Biomedical subjects

Douglas E Faunce

Publications and source records attributed to Douglas E Faunce.

12 recordsLinked to original sources

PubMed2005

The effect of MCP-1 depletion on chemokine and chemokine-related gene expression: evidence for a complex network in acute inflammation.

The expression of chemokines has been suggested to involve an interdependent network, with the absence of a single chemokine affecting the expression of multiple other chemokines. Monocyte chemoattractant protein (MCP-1), a member of C-C chemokine superfamily, plays a critical role in the recruitment and activation of leukocytes during acute inflammation. To examine the effect of the loss of MCP-1 on expression of the chemokine network, we compared the mRNA expression profiles of MCP-1(-/-) and wild type mice during the acute inflammatory phase of excisional wounds. Utilizing a mouse cDNA array containing 514 chemokine and chemokine related genes, the loss of MCP-1 was observed to cause a significant upregulation of nine genes (Decorin, Persephin, IL-1beta, MIP-2, MSP, IL1ra, CCR5, CCR3, IL-11) and significant downregulation of two genes (CCR4 and CD3Z) in acute wounds. The array data was confirmed by semi-quantitative RT-PCR. The effect of MCP-1 deletion on chemokine expression was further examined in isolated macrophages. Compared to wild type, LPS-stimulated peritoneal macrophages from MCP-1(-/-) mice showed a significant increase in the expression of RANTES, MIP-1beta, MIP-1alpha and MIP-2 mRNA. The data suggest that loss of a single chemokine perturbs the chemokine network not only in the setting of acute inflammation but even in an isolated inflammatory cell, the macrophage.

Animals↗

PubMed2004

Aging and innate immune cells.

The innate immune system serves an important role in preventing microbial invasion. However, it experiences significant changes with advancing age. Among the age-associated changes are: Aged macrophages and neutrophils have impaired respiratory burst and reactive nitrogen intermediates as a result of altered intracellular signaling, rendering them less able to destroy bacteria. Aged neutrophils are also less able to respond to rescue from apoptosis. Aged dendritic cells (DC) are less able to stimulate T and B cells. The altered T cell stimulation is a result of changes in human leukocyte antigen expression and cytokine production, and lower B cell stimulation is a result of changes in DC immune complex binding. Natural killer (NK) cells from the elderly are less capable of destroying tumor cells. NK T cells increase in number and have greater interleukin-4 production with age. Levels of various complement components are also altered with advancing age.

Aging↗

PubMed2004

Cutting edge: in vitro-generated tolerogenic APC induce CD8+ T regulatory cells that can suppress ongoing experimental autoimmune encephalomyelitis.

APC exposed to TGFbeta2 and Ag (tolerogenic APC) promote peripheral Ag-specific tolerance via the induction of CD8(+) T regulatory cells capable of suppressing Th1 and Th2 immunity. We postulated that tolerogenic APC might reinstate tolerance toward self-neuronal Ags and ameliorate ongoing experimental autoimmune encephalomyelitis (EAE). Seven days after immunization with myelin basic protein (MBP), mice received MBP-specific tolerogenic APC, and EAE was evaluated clinically. To test for the presence and the phenotype of T regulatory cells, CD4 and/or CD8 T cells from tolerogenic APC-treated mice were transferred to naive mice before their immunization with MBP. The MBP-specific tolerogenic APC decreased both the severity and incidence of ongoing EAE. Tolerance to self-neuronal Ags was induced in naive recipient mice via adoptive transfer of CD8(+), but not CD4(+) T cells. Rational use of in vitro-generated tolerogenic APC may lead to novel therapy for autoimmune disease.

Animals↗

PubMed2004

Ethanol and burn injury: estrogen modulation of immunity.

