Publications by authors named "Sara Kriynovich"

5 Publications

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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

Linking the "two-hit" response following injury to enhanced TLR4 reactivity.

J Leukoc Biol 2005 Jan 20;77(1):16-23. Epub 2004 Oct 20.

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

Severe injury can initiate an exaggerated systemic inflammatory response and multiple organ failure (MOF) if a subsequent immune stimulus, "second hit", occurs. Using a mouse thermal injury model, we tested whether changes in innate immune cell reactivity following injury can contribute to the development of heightened inflammation and MOF. Using high-purity Escherichia coli lipopolysaccharide (LPS) to selectively stimulate Toll-like receptor 4 (TLR4), we demonstrate augmented interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), and IL-6 production by 1 day but particularly, at 7 days after injury. The in vivo significance of enhanced TLR4 responsiveness was explored by challenging sham or burn mice with LPS at 1 or 7 days after injury and determining mortality along with in vivo cytokine and chemokine levels. Mortality was high (75%) in LPS-challenged burn but not sham mice at 7 days, although not at 1 day, after injury. Death was associated with leukocyte sequestration in the lungs and livers along with increased proinflammatory cytokine and chemokine levels in these organs. Blocking TNF-alpha activity prevented this mortality, suggesting that excessive TNF-alpha production contributes to this lethal response. These findings demonstrate the potential lethality of excessive TLR4 reactivity after injury and provide an explanation for the exaggerated inflammatory response to a second hit, which can occur following severe injury.
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http://dx.doi.org/10.1189/jlb.0704382DOI Listing
January 2005

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

Injury primes the innate immune system for enhanced Toll-like receptor reactivity.

J Immunol 2003 Aug;171(3):1473-83

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

Severe injury causes a dramatic host response that disrupts immune homeostasis and predisposes the injured host to opportunistic infections. Because Toll-like receptors (TLRs) recognize conserved microbial Ags and endogenous danger signals that may be triggered by injury, we wanted to determine how injury influences TLR responses. Using an in vivo injury model, we demonstrate that injury significantly increased TLR2- and TLR4-induced IL-1beta, IL-6, and TNF-alpha production by spleen cells. This influence of injury on TLR reactivity was observed as early as 1 day after injury and persisted for at least 7 days. The outcome of similar studies performed using TLR4-mutant C57BL/10ScN/Cr mice revealed that TLR2 responses remained primed, thus suggesting that injury-induced priming can occur independently of endogenous TLR4 signaling. Increased TLR4 reactivity was also observed in vivo, because LPS-challenged injured mice demonstrated significantly higher cytokine expression levels in the lung, liver, spleen, and plasma. Macrophages and dendritic cells were the major source of these cytokines as judged by intracellular cytokine staining. Moreover, ex vivo studies using enriched macrophage and dendritic cell populations confirmed that T cells did not contribute to the enhanced TLR2 and TLR4 responses. The results of flow cytometry studies using TLR2- and TLR4-MD-2-specific Abs indicated that injury did not markedly alter cell surface TLR2 or TLR4-MD-2 expression. Taken together, these findings establish that injury primes the innate immune system for enhanced TLR2- and TLR4-mediated responses and provides evidence to suggest that augmented TLR reactivity might contribute to the development of heightened systemic inflammation following severe injury.
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http://dx.doi.org/10.4049/jimmunol.171.3.1473DOI Listing
August 2003