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THU0046 CD8+ T Cell Reactivity Against Apoptotic Self-Epitopes in Rheumatoid Arthritis Patients Treated with Etanercept
  1. A. Citro1,
  2. R. Scrivo1,
  3. H. Martini1,
  4. F. Miranda1,
  5. V. Barnaba1,
  6. G. Valesini1
  1. 1Medicina Interna e Specialità Mediche, Sapienza, Università di Roma, Roma, Italy

Abstract

Background Apoptosis seems to play a key role in autoimmune diseases (1). We have previously shown that T cell apoptosis generates a wide array of caspase-cleaved proteins, which can be cross-presented by dendritic cells to a broad repertoire of autoreactive CD8+ T cells. This process is involved in establishing chronic immune activation in HIV and HCV infections, but no data are currently available for rheumatoid arthritis (RA) (2-3).

Objectives To evaluate whether self-apoptotic-specific CD8+ T cells may sustain chronic inflammation in RA and their possible modulation during treatment with etanercept.

Methods Consecutive patients with RA classified according to the 1987 ACR criteria and designated to initiate treatment with biologics due to active disease were enrolled after obtaining informed consent. Healthy donors (HD) matched for sex and age with patients were also included. Before and after 1, 3, 6 months of therapy patients underwent blood draw to perform lymphocytic analysis. Self-specific CD8+ T cells were enumerated in the peripheral blood of HLA-A2+ patients or HD by using dextramers of HLA-A*0201 molecules complexed to apoptotic epitopes. IFNγ production by autoreactive CD8+ T cells in response to apoptotic peptides was tested by IFNγ-ELISPOT assay. The specific CD8+ T cell function was better defined based on cytokine production (IL17, IFNγ) within 18 h of contact with the relevant peptides by surface/intracellular cytometry. The clinical response to etanercept (none, moderate, good) was evaluated according to the EULAR criteria.

Results 11 biologic-naïve RA patients (F/M=10/1; mean age 50 years, range 36-68; mean disease duration 70 months, range 6-240) initiated treatment with etanercept. After 6 months 6 patients were considered responders. Increased frequencies of both circulating apoptotic T cells and self-reactive CD8+ T cells in RA patients compared with HD (n=8) at baseline (p=0.0006 and p<0.0001, respectively). These responses were related with IFNγ+CD8+ T cells specific to a large apoptotic epitope repertoire recognized in RA patients. Moreover, autoreactive CD8+ T cells produced moderate amounts of IL17 and IFNγ in RA patients. Interestingly, at baseline a significant difference in the frequency of self-apoptotic peptide-specific CD8+ T cells was found in responders compared to patients not responding (p=0.038). After starting therapy, we observed an early dramatic decrease of the self-reactive CD8+ T cell frequencies only in the group of the responders (p<0.0001).

Conclusions These data support the possibility that chronic inflammation in RA may be sustained, at least in part, by an autoimmune reaction towards apoptotic T cells. The presence of these self-reactive T cells, markedly increased in responders patients already at baseline, may be useful to predict the response to anti-TNF therapy.

References

  1. Luis E. et al. Nature Reviews Rheumatology 6, 280-289, 2010

  2. Rawson PM et al. Nat. Med. 13: 1431-9, 2007

  3. Franceschini et al. PLos Pathog. 2012;8(6)

Disclosure of Interest None Declared

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