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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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The absolute number of CD4+FoxP3+ Treg cells in the spleens and LNs.Both PC61 administration and irradiation reduced the number of CD4+FoxP3+ Treg cells in spleen, iLN and mLN. Irradiation resulted in a more rapid restoration of Treg cells after day 7. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in the Treg absolute numbers in spleen, iLN and mLN (all p<0.01). Differences between all pairs (PC61+sham irradiation vs Rat IgG+sham irradiation, PC61+irradiation vs PC61+sham irradiation, Rat IgG+sham irradiation compare to Rat IgG+irradiation, Rat IgG+sham irradiation compare to PC61+irradiation, PC61+sham irradiation compared to Rat IgG+irradiation and PC61+sham irradiation compared to PC61+irradiation treatment groups) 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-g005: The absolute number of CD4+FoxP3+ Treg cells in the spleens and LNs.Both PC61 administration and irradiation reduced the number of CD4+FoxP3+ Treg cells in spleen, iLN and mLN. Irradiation resulted in a more rapid restoration of Treg cells after day 7. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in the Treg absolute numbers in spleen, iLN and mLN (all p<0.01). Differences between all pairs (PC61+sham irradiation vs Rat IgG+sham irradiation, PC61+irradiation vs PC61+sham irradiation, Rat IgG+sham irradiation compare to Rat IgG+irradiation, Rat IgG+sham irradiation compare to PC61+irradiation, PC61+sham irradiation compared to Rat IgG+irradiation and PC61+sham irradiation compared to PC61+irradiation treatment groups) 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: In the radiation-treated mice, the absolute numbers of Treg cells decreased over the first week and repopulated quickly thereafter in spleen and iLN. PC61+HBI treatment resulted in the most significant decrease in the number of Treg cells, with recovery incomplete by day 14 (Figure 5).


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)

The absolute number of CD4+FoxP3+ Treg cells in the spleens and LNs.Both PC61 administration and irradiation reduced the number of CD4+FoxP3+ Treg cells in spleen, iLN and mLN. Irradiation resulted in a more rapid restoration of Treg cells after day 7. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in the Treg absolute numbers in spleen, iLN and mLN (all p<0.01). Differences between all pairs (PC61+sham irradiation vs Rat IgG+sham irradiation, PC61+irradiation vs PC61+sham irradiation, Rat IgG+sham irradiation compare to Rat IgG+irradiation, Rat IgG+sham irradiation compare to PC61+irradiation, PC61+sham irradiation compared to Rat IgG+irradiation and PC61+sham irradiation compared to PC61+irradiation treatment groups) 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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569437&req=5

pone-0056607-g005: The absolute number of CD4+FoxP3+ Treg cells in the spleens and LNs.Both PC61 administration and irradiation reduced the number of CD4+FoxP3+ Treg cells in spleen, iLN and mLN. Irradiation resulted in a more rapid restoration of Treg cells after day 7. Data are shown as Mean±SD (n = 4). Two way ANOVA showed significant interactions over time between treatments in the Treg absolute numbers in spleen, iLN and mLN (all p<0.01). Differences between all pairs (PC61+sham irradiation vs Rat IgG+sham irradiation, PC61+irradiation vs PC61+sham irradiation, Rat IgG+sham irradiation compare to Rat IgG+irradiation, Rat IgG+sham irradiation compare to PC61+irradiation, PC61+sham irradiation compared to Rat IgG+irradiation and PC61+sham irradiation compared to PC61+irradiation treatment groups) 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: In the radiation-treated mice, the absolute numbers of Treg cells decreased over the first week and repopulated quickly thereafter in spleen and iLN. PC61+HBI treatment resulted in the most significant decrease in the number of Treg cells, with recovery incomplete by day 14 (Figure 5).

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