Publications by authors named "Sinead M Dolan"

4 Publications

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Injury-induced GR-1+ macrophage expansion and activation occurs independently of CD4 T-cell influence.

Shock 2011 Aug;36(2):162-9

Department of Surgery (Immunology), Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.

Burn injury initiates an enhanced inflammatory condition referred to as the systemic inflammatory response syndrome or the two-hit response phenotype. Prior reports indicated that macrophages respond to injury and demonstrate a heightened reactivity to Toll-like receptor stimulation. Since we and others observed a significant increase in splenic GR-1 F4/80 CD11b macrophages in burn-injured mice, we wished to test if these macrophages might be the primary macrophage subset that shows heightened LPS reactivity. We report here that burn injury promoted higher level TNF-α expression in GR-1, but not GR-1 macrophages, after LPS activation both in vivo and ex vivo. We next tested whether CD4 T cells, which are known to suppress injury-induced inflammatory responses, might control the activation and expansion of GR-1 macrophages. Interestingly, we found that GR-1 macrophage expansion and LPS-induced TNF-α expression were not significantly different between wild-type and CD4 T cell-deficient CD4(-/-) mice. However, further investigations showed that LPS-induced TNF-α production was significantly influenced by CD4 T cells. Taken together, these data indicate that GR-1 F4/80 CD11b macrophages represent the primary macrophage subset that expands in response to burn injury and that CD4 T cells do not influence the GR-1 macrophage expansion process, but do suppress LPS-induced TNF-α production. These data suggest that modulating GR-1 macrophage activation as well as CD4 T cell responses after severe injury may help control the development of systemic inflammatory response syndrome and the two-hit response phenotype.
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http://dx.doi.org/10.1097/SHK.0b013e31821af669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139815PMC
August 2011

Burn injury induces an early activation response by lymph node CD4+ T cells.

Shock 2006 Feb;25(2):135-40

Department of Surgery (Immunology), Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Several reports have shown that burn injury primes the immune system for an early and vigorous proinflammatory CD4 T cell response, suggesting that injury might signal CD4 T cell activation. We addressed this possibility by investigating changes in CD4 T cell activation marker expression, proliferation, and T cell receptor (TCR) usage at several early time points after burn injury. Using a sensitive flow cytometry approach to measure changes in the expression of Ki-67 antigen, a nuclear protein detected only in proliferating cells, we observed an early burst of proliferation by lymph node, but not spleen, CD4 T cells 12 h after burn injury. In contrast, mice that were treated with the bacterial superantigen staphylococcal enterotoxin B (SEB) as a positive control for in vivo T cell activation did not show this early proliferation. Instead, we observed a significant increase in proliferating lymph node and spleen CD4 and CD8 T cells by 3 days after SEB treatment. Burn injury induced higher cell surface CD25 and CD152 expression on lymph node CD4 T cells, whereas SEB treatment increased CD25 and CD69 expression on CD4 and CD8 T cells. Finally, we found that burn injury induced a proliferative response at 12 h by an oligoclonal subset of TCR Vbeta-chain-expressing CD4 T cells (Vbeta4, Vbeta6, Vbeta11, and Vbeta14). Interestingly, CD4 T cells expressing the Vbeta11-TCR remained significantly increased in the lymph nodes 3 days after burn injury. Taken together, these findings indicate that burn injury induces an early proliferation and activation of CD4 T cells in the regional lymph nodes and that these proliferating cells show restricted TCR Vbeta-chain usage consistent with the idea that injury triggers an early T cell activation signal.
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http://dx.doi.org/10.1097/01.shk.0000190824.51653.32DOI Listing
February 2006

Burn injury initiates a shift in superantigen-induced T cell responses and host survival.

J Immunol 2004 Apr;172(8):4883-92

Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Severe injury induces a temporal shift in immune reactivity that can cause serious complications or even death. We previously reported that mice exposed to bacterial superantigen (SAg) early after injury undergo a strong SAg response with lethal consequences. This study compares the early and late effects of burn injury on SAg reactivity in vivo to establish how injury influences adaptive immune responses. We found that mice challenged with ordinarily sublethal doses of staphylococcal enterotoxin A or staphylococcal enterotoxin B at 1 day after burn injury exhibited high mortality, whereas no mortality occurred at 7 days after injury. This shift in mortality correlated with higher Th2-type cytokines (IL-4 and IL-10) being expressed by CD4(+) and CD8(+) T cells from burn as opposed to sham mice at 7 days after injury. Lymph node cells from burn-injured mice also produced higher levels of Th2-type cytokines at 7 days after injury. The results of cell-mixing studies using CD4(+) and CD8(+) T cells mixed with APCs from sham or burn mice suggested that changes in both T cells and APCs are involved in the altered SAg response. Finally, the biological significance of altered SAg reactivity following injury was shown by demonstrating that blocking IL-10 activity in vivo caused higher SAg-induced mortality at 7 days after injury. These findings support the idea that injury promotes a Th2-type shift in adaptive immune reactivity. Although prior studies link this counterinflammatory-type response to lowered resistance to infection, the present results suggest it may sometimes benefit the injured host.
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http://dx.doi.org/10.4049/jimmunol.172.8.4883DOI Listing
April 2004

Burn injury promotes antigen-driven Th2-type responses in vivo.

J Immunol 2003 Oct;171(8):3983-90

Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.

Severe injury induces detrimental changes in immune function, often leaving the host highly susceptible to developing life-threatening opportunistic infections. Advances in our understanding of how injury influences host immune responses suggest that injury causes a phenotypic imbalance in the regulation of Th1- and Th2-type immune responses. We report in this study, using a TCR transgenic CD4(+) T cell adoptive transfer approach, that injury skews T cell responses toward increased Th2-type reactivity in vivo without substantially limiting Ag-driven CD4(+) T cell expansion. The increased Th2-type response did not occur unless injured mice were immunized with specific Ag, suggesting that the phenotypic switch is Ag dependent. These findings establish that severe injury induces fundamental changes in the induction of Ag-specific CD4(+) Th cell responses favoring the development of Th2-type immune reactivity in vivo.
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http://dx.doi.org/10.4049/jimmunol.171.8.3983DOI Listing
October 2003