A good deal of clinical evidence supports the idea that ethanol exposure is a causative factor in the occurrence of burn or other traumatic injury. In addition, more recent evidence reveals that individuals who sustain injury while under the influence of ethanol suffer from increased morbidity and mortality compared with those with comparable injuries who did not consume ethanol. Many of the complications seen in ethanol-exposed, burn-injured subjects result from depressed immune responses, which render the host unable to fight off infectious organisms. Both injury and ethanol exposure independently affect cellular immune responses, including delayed-type hypersensitivity and splenocyte proliferative responses, and the combined insult of ethanol exposure and injury acts in conjunction to increase further the magnitude and duration of immunosuppression. It is interesting that these immune responses can be restored experimentally in male, but not in female, mice by administration of low, proestrous levels of estrogen. The complexity of the responses after injury in ethanol-exposed subjects is multiplied when the sex of the subjects is added to the equation. This is due, in part, to the effect of the combined insult of injury and ethanol on the production of gonadal steroid hormones in males and females and the direct effects of those hormones on cytokine gene expression in sensitive cell types such as the macrophage. Evidence seems to indicate that cellular immune responses after ethanol exposure and burn injury differ in kinetics and magnitude for male and female subjects, and, hence, the therapeutic interventions to treat burn-injured patients should take into account both sex and ethanol exposure.

Animals↗

PubMed2003

Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression.

Age-related changes in immunity render elderly individuals more susceptible to infections than the young. Previous work by our laboratory and others showed that macrophages from aged mice are functionally impaired. Macrophages produce proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6, when stimulated with lipopolysaccharide (LPS), which signals through Toll-like receptor-4 (TLR4) and requires activation of mitogen-activated protein kinases (MAPKs). We investigated whether aging is associated with alterations in TNF-alpha and IL-6 production and MAPK expression and activation in thioglycollate-elicited peritoneal macrophages from mice. Kinetics and LPS dose-responsiveness of macrophage TNF-alpha production did not differ by age. Unstimulated macrophages did not differ by age in their cytokine production. However, LPS-stimulated (100 ng/mL) cultures from aged mice produced 100 +/- 30 pg/mL TNF-alpha and 6000 +/- 2000 pg/mL IL-6, and those from young mice produced 280 +/- 50 pg/mL and 10,650 +/- 10 pg/mL, respectively (P<0.05). Likewise, levels of activated MAPKs did not differ by age in unstimulated macrophages, and LPS-stimulated macrophages from aged mice had <70% activated p38 and c-jun NH(2)-terminal kinase (JNK) than those of young controls. Of particular interest, we observed >25% reduction of total p38 and JNK in macrophages from aged mice relative to young. In addition, surface TLR4 levels did not vary with age. We conclude that macrophages from aged mice exhibited suppressed proinflammatory cytokine production, which correlated with diminished total levels and LPS-stimulated activation of p38 and JNK. These observations suggest that decreased MAPK expression could be a mechanism responsible for age-related deterioration of the immune system.

Age Factors↗

PubMed2003

CD4+ NKT cells, but not conventional CD4+ T cells, are required to generate efferent CD8+ T regulatory cells following antigen inoculation in an immune-privileged site.

Following inoculation of Ag into the anterior chamber (a.c.), systemic tolerance develops that is mediated in part by Ag-specific efferent CD8(+) T regulatory (Tr) cells. This model of tolerance is called a.c.-associated immune deviation. The generation of the efferent CD8(+) Tr cell in a.c.-associated immune deviation is dependent on IL-10-producing, CD1d-restricted, invariant Valpha14(+) NKT (iNKT) cells. The iNKT cell subpopulations are either CD4(+) or CD4(-)CD8(-) double negative. This report identifies the subpopulation of iNKT cells that is important for induction of the efferent Tr cell. Because MHC class II(-/-) (class II(-/-)) mice generate efferent Tr cells following a.c. inoculation, we conclude that conventional CD4(+) T cells are not needed for the development of efferent CD8(+) T cells. Furthermore, Ab depletion of CD4(+) cells in both wild-type mice (remove both conventional and CD4(+) NKT cells) and class II(-/-) mice (remove CD4(+) NKT cells) abrogated the generation of Tr cells. We conclude that CD4(+) NKT cells, but not the class II molecule or conventional CD4(+) T cells, are required for generation of efferent CD8(+) Tr cells following Ag introduction into the eye. Understanding the mechanisms that lead to the generation of efferent CD8(+) Tr cells may lead to novel immunotherapy for immune inflammatory diseases.

Animals↗

PubMed2003

Advanced age negatively influences mesenteric lymph node T cell responses after burn injury.

