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CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis.

Citro A, Scrivo R, Martini H, Martire C, De Marzio P, Vestri AR, Sidney J, Sette A, Barnaba V, Valesini G - PLoS ONE (2015)

Bottom Line: CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases.More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy.These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Viale del Policlinico 155, 00161 Rome, Italy.

ABSTRACT
CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

No MeSH data available.


Related in: MedlinePlus

AE-specific CD8+ T cells predict RA patients who will (or will not) benefit from etanercept therapy (A-D).(A) Representative flow cytometry analysis of dextramer+CD8+ T cells specific to AE in an RA patient and an HD. Zebra plot analyses show the percentage of dextramer+CD8+ cells. (B) Percentage of dextramer+CD8+ cells in 14 HDs and 15 patients (each symbol represents the percentage of a single dextramer+CD8+ cell population) (left graph); sum of the percentages of all dextramer+CD8+ T cells detected in the single HD or patient (each symbol represents the sum of dextramer percentages in a single individual) (right graph). (C) Percentage of dextramer+CD8+ cells in 14 HDs, 9 Rs to etanercept, and 6 NRs (each symbol represents the percentage of a single dextramer+CD8+ cell population) (left graph); sum of the percentages of all dextramer+CD8+ T cells detected in the single HD, R, and NR (each symbol represents the sum of dextramer percentages in a single individual) (right graph). Analyses were performed at time 0 (before the start of therapy). Statistical analysis was performed with the Mann-Whitney test. **P < 0.001; ***P < 0.0001. (D) ROC curve analyses for R and NR patients. AUC = area under receiver operating characteristic curve. * = predictive value of positive test. # = predictive value of negative test.
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pone.0128607.g002: AE-specific CD8+ T cells predict RA patients who will (or will not) benefit from etanercept therapy (A-D).(A) Representative flow cytometry analysis of dextramer+CD8+ T cells specific to AE in an RA patient and an HD. Zebra plot analyses show the percentage of dextramer+CD8+ cells. (B) Percentage of dextramer+CD8+ cells in 14 HDs and 15 patients (each symbol represents the percentage of a single dextramer+CD8+ cell population) (left graph); sum of the percentages of all dextramer+CD8+ T cells detected in the single HD or patient (each symbol represents the sum of dextramer percentages in a single individual) (right graph). (C) Percentage of dextramer+CD8+ cells in 14 HDs, 9 Rs to etanercept, and 6 NRs (each symbol represents the percentage of a single dextramer+CD8+ cell population) (left graph); sum of the percentages of all dextramer+CD8+ T cells detected in the single HD, R, and NR (each symbol represents the sum of dextramer percentages in a single individual) (right graph). Analyses were performed at time 0 (before the start of therapy). Statistical analysis was performed with the Mann-Whitney test. **P < 0.001; ***P < 0.0001. (D) ROC curve analyses for R and NR patients. AUC = area under receiver operating characteristic curve. * = predictive value of positive test. # = predictive value of negative test.

Mentions: To explore the possibility that the frequencies of CD8+ T cells specific to AE, as detected by ELISPOT assay, did not differ between Rs and NRs (Fig 1A) because our ELISPOT system identified only IFN-γ+ cells, we conducted further testing. In particular, we used the class I molecule multimer technology, thereby allowing the entire AE-specific CD8+ T cell population to be counted with the same epitope specificity, irrespective of their differentiation phase, as well as T cells with an “exhaustion phenotype,” representing the reducing capacity of cells to perform effector functions [27]. We enumerated AE-specific CD8+ T cells in the peripheral blood of 15 HLA-A2+ RA patients submitted to etanercept (of whom 9 would be Rs and 6 would be NRs) by using dextramers of HLA-A*0201 molecules complexed to ACTB266-274, MYH9478-486, MYH9741-749, VIME78-87, or VIME225-233 peptides (Fig 2).


CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis.

Citro A, Scrivo R, Martini H, Martire C, De Marzio P, Vestri AR, Sidney J, Sette A, Barnaba V, Valesini G - PLoS ONE (2015)

AE-specific CD8+ T cells predict RA patients who will (or will not) benefit from etanercept therapy (A-D).(A) Representative flow cytometry analysis of dextramer+CD8+ T cells specific to AE in an RA patient and an HD. Zebra plot analyses show the percentage of dextramer+CD8+ cells. (B) Percentage of dextramer+CD8+ cells in 14 HDs and 15 patients (each symbol represents the percentage of a single dextramer+CD8+ cell population) (left graph); sum of the percentages of all dextramer+CD8+ T cells detected in the single HD or patient (each symbol represents the sum of dextramer percentages in a single individual) (right graph). (C) Percentage of dextramer+CD8+ cells in 14 HDs, 9 Rs to etanercept, and 6 NRs (each symbol represents the percentage of a single dextramer+CD8+ cell population) (left graph); sum of the percentages of all dextramer+CD8+ T cells detected in the single HD, R, and NR (each symbol represents the sum of dextramer percentages in a single individual) (right graph). Analyses were performed at time 0 (before the start of therapy). Statistical analysis was performed with the Mann-Whitney test. **P < 0.001; ***P < 0.0001. (D) ROC curve analyses for R and NR patients. AUC = area under receiver operating characteristic curve. * = predictive value of positive test. # = predictive value of negative test.
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pone.0128607.g002: AE-specific CD8+ T cells predict RA patients who will (or will not) benefit from etanercept therapy (A-D).(A) Representative flow cytometry analysis of dextramer+CD8+ T cells specific to AE in an RA patient and an HD. Zebra plot analyses show the percentage of dextramer+CD8+ cells. (B) Percentage of dextramer+CD8+ cells in 14 HDs and 15 patients (each symbol represents the percentage of a single dextramer+CD8+ cell population) (left graph); sum of the percentages of all dextramer+CD8+ T cells detected in the single HD or patient (each symbol represents the sum of dextramer percentages in a single individual) (right graph). (C) Percentage of dextramer+CD8+ cells in 14 HDs, 9 Rs to etanercept, and 6 NRs (each symbol represents the percentage of a single dextramer+CD8+ cell population) (left graph); sum of the percentages of all dextramer+CD8+ T cells detected in the single HD, R, and NR (each symbol represents the sum of dextramer percentages in a single individual) (right graph). Analyses were performed at time 0 (before the start of therapy). Statistical analysis was performed with the Mann-Whitney test. **P < 0.001; ***P < 0.0001. (D) ROC curve analyses for R and NR patients. AUC = area under receiver operating characteristic curve. * = predictive value of positive test. # = predictive value of negative test.
Mentions: To explore the possibility that the frequencies of CD8+ T cells specific to AE, as detected by ELISPOT assay, did not differ between Rs and NRs (Fig 1A) because our ELISPOT system identified only IFN-γ+ cells, we conducted further testing. In particular, we used the class I molecule multimer technology, thereby allowing the entire AE-specific CD8+ T cell population to be counted with the same epitope specificity, irrespective of their differentiation phase, as well as T cells with an “exhaustion phenotype,” representing the reducing capacity of cells to perform effector functions [27]. We enumerated AE-specific CD8+ T cells in the peripheral blood of 15 HLA-A2+ RA patients submitted to etanercept (of whom 9 would be Rs and 6 would be NRs) by using dextramers of HLA-A*0201 molecules complexed to ACTB266-274, MYH9478-486, MYH9741-749, VIME78-87, or VIME225-233 peptides (Fig 2).

Bottom Line: CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases.More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy.These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Viale del Policlinico 155, 00161 Rome, Italy.

ABSTRACT
CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

No MeSH data available.


Related in: MedlinePlus