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Mycobacterium tuberculosis specific CD8(+) T cells rapidly decline with antituberculosis treatment.

Nyendak MR, Park B, Null MD, Baseke J, Swarbrick G, Mayanja-Kizza H, Nsereko M, Johnson DF, Gitta P, Okwera A, Goldberg S, Bozeman L, Johnson JL, Boom WH, Lewinsohn DA, Lewinsohn DM, Tuberculosis Research Unit and the Tuberculosis Trials Consorti - PLoS ONE (2013)

Bottom Line: At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%.In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment.Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Oregon Health and Science University, Portland, Oregon, United States of America.

ABSTRACT

Rationale: Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment.

Objectives: We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment.

Materials and methods: We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4(+) and CD8(+) T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24.

Results: There was a significant difference in the Mtb specific CD8(+) T response, but not the CD4(+) T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment. The Mtb specific CD4(+) T cell response, but not the CD8(+) response, was negatively impacted by the body mass index.

Conclusions: Our data provide evidence that the Mtb specific CD8(+) T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression.

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Mycobacterium tuberculosis (Mtb) specific T cell responses during antituberculosis treatment in subjects with baseline malnutrition (BMI≤17).The subgroup of subjects, who started therapy with a BMI≤17 with baseline and week 24 analyzable ELISPOT data (n = 11) are shown. The magnitude of the Mtb specific T cell response is shown by IFN-γ ELISPOT to ESAT-6 and CFP-10 and reported in spot forming units per 250,000 T cells. Connected lines at baseline and week 24 reflect a individual subject's profile for the Mtb specific CD4+ T cell response (A) and the Mtb specific CD8+ T cell response (B).
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pone-0081564-g004: Mycobacterium tuberculosis (Mtb) specific T cell responses during antituberculosis treatment in subjects with baseline malnutrition (BMI≤17).The subgroup of subjects, who started therapy with a BMI≤17 with baseline and week 24 analyzable ELISPOT data (n = 11) are shown. The magnitude of the Mtb specific T cell response is shown by IFN-γ ELISPOT to ESAT-6 and CFP-10 and reported in spot forming units per 250,000 T cells. Connected lines at baseline and week 24 reflect a individual subject's profile for the Mtb specific CD4+ T cell response (A) and the Mtb specific CD8+ T cell response (B).

Mentions: To explain this difference between the Mtb specific CD4+ and CD8+ T cell responses over the 24 weeks of treatment, we postulated that nutritional status could be differentially affecting Mtb specific CD4+ and CD8+ T cell responses. As a secondary analysis, we sought to determine whether an association between the Mtb specific CD4+ or CD8+ T response, if associated with time on treatment, might be correlated with malnutrition. In this regard, protein calorie malnutrition has been associated with reduced lymphocyte replication as well as a lower IFN-γ response in animal models [29], [30]. Furthermore, in a prior study looking at a HIV-negative cohort undergoing antituberculosis treatment, depressed IFN-γ in response to purified protein derivative was observed over a 12 month observation period [31]. To explore if the Mtb specific T cell response was affected by malnutrition, we used the BMI as a biomarker. Forty-eight subjects had both ELISPOT and BMI data for analysis at baseline. The Mtb specific CD4+ T cell response at baseline was significantly reduced in subjects with moderate to severe malnutrition (BMI≤17; n = 14) compared with subjects with a BMI>17 (n = 34; p = 0.0067). The Mtb specific CD8+ T cell response was less affected by baseline BMI (Table 3 and Figure 3). We postulated that during treatment, as BMI improved, the Mtb specific T cell response would improve. Eleven of the original 14 subjects with a baseline BMI≤17 had longitudinal data (Figure 4). In the subgroup of subjects that began antituberculosis treatment with a low BMI, no clear pattern emerges for the Mtb specific CD4+ T cell response, however, the Mtb specific CD8+ T cell response appears to decline for several subjects, as seen in the full cohort (Figure 4). We evaluated other covariates to assess the impact on the Mtb specific T cell response, including sex, age, baseline AFB smear grade, cavitary disease, and radiographic extent of disease. These covariates did not alter the Mtb specific T cell response thus were not included in the multivariate analysis.