While the pathophysiology of burn injury is well established in young adults, the factors that contribute to pathogenesis and increased death in elderly burn patients are not defined. The purpose of this study is to determine the effects of burn injury on mesenteric lymph node (MLN) T cell responses in young and aged mice. MLN is a cluster of lymph nodes that drains various parts of the intestine and is known to play role in clearance bacteria originating from the intestinal lumen. Results presented here suggest a significant suppression in Con A-induced MLN cell proliferation and IL-2 production in uninjured aged mice compared with uninjured young mice. Following 24 h after injury, although, a significant decrease in lymph node cell proliferation and IL-2 production was observed in both young and aged mice compared with their respective sham-injured animals, the suppression was more in aged mice. In addition we found a reduction in IFN-gamma, a Th-1 cytokine by MLN T cells from aged burned mice relative to young burn (P<0.05) or sham-injured mice (P<0.01). The Th-2 cytokine IL-4, on the other hand, was significantly increased in both young and aged burn-injured mice MLN T cells compared with their respective sham-injured mice. These results show that burn injury causes a greater suppression in MLN T cells ability to proliferate and a more pronounced shift to Th-2 phenotype in aged mice as compared with young mice. Such decreases in T cell functions may impair MLN's ability to clear the bacterial pathogens originating from intestine and thereby contribute to increased pathogenesis in injured host.

Age Factors↗

PubMed2003

Aging enhances lymphocyte cytokine defects after injury.

Mortality and sepsis after a traumatic injury is greater in the elderly than in young individuals. The altered lymphocyte response observed to occur in healthy aged individuals is proposed to be a contributing factor to increased mortality. The immune response associated with the increased mortality was explored using a murine scald injury model. In the absence of injury, aged mice had depressed delayed-type hypersensitivity (DTH) and splenocyte proliferative responses relative to young mice. There was also an increase with age in the production of the TH2 cytokines interleukin (IL)-4 and IL-10 by splenocytes. There was no change in the TH1 cytokines IFNgamma or IL-12 with age. However, IL-2 production was significantly lower. Following injury, there was a further decrease in the DTH response of aged injured mice, compared with aged sham mice. In addition, there was a decrease in all of the cytokines examined, regardless of age. In contrast, IFNgamma and IL-2 were significantly lower in the aged injured animals compared with the young injured animals. These results suggest that the lack of an adequate amount of TH1 cytokines shortly after injury in the aged mice may parallel the increased incidence of sepsis and death that occurs in aged burn patients.

Aging↗

PubMed2003

Effect of acute ethanol exposure on the dermal inflammatory response after burn injury.

BACKGROUND: More than 100,000 people each year are admitted to U.S. hospitals for severe burn injury. Strikingly, ethanol use prior to injury is apparent in nearly 50% of burn patients, rendering them six times more likely to die from infection than patients not exposed to ethanol. We previously reported that the kinetics and magnitude of neutrophil chemokine production and subsequent accumulation of neutrophils in the lung was dramatically altered when ethanol exposure preceded injury. Here, we tested whether burn injury and ethanol exposure combined, altered susceptibility to infection, neutrophil chemoattractant production, and neutrophil accumulation at the site of the burn wound. METHODS: Male B(6)D(2)F1 mice were administered a dose of ethanol designed to achieve 90-100 mg/dl circulating levels and 30 min later subjected to a 15% total body surface area dorsal scald injury. Susceptibility to topically applied Pseudomonas aeruginosa was examined. At various times after injury, burn wound and normal tissues were collected for assessments of neutrophil counts, myeloperoxidase quantitation, and neutrophil chemoattractant (KC and MIP-2) production. RESULTS: Ethanol exposure prior to burn injury enhanced susceptibility to infection after burn and was associated with significantly elevated production of KC, but not MIP-2, at the wound site. Despite the enhanced elevation of KC, neutrophil accumulation in the wounds of ethanol exposed, burn injured mice did not differ from those that received burn injury alone. TNFalpha (a potent activator of neutrophils), however, was found to be significantly elevated in the wounds of mice that received only burn injury, but not in those that received injury in combination with prior ethanol exposure. CONCLUSION: In the presence of ethanol, neutrophils are adequately recruited to the site of burn injury, but their host defense functions are impaired, perhaps due to the lack of proinflammatory cytokines such as TNFalpha.

