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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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Cell numbers in the spleens and lymph nodes.Mice were injected with PC61 or rat IgG MAb 3 days prior to receiving 13 Gy of HBI or sham irradiation. Cells in the (A) spleen, (B) iLN and (C) mLN were counted on the days indicated. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in spleen, iLN and mLN cell count (all p<0.01). No differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time in the spleen, iLN and mLN (p≥0.128). No significant differences were found between the PC61+sham irradiation compared to Rat IgG+sham irradiation treatment group profiles over time (all p≥0.072). 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-g002: Cell numbers in the spleens and lymph nodes.Mice were injected with PC61 or rat IgG MAb 3 days prior to receiving 13 Gy of HBI or sham irradiation. Cells in the (A) spleen, (B) iLN and (C) mLN were counted on the days indicated. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in spleen, iLN and mLN cell count (all p<0.01). No differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time in the spleen, iLN and mLN (p≥0.128). No significant differences were found between the PC61+sham irradiation compared to Rat IgG+sham irradiation treatment group profiles over time (all p≥0.072). 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 determine the effects of radiation with and without the depletion of Treg cells on systemic leukocyte counts, alterations in the total number of cells in the spleen, iLN and mLN, as well as alterations in the proportions of various leukocyte subsets were determined at 4 hrs and 1, 3, 7 and 14 days following irradiation. Radiation significantly decreased the number of total spleen, iLN and mLN cells in the mice treated with both HBI and rat IgG and HBI+PC61. Cell numbers decreased as early as 4 hrs, reached a nadir of about 10–15% of the normal control levels 3 days following irradiation, and gradually increased thereafter (Figure 2). Depletion of Treg cells with PC61 did not substantially influence HBI-induced decreases in the number of leukocytes in the spleen and LNs


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)

Cell numbers in the spleens and lymph nodes.Mice were injected with PC61 or rat IgG MAb 3 days prior to receiving 13 Gy of HBI or sham irradiation. Cells in the (A) spleen, (B) iLN and (C) mLN were counted on the days indicated. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in spleen, iLN and mLN cell count (all p<0.01). No differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time in the spleen, iLN and mLN (p≥0.128). No significant differences were found between the PC61+sham irradiation compared to Rat IgG+sham irradiation treatment group profiles over time (all p≥0.072). 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-g002: Cell numbers in the spleens and lymph nodes.Mice were injected with PC61 or rat IgG MAb 3 days prior to receiving 13 Gy of HBI or sham irradiation. Cells in the (A) spleen, (B) iLN and (C) mLN were counted on the days indicated. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in spleen, iLN and mLN cell count (all p<0.01). No differences were detected between PC61+irradiation compared to Rat IgG+irradiation treatment group profiles over time in the spleen, iLN and mLN (p≥0.128). No significant differences were found between the PC61+sham irradiation compared to Rat IgG+sham irradiation treatment group profiles over time (all p≥0.072). 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 determine the effects of radiation with and without the depletion of Treg cells on systemic leukocyte counts, alterations in the total number of cells in the spleen, iLN and mLN, as well as alterations in the proportions of various leukocyte subsets were determined at 4 hrs and 1, 3, 7 and 14 days following irradiation. Radiation significantly decreased the number of total spleen, iLN and mLN cells in the mice treated with both HBI and rat IgG and HBI+PC61. Cell numbers decreased as early as 4 hrs, reached a nadir of about 10–15% of the normal control levels 3 days following irradiation, and gradually increased thereafter (Figure 2). Depletion of Treg cells with PC61 did not substantially influence HBI-induced decreases in the number of leukocytes in the spleen and LNs

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