期刊论文详细信息
Journal of Translational Medicine
Reduced T-cell repertoire restrictions in abatacept-treated rheumatoid arthritis patients
Paolo Airò2  Angela Tincani2  Diego Bertoli1  Marco Chiarini1  Cinzia Zanotti1  Mirko Scarsi2  Luisa Imberti1 
[1] Centro Ricerca Emato-oncologica AIL (CREA), Diagnostics Department, Spedali Civili of Brescia, p.le Spedali Civili di Brescia, 1, Brescia, 25123, Italy;Rheumatology and Clinical Immunology, Spedali Civili of Brescia, Brescia, Italy
关键词: T-cell repertoire;    Rheumatoid arthritis;    Abatacept;   
Others  :  1146199
DOI  :  10.1186/s12967-014-0363-2
 received in 2014-08-26, accepted in 2014-12-15,  发布年份 2015
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【 摘 要 】

Background

CD28neg T cells, which display functional characteristic of oligoclonally expanded cytotoxic memory T lymphocytes, are believed to be pathologically relevant in rheumatoid arthritis manifestation. The CD28 co-stimulation blockade by abatacept can prevent the generation of CD28neg T-cell populations in these patients.

Methods

Samples were obtained before and after 12 months of abatacept therapy. T-cell phenotype and T-cell receptor diversity were evaluated by flow cytometry and complementarity-determining region-3 spectratyping, respectively, while telomerase reverse-transcriptase gene level was measured by real-time PCR.

Results

Abatacept induces a decrease of the percentage and number of CD4+CD28neg T cells and a reduction of T-cell repertoire restrictions; these features are directly correlated. Thymic output and telomerase activity are not modified by the therapy.

Conclusions

Abatacept-induced decrease of peripheral T-cell repertoire restrictions can due to a reduced generation of senescent, chronically stimulated CD4+CD28neg T cells.

【 授权许可】

   
2015 Imberti et al.; licensee BioMed Central.

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【 参考文献 】
  • [1]Schmidt D, Goronzy JJ, Weyand CM: CD4 + CD7-CD28-T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest 1996, 97:2027-2037.
  • [2]Vallejo AN, Brandes JC, Weyand CM, Goronzy JJ: Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J Immunol 1999, 162:6572-6579.
  • [3]Vallejo AN, Weyand CM, Goronzy JJ: T-cell senescence: a culprit of immune abnormalities in chronic inflammation and persistent infection. Trends Mol Med 2004, 10:119-124.
  • [4]Broux B, Markovic-Plese S, Stinissen P, Hellings N: Pathogenic features of CD4 + CD28- T cells in immune disorders. Trends Mol Med 2012, 18:446-453.
  • [5]Pawlik A, Ostanek L, Brzosko I, Brzosko M, Masiuk M, Machalinski B, Gawronska-Szklarz B: The expansion of CD4 + CD28- T cells in patients with rheumatoid arthritis. Arthritis Res Ther 2003, 5:R210-R213. BioMed Central Full Text
  • [6]Cutolo M, Nadler SG: Advances in CTLA-4-Ig-mediated modulation of inflammatory cell and immune response activation in rheumatoid arthritis. Autoimmun Rev 2013, 12:758-767.
  • [7]Ndejembi MP, Teijaro JR, Patke DS, Bingaman AW, Chandok MR, Azimzadeh A, Nadler SG, Farber DL: Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway. J Immunol 2006, 177:7698-7706.
  • [8]Pieper J, Herrath J, Raghavan S, Muhammad K, Vollenhoven RV, Malmström V: CTLA4-Ig (abatacept) therapy modulates T cell effector functions in autoantibody-positive rheumatoid arthritis patients. BMC Immunol 2013, 14:34. BioMed Central Full Text
  • [9]Scarsi M, Ziglioli T, Airo’ P: Baseline numbers of circulating CD28-negative T cells may predict clinical response to abatacept in patients with rheumatoid arthritis. J Rheumatol 2011, 38:2105-2111.
  • [10]Airò P, Scarsi M: Targeting CD4 + CD28- T cells by blocking CD28 co-stimulation. Trends Mol Med 2013, 19:1-2.
  • [11]Fujii H, Shao L, Colmegna I, Goronzy JJ, Weyand CM: Telomerase insufficiency in rheumatoid arthritis. Proc Natl Acad Sci U S A 2009, 106:4360-4365.
  • [12]Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, Aletaha D, van Riel PL: Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009, 68:954-960.
  • [13]Akatsuka Y, Martin EG, Madonik A, Barsoukov AA, Hansen JA: Rapid screening of T-cell receptor (TCR) variable gene usage by multiplex PCR: application for assessment of clonal composition. Tissue Antigens 1999, 53:122-134.
  • [14]Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C, Karmochkine M, Raguin G, Autran B, Debré P: Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med 1998, 4:215-221.
  • [15]Warnke C, Mausberg AK, Stettner M, Dehmel T, Nekrich L, Meyer zu Horste G, Hartung HP, Fogdell-Hahn A, Adams O, Kieseier BC: Natalizumab affects the T-cell receptor repertoire in patients with multiple sclerosis. Neurology 2013, 81:1400-1408.
  • [16]Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM: T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A 2000, 97:9203-9208.
  • [17]Soares MV, Borthwick NJ, Maini MK, Janossy G, Salmon M, Akbar AN: IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire. J Immunol 1998, 161:5909-5917.
  • [18]Pierer M, Rossol M, Kaltenhäuser S, Arnold S, Häntzschel H, Baerwald C, Wagner U: Clonal expansions in selected TCR BV families of rheumatoid arthritis patients are reduced by treatment with the TNFα inhibitors etanercept and infliximab. Rheumatol Int 2011, 31:1023-1029.
  • [19]Houston EG Jr, Higdon LE, Fink PJ: Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool. Proc Natl Acad Sci U S A 2011, 108:5366-5371.
  • [20]Weng NP, Levine BL, June CH, Hodes RJ: Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med 1996, 183:2471-2479.
  • [21]Hodes RJ, Hathcock KS, Weng NP: Telomeres in T and B cells. Nat Rev Immunol 2002, 2:699-706.
  • [22]Mirenda V, Jarmin SJ, David R, Dyson J, Scott D, Gu Y, Lechler RI, Okkenhaug K, Marelli-Berg FM: Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28. Blood 2007, 109:2968-2977.
  • [23]Fasth AE, Snir O, Johansson AA, Nordmark B, Rahbar A, Af Klint E, Björkström NK, Ulfgren AK, van Vollenhoven RF, Malmström V, Trollmo C: Skewed distribution of proinflammatory CD4 + CD28null T cells in rheumatoid arthritis. Arthritis Res Ther 2007, 9:R87. BioMed Central Full Text
  • [24]Scarsi M, Zanotti C, Chiarini M, Imberti L, Piantoni S, Frassi M, Tincani A, Airò P: Reduction of peripheral blood γ-IFN and IL-17 producing T cells after therapy with abatacept for rheumatoid arthritis. Clin Exp Rheumatol 2014, 32:204-210.
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