Animals↗

PubMed2003

A role for CD1d-restricted NKT cells in injury-associated T cell suppression.

Natural killer T (NKT) cells are known to modulate T cell responses during autoimmunity, tolerance, and antitumor immunity; however, their potential role in regulating the immune response to injury has not been reported. Using a murine model of burn injury, we investigated whether CD1d-restricted NKT cells played a role in the T cell suppression that occurs early after injury. A functional role for CD1d stimulation of NKT cells in the injury-related immune suppression was demonstrated by experiments in which the suppression of antigen (Ag)-specific delayed-type hypersensitivity and in vitro T cell-proliferative responses were prevented if mice were given anti-CD1d monoclonal antibody (mAb) systemically just before injury. The CD1d-NKT cell-dependent suppression of the T cell response after injury occurred in the absence of quantitative changes in NKT cells themselves or CD1d(+) Ag-presenting cells. We observed that elevated production of the immunosuppressive cytokine interleukin (IL)-4 correlated with burn-induced immune dysfunction, and we found that NKT cells but not conventional T cells were the source of IL-4 early after injury. Lastly, we observed that the injury-induced production of NKT cell-derived IL-4 could be blocked by systemic treatment of burn-injured mice with anti-CD1d mAb. Together, our results reveal a novel mechanism involving CD1d stimulation of NKT cells in the onset of T cell suppression that occurs subsequent to injury.

Animals↗

PubMed2002

NKT cell-derived RANTES recruits APCs and CD8+ T cells to the spleen during the generation of regulatory T cells in tolerance.

The induction of peripheral tolerance via immune privileged sites such as the eye requires splenic colocalization of NKT cells and CD1d(+) tolerogenic F4/80(+) APCs, both of which are needed for the generation of CD8(+)-regulatory T (Tr) cells. Whereas tolerogenic APCs secrete the chemokine macrophage-inflammatory protein-2 for the purpose of recruiting NKT cells, the signals responsible for recruiting potential Tr cells and additional APCs to the spleen are not known. Here we examined the ability of CD1d-stimulated NKT cells to produce chemokines that can recruit other cells needed for tolerance. Our results show that NKT cells stimulated by either CD1d-transfected fibroblasts in vitro or CD1d(+) tolerogenic APCs both in vivo and ex vivo produced RANTES in a CD1d-dependent manner. The requirement for RANTES in tolerance was demonstrated by studies in which RANTES blockade in vivo prevented not only APC accumulation in the spleen but also the generation of CD8(+) Tr cells that suppress Th1 immunity. Thus, CD1d-restricted NKT cells provide critical signals for orchestrating the accumulation of cells needed for tolerance induction. These data expand our current knowledge of RANTES beyond its role in Th1 immune responses to show its importance in tolerance induction and add a novel aspect to our understanding of the role of NKT cells in tolerance. Understanding the precise mechanisms involved in tolerance induction may lead to more effective therapeutic strategies for autoimmunity and graft rejection.

Animals↗

PubMed2002

Alcohol, injury, and cellular immunity.

It is widely accepted that alcohol exposure is a causative factor in the occurrence of burn or other traumatic injury. It is less well known that individuals who have consumed alcohol before sustaining an injury suffer from increased morbidity and mortality compared with the morbidity and mortality of non-alcohol-consuming subjects with similar injuries. Complications due to bacterial infection are the most common burn sequelae in injured patients and are frequently associated with depressed immunity. Independently, alcohol exposure and injury have been shown to influence cellular immunity negatively. These changes in immunity are closely linked to injury- or alcohol-induced alterations in the cytokine milieu in both clinical studies and animal models. Not surprisingly, the combination of insult of alcohol exposure and burn injury results in immune suppression that is greater in magnitude and duration compared with either insult alone. The combined effects of alcohol and injury on immunity have been examined in a limited number of studies. However, results of these studies support the suggestion that altered cytokine production is an integral part of the immune dysregulation and increased mortality that is observed. In particular, the increased presence of macrophage-derived mediators observed after burn or alcohol exposure alone seems to be synergistically increased in a combined injury model. Although more research is needed, it is likely that therapeutic modalities that include manipulation of cytokine networks to boost cellular immunity may improve outcome for patients who sustain injuries subsequent to consuming alcohol.

Alcohol Drinking↗