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Partial depletion of regulatory T cells does not influence the inflammation caused by high dose hemi-body irradiation.

Ma S, Richardson JA, Bitmansour A, Solberg TD, Pidikiti R, Song K, Stojadinovic S, Vitetta ES, Meyer JJ - PLoS ONE (2013)

Bottom Line: HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI.The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%).The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

ABSTRACT
There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizing radiation on inflammation and tissue injury were analyzed in C57BL/6 mice. An anti-CD25 antibody (PC61) was administered 3 days prior to 13 Gy lower-half hemi-body irradiation (HBI). The blood, spleen, mesenteric lymph nodes (mLNs) and inguinal lymph nodes (iLNs) were harvested at various times thereafter. Alterations in the proportion of leukocyte subsets including CD4(+) T cells, CD8(+) T cells, Treg cells, B cells, NK cells, NK1.1(+) T cells, macrophages and granulocytes were analyzed by FACS. The lungs, liver, pancreas, stomach, jejunum, duodenum, ileum, colon and kidney were harvested and studied by H&E staining. Expression of inflammatory mediators in plasma and tissue were investigated by ELISA. HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI. The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%). Irradiation significantly increased the proportion of Treg cells in the spleen, iLN and mLN. HBI induced a systemic inflammatory reaction as demonstrated by increased plasma levels of IL-6, KC/CXCL1 and circulating granulocytes in the blood. Neutrophils also infiltrated the small bowel. The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI. These data demonstrate that partial depletion of Treg cells in these mice does not influence HBI-induced inflammatory response and tissue injury, and that combining anti-CD25 therapy with radiation may be safe and well tolerated in a clinical setting.

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Inflammatory mediators in plasma.Plasma levels of (A) IL-6 and (B) KC/CXCL1 were determined at different time points after treatment. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments (all p<0.01). No differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time in the levels of IL-6 (p≥0.099) and KC/CXCL1 (p≥0.475). No significant differences were found between the PC61+sham irradiation compared to Rat IgG+sham irradiation treatment group profiles over time (all p>0.05). Differences between all other pair-wise comparisons of treatment group profiles over time were significant (p<0.05). All post hoc pairwise comparisons were performed with Tukey's multiple comparisons. This is one representative experiment of three performed.
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pone-0056607-g006: Inflammatory mediators in plasma.Plasma levels of (A) IL-6 and (B) KC/CXCL1 were determined at different time points after treatment. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments (all p<0.01). No differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time in the levels of IL-6 (p≥0.099) and KC/CXCL1 (p≥0.475). No significant differences were found between the PC61+sham irradiation compared to Rat IgG+sham irradiation treatment group profiles over time (all p>0.05). Differences between all other pair-wise comparisons of treatment group profiles over time were significant (p<0.05). All post hoc pairwise comparisons were performed with Tukey's multiple comparisons. This is one representative experiment of three performed.

Mentions: To evaluate the systemic inflammatory response to radiation+/−depletion of Treg cells, inflammatory mediators in the plasma and the proportion of circulating granulocytes were determined at 4 hrs and days 1, 3 7 and 14 following irradiation. Four hours after radiation exposure, plasma levels of IL-6 and KC/CXCL1 significantly increased. At one and three days following irradiation, IL-6 levels returned to control levels while KC/CXCL1 remained significantly elevated (Figure 6). At 7 and 14 days following irradiation, levels of KC/CXCL1 returned to control levels (data not shown). Identical patterns were observed in irradiated mice in which Treg cells were depleted with PC61. Levels of IL-1β, IL-10, TNF-α, IFN-γ and TGF-β were undetectable in the plasma in all four groups of mice throughout the time course studied (data not shown). The percentages of circulating granulocytes were increased at 7 and 14 days following irradiation as shown in Figure 3; this was not influence by treatment with PC61.


Partial depletion of regulatory T cells does not influence the inflammation caused by high dose hemi-body irradiation.

Ma S, Richardson JA, Bitmansour A, Solberg TD, Pidikiti R, Song K, Stojadinovic S, Vitetta ES, Meyer JJ - PLoS ONE (2013)

Inflammatory mediators in plasma.Plasma levels of (A) IL-6 and (B) KC/CXCL1 were determined at different time points after treatment. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments (all p<0.01). No differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time in the levels of IL-6 (p≥0.099) and KC/CXCL1 (p≥0.475). No significant differences were found between the PC61+sham irradiation compared to Rat IgG+sham irradiation treatment group profiles over time (all p>0.05). Differences between all other pair-wise comparisons of treatment group profiles over time were significant (p<0.05). All post hoc pairwise comparisons were performed with Tukey's multiple comparisons. This is one representative experiment of three performed.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3569437&req=5

pone-0056607-g006: Inflammatory mediators in plasma.Plasma levels of (A) IL-6 and (B) KC/CXCL1 were determined at different time points after treatment. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments (all p<0.01). No differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time in the levels of IL-6 (p≥0.099) and KC/CXCL1 (p≥0.475). No significant differences were found between the PC61+sham irradiation compared to Rat IgG+sham irradiation treatment group profiles over time (all p>0.05). Differences between all other pair-wise comparisons of treatment group profiles over time were significant (p<0.05). All post hoc pairwise comparisons were performed with Tukey's multiple comparisons. This is one representative experiment of three performed.
Mentions: To evaluate the systemic inflammatory response to radiation+/−depletion of Treg cells, inflammatory mediators in the plasma and the proportion of circulating granulocytes were determined at 4 hrs and days 1, 3 7 and 14 following irradiation. Four hours after radiation exposure, plasma levels of IL-6 and KC/CXCL1 significantly increased. At one and three days following irradiation, IL-6 levels returned to control levels while KC/CXCL1 remained significantly elevated (Figure 6). At 7 and 14 days following irradiation, levels of KC/CXCL1 returned to control levels (data not shown). Identical patterns were observed in irradiated mice in which Treg cells were depleted with PC61. Levels of IL-1β, IL-10, TNF-α, IFN-γ and TGF-β were undetectable in the plasma in all four groups of mice throughout the time course studied (data not shown). The percentages of circulating granulocytes were increased at 7 and 14 days following irradiation as shown in Figure 3; this was not influence by treatment with PC61.

Bottom Line: HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI.The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%).The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

ABSTRACT
There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizing radiation on inflammation and tissue injury were analyzed in C57BL/6 mice. An anti-CD25 antibody (PC61) was administered 3 days prior to 13 Gy lower-half hemi-body irradiation (HBI). The blood, spleen, mesenteric lymph nodes (mLNs) and inguinal lymph nodes (iLNs) were harvested at various times thereafter. Alterations in the proportion of leukocyte subsets including CD4(+) T cells, CD8(+) T cells, Treg cells, B cells, NK cells, NK1.1(+) T cells, macrophages and granulocytes were analyzed by FACS. The lungs, liver, pancreas, stomach, jejunum, duodenum, ileum, colon and kidney were harvested and studied by H&E staining. Expression of inflammatory mediators in plasma and tissue were investigated by ELISA. HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI. The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%). Irradiation significantly increased the proportion of Treg cells in the spleen, iLN and mLN. HBI induced a systemic inflammatory reaction as demonstrated by increased plasma levels of IL-6, KC/CXCL1 and circulating granulocytes in the blood. Neutrophils also infiltrated the small bowel. The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI. These data demonstrate that partial depletion of Treg cells in these mice does not influence HBI-induced inflammatory response and tissue injury, and that combining anti-CD25 therapy with radiation may be safe and well tolerated in a clinical setting.

Show MeSH
Related in: MedlinePlus