Mycobacterium tuberculosis specific CD8(+) T cells rapidly decline with antituberculosis treatment.

Nyendak MR, Park B, Null MD, Baseke J, Swarbrick G, Mayanja-Kizza H, Nsereko M, Johnson DF, Gitta P, Okwera A, Goldberg S, Bozeman L, Johnson JL, Boom WH, Lewinsohn DA, Lewinsohn DM, Tuberculosis Research Unit and the Tuberculosis Trials Consorti - PLoS ONE (2013)

Mycobacterium tuberculosis (Mtb) specific T cell responses during antituberculosis treatment in subjects with baseline malnutrition (BMI≤17).The subgroup of subjects, who started therapy with a BMI≤17 with baseline and week 24 analyzable ELISPOT data (n = 11) are shown. The magnitude of the Mtb specific T cell response is shown by IFN-γ ELISPOT to ESAT-6 and CFP-10 and reported in spot forming units per 250,000 T cells. Connected lines at baseline and week 24 reflect a individual subject's profile for the Mtb specific CD4+ T cell response (A) and the Mtb specific CD8+ T cell response (B).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852504&req=5

pone-0081564-g004: Mycobacterium tuberculosis (Mtb) specific T cell responses during antituberculosis treatment in subjects with baseline malnutrition (BMI≤17).The subgroup of subjects, who started therapy with a BMI≤17 with baseline and week 24 analyzable ELISPOT data (n = 11) are shown. The magnitude of the Mtb specific T cell response is shown by IFN-γ ELISPOT to ESAT-6 and CFP-10 and reported in spot forming units per 250,000 T cells. Connected lines at baseline and week 24 reflect a individual subject's profile for the Mtb specific CD4+ T cell response (A) and the Mtb specific CD8+ T cell response (B).
Mentions: To explain this difference between the Mtb specific CD4+ and CD8+ T cell responses over the 24 weeks of treatment, we postulated that nutritional status could be differentially affecting Mtb specific CD4+ and CD8+ T cell responses. As a secondary analysis, we sought to determine whether an association between the Mtb specific CD4+ or CD8+ T response, if associated with time on treatment, might be correlated with malnutrition. In this regard, protein calorie malnutrition has been associated with reduced lymphocyte replication as well as a lower IFN-γ response in animal models [29], [30]. Furthermore, in a prior study looking at a HIV-negative cohort undergoing antituberculosis treatment, depressed IFN-γ in response to purified protein derivative was observed over a 12 month observation period [31]. To explore if the Mtb specific T cell response was affected by malnutrition, we used the BMI as a biomarker. Forty-eight subjects had both ELISPOT and BMI data for analysis at baseline. The Mtb specific CD4+ T cell response at baseline was significantly reduced in subjects with moderate to severe malnutrition (BMI≤17; n = 14) compared with subjects with a BMI>17 (n = 34; p = 0.0067). The Mtb specific CD8+ T cell response was less affected by baseline BMI (Table 3 and Figure 3). We postulated that during treatment, as BMI improved, the Mtb specific T cell response would improve. Eleven of the original 14 subjects with a baseline BMI≤17 had longitudinal data (Figure 4). In the subgroup of subjects that began antituberculosis treatment with a low BMI, no clear pattern emerges for the Mtb specific CD4+ T cell response, however, the Mtb specific CD8+ T cell response appears to decline for several subjects, as seen in the full cohort (Figure 4). We evaluated other covariates to assess the impact on the Mtb specific T cell response, including sex, age, baseline AFB smear grade, cavitary disease, and radiographic extent of disease. These covariates did not alter the Mtb specific T cell response thus were not included in the multivariate analysis.

Bottom Line: At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%.In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment.Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Oregon Health and Science University, Portland, Oregon, United States of America.

ABSTRACT

Rationale: Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment.

Objectives: We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment.

Materials and methods: We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4(+) and CD8(+) T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24.

Results: There was a significant difference in the Mtb specific CD8(+) T response, but not the CD4(+) T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment. The Mtb specific CD4(+) T cell response, but not the CD8(+) response, was negatively impacted by the body mass index.

Conclusions: Our data provide evidence that the Mtb specific CD8(+) T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression.

Show MeSH
Related in: MedlinePlus