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Biomedical subjects

L L Moldawer

Publications and source records attributed to L L Moldawer.

At least 19 recordsLinked to original sources
PubMed2001

Adenoviral delivery of human and viral IL-10 in murine sepsis.

Adenovirus (Ad) gene therapy has been proposed as a drug-delivery system for the targeted administration of protein-based therapies, including growth factors and biological response modifiers. However, inflammation associated with Ad transduction has raised concern about its safety and efficacy in acute inflammatory diseases. In the present report, intratracheal and i.v. administration of a first-generation adenoviral recombinant (E1,E3 deleted) either containing an empty cassette or expressing the anti-inflammatory cytokines viral or human IL-10 (IL-10) was administered to mice subjected to zymosan-induced multisystem organ failure or to acute necrotizing pancreatitis. Pretreatment of mice with the intratracheal instillation of Ad expressing human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflammatory cytokine response, and reduced mortality in the zymosan-induced model, whereas pretreatment with a control adenoviral recombinant did not significantly exacerbate the response. Pretreatment of mice with pancreatitis using adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered systemically, but not intratracheally. We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and expression of the anti-inflammatory protein IL-10 can be used to suppress the underlying inflammatory process.

Adenoviridae↗
PubMed2001

Central leptin gene therapy suppresses body weight gain, adiposity and serum insulin without affecting food consumption in normal rats: a long-term study.

The weight-reducing effects of leptin are predominantly mediated through the hypothalamus in the brain. Gene therapy strategies designed for weight control have so far tested the short-term effect of peripherally delivered viral vectors encoding the leptin gene. In order to circumvent the multiple peripheral effects of hyperleptinemia and to overcome the age-related development of leptin resistance due to multiple factors, including defective leptin transport across the blood brain barrier, we determined whether delivery of viral vectors directly into the brain is a viable therapeutic strategy for long-term weight control in normal wild-type rats. A recombinant adeno-associated virus (rAAV) vector encoding rat leptin (Ob) cDNA was generated (rAAV-betaOb). When administered once intracerebroventricularly (i.c.v.), rAAV-betaOb suppressed the normal time-related weight gain for extended periods of time in adult Sprague-Dawley rats. The vector expression was confirmed by immunocytochemical localization of GFP and RT-PCR analysis of leptin in the hypothalamus. This sustained restraint on weight gain was not due to shifts in caloric consumption because food-intake was similar in rAAV-betaOb-treated and rAAV-GFP-treated control rats throughout the experiment. Weight gain suppression, first apparent after 2 weeks, was a result of reduced white fat depots and was accompanied by drastically reduced serum leptin and insulin concentrations in conjunction with normoglycemia. Additionally, there was a marked increase in uncoupling protein-1 (UCP1) mRNA expression in brown adipose tissue, thereby indicating increased energy expenditure through thermogenesis. Seemingly, a selective enhancement in energy expenditure following central delivery of the leptin gene is a viable therapeutic strategy to control the age-related weight gain and provide protection from the accompanying multiple peripheral effects of hyperleptinemia and hyperinsulinemia.

Adenoviridae↗
PubMed2001

Urinary cytokines for assessing inflammation in HIV-associated wasting.

The relationship between cytokines and HIV-related weight loss has not been well established. Unlike most cytokines that are secreted in a paracrine manner, IL-6, sTNFR-II, and IL-1ra are readily detected in the systemic circulation and serve as markers of the inflammatory response. Twenty-four-hour urine concentrations of these proteins are believed to provide an integrative assessment of their systemic levels over the preceding hours. We sought to determine whether spot measurements of IL-6, sTNFR-II, and IL-1ra could be related to subsequent 24 h concentrations and prior weight loss. Eighteen subjects with severe wasting (average BMI=18+/-3 kg/m2with 19+/-13 kg of weight loss) and six HIV-negative healthy subjects were tested. Compared to values in controls, 24-h urinary concentrations of the three proteins adjusted for creatinine excreted were elevated in 44%, 89%, and 72% of patients, respectively. Twenty-four-hour concentrations were highly correlated with the spot concentrations (r=0.80, 0.87, 0.84, respectively, P<0.001). IL-1ra concentrations (24 h and spot) were correlated with weight loss in the previous 6 months, lifetime rate of weight loss and the 6 month rate of weight loss (spot: r=0.66, 0.73, 0.68, respectively, P< or =0.001). These data suggest that spot urinary collections can be used to estimate 24 h excretion rates. This strategy may be useful in assessing the inflammatory response in HIV-associated wasting.

Adult↗
PubMed2001

Considering immunomodulatory therapies in the septic patient: should apoptosis be a potential therapeutic target?

Treatment of sepsis and septic shock remains a clinical conundrum. Recent prospective trials with anti-cytokine and anti-inflammatory therapies have shown only modest clinical benefit. The successful treatment of the patient with sepsis syndrome will likely require multi-modal therapies aimed at several of the immunological and physiological disturