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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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Leukocyte subsets in the spleen and blood.In spleen, irradiation reduced proportions of B cells, CD4+ T cells and CD8+ T cells; increased proportions of NK1.1+ T cells and granulocytes. In blood, B cells were most radiosensitive; NK cells were most resistant; granulocytes increased on days 7 and 14. Data are expressed as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in all cell subsets (p<0.01) except NK1.1+ T cells in blood (p = 0.288). No significant differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time for any of the subsets in the spleen (p≥0.322) and blood (p≥0.095). 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-g003: Leukocyte subsets in the spleen and blood.In spleen, irradiation reduced proportions of B cells, CD4+ T cells and CD8+ T cells; increased proportions of NK1.1+ T cells and granulocytes. In blood, B cells were most radiosensitive; NK cells were most resistant; granulocytes increased on days 7 and 14. Data are expressed as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in all cell subsets (p<0.01) except NK1.1+ T cells in blood (p = 0.288). No significant differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time for any of the subsets in the spleen (p≥0.322) and blood (p≥0.095). 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: The proportion of splenic B cells, CD4+ T cells and CD8+ T cells decreased while NKT cells, granulocytes and macrophages increased after HBI. Also, B cells decreased even more dramatically in the blood while the proportion of NK cells and granulocytes increased following irradiation (Figure 3). There were no differences in the depletion of specific leukocyte subsets in mice undergoing HBI alone vs HBI+depletion of Treg cells. In general, B cells were the most radiosensitive, CD4+ T cells and CD8+ T cells were moderately sensitive, while NKT cells, macrophages and granulocytes were relatively radioresistant. NK cells were the most radioresistant.


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)

Leukocyte subsets in the spleen and blood.In spleen, irradiation reduced proportions of B cells, CD4+ T cells and CD8+ T cells; increased proportions of NK1.1+ T cells and granulocytes. In blood, B cells were most radiosensitive; NK cells were most resistant; granulocytes increased on days 7 and 14. Data are expressed as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in all cell subsets (p<0.01) except NK1.1+ T cells in blood (p = 0.288). No significant differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time for any of the subsets in the spleen (p≥0.322) and blood (p≥0.095). 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-g003: Leukocyte subsets in the spleen and blood.In spleen, irradiation reduced proportions of B cells, CD4+ T cells and CD8+ T cells; increased proportions of NK1.1+ T cells and granulocytes. In blood, B cells were most radiosensitive; NK cells were most resistant; granulocytes increased on days 7 and 14. Data are expressed as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in all cell subsets (p<0.01) except NK1.1+ T cells in blood (p = 0.288). No significant differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time for any of the subsets in the spleen (p≥0.322) and blood (p≥0.095). 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: The proportion of splenic B cells, CD4+ T cells and CD8+ T cells decreased while NKT cells, granulocytes and macrophages increased after HBI. Also, B cells decreased even more dramatically in the blood while the proportion of NK cells and granulocytes increased following irradiation (Figure 3). There were no differences in the depletion of specific leukocyte subsets in mice undergoing HBI alone vs HBI+depletion of Treg cells. In general, B cells were the most radiosensitive, CD4+ T cells and CD8+ T cells were moderately sensitive, while NKT cells, macrophages and granulocytes were relatively radioresistant. NK cells were the most radioresistant.

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