C ,Entingh AJ ,Wold WS ,Gooding LR ,Laster SM . Activation of intracellular proteases is an early event in TNF-induced apoptosis. J Immunol. 1995;154:1707-16. [PMID:7836755 ] MedlineGoogle Scholar - 76.
Wong GH ,Goeddel DV . Fas antigen and p55 TNF receptor signal apoptosis through distinct pathways. J Immunol. 1994;152:1751-5. [PMID:7509828 ] MedlineGoogle Scholar - 77.
Thornberry NA ,Molineaux SM . Interleukin-1 β converting enzyme: a novel cysteine protease required for IL-1 β production and implicated in programmed cell death. Protein Sci. 1995;4:3-12. [PMID:7773174 ] CrossrefMedlineGoogle Scholar - 78.
Schirmer M ,Vallejo AN ,Weyand CM ,Goronzy JJ . Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+ CD28- T cells from rheumatoid arthritis patients. J Immunol. 1998;161:1018-25. [PMID:9670983 ] MedlineGoogle Scholar - 79.
Breedveld FC . Future trends in the treatment of rheumatoid arthritis: cytokine targets. Rheumatology Oxford. 1999;38Suppl 2 11-3. [PMID:10646483 ] MedlineGoogle Scholar - 80.
van Roon JA ,van Roy JL ,Gmelig-Meyling FH ,Lafeber FP ,Bijlsma JW . Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-10 and interleukin-4. Arthritis Rheum. 1996;39:829-35. [PMID:8639180 ] CrossrefMedlineGoogle Scholar - 81.
St Clair EW . Interleukin 10 treatment for rheumatoid arthritis. Ann Rheum Dis. 1999;58Suppl 1 I99-I102. [PMID:10577984 ] CrossrefMedlineGoogle Scholar - 82.
Herzog C ,Walker C ,Müller W ,Rieber P ,Reiter C ,Riethmüller G ,et al . Anti-CD4 antibody treatment of patients with rheumatoid arthritis: I. Effect on clinical course and circulating T cells. J Autoimmun. 1989;2:627-42. [PMID:2572230 ] CrossrefMedlineGoogle Scholar - 83.
Strand V ,Lipsky PE ,Cannon GW ,Calabrese LH ,Wiesenhutter C ,Cohen SB ,et al . Effects of administration of an anti-CD5 plus immunoconjugate in rheumatoid arthritis. Results of two phase II studies. The CD5 Plus Rheumatoid Arthritis Investigators Group. Arthritis Rheum. 1993;36:620-30. [PMID:7683881 ] CrossrefMedlineGoogle Scholar - 84.
Moreland LW ,Haverty TP ,Wacholtz MC ,Knowles RW ,Bucy RP ,Heck LW ,et al . Nondepleting humanized anti-CD4 monoclonal antibody in patients with refractory rheumatoid arthritis. J Rheumatol. 1998;25:221-8. [PMID:9489810 ] MedlineGoogle Scholar - 85.
Das P ,Bradley DS ,Geluk A ,Griffiths MM ,Luthra HS ,David CS . An HLA-DRB1*0402 derived peptide (HV3 65-79) prevents collagen-induced arthritis in HLA-DQ8 transgenic mice. Hum Immunol. 1999;60:575-82. [PMID:10426274 ] CrossrefMedlineGoogle Scholar - 86.
Hammer J ,Gallazzi F ,Bono E ,Karr RW ,Guenot J ,Valsasnini P ,et al . Peptide binding specificity of HLA-DR4 molecules: correlation with rheumatoid arthritis association. J Exp Med. 1995;181:1847-55. [PMID:7722459 ] CrossrefMedlineGoogle Scholar - 87.
Hammer J ,Takacs B ,Sinigaglia F . Identification of a motif for HLA-DR1 binding peptides using M13 display libraries. J Exp Med. 1992;176:1007-13. [PMID:1402647 ] CrossrefMedlineGoogle Scholar - 88.
Dittel BN ,Sant'Angelo DB ,Janeway CA . Peptide antagonists inhibit proliferation and the production of IL-4 and/or IFN-γ in T helper 1, T helper 2, and T helper 0 clones bearing the same TCR. J Immunol. 1997;158:4065-73. [PMID:9126964 ] MedlineGoogle Scholar - 89.
Moreland LW ,Heck LW ,Koopman WJ ,Saway PA ,Adamson TC ,Fronek Z ,et al . V β 17 T cell receptor peptide vaccination in rheumatoid arthritis: results of phase I dose escalation study. J Rheumatol. 1996;23:1353-62. [PMID:8856613 ] MedlineGoogle Scholar - 90.
Evans CH ,Robbins PD . Progress toward the treatment of arthritis by gene therapy. Ann Med. 1995;27:543-6. [PMID:8541029 ] CrossrefMedlineGoogle Scholar - 91.
Kobayashi T ,Okamoto K ,Kobata T ,Hasunuma T ,Kato T ,Hamada H ,et al . Novel gene therapy for rheumatoid arthritis by FADD gene transfer: induction of apoptosis of rheumatoid synoviocytes but not chondrocytes. Gene Ther. 2000;7:527-33. [PMID:10757027 ] CrossrefMedlineGoogle Scholar - 92.
Yao Q ,Glorioso JC ,Evans CH ,Robbins PD ,Kovesdi I ,Oligino TJ ,et al . Adenoviral mediated delivery of FAS ligand to arthritic joints causes extensive apoptosis in the synovial lining. J Gene Med. 2000;2:210-9. [PMID:10894267 ] CrossrefMedlineGoogle Scholar
Author, Article, and Disclosure Information
Affiliations:
From Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Acknowledgments: The authors thank Drs. John Abruzzo, Pam Norton, Andrew Koenig, and Stacy Fitch for their careful review and helpful suggestions in the preparation of this manuscript.
Grant Support: By the Mona Schneidman Foundation.
Corresponding Author: J. Bruce Smith, MD, Jefferson Medical College, 613 Curtis Building, Philadelphia, PA 19107.
Current Author Addresses: Dr. Smith: Jefferson Medical College, 1015 Walnut Street, Suite 613–Curtis Building, Philadelphia, PA 19107.
Dr. Haynes: Jefferson Medical College, 1015 Walnut Street, Philadelphia, PA 19107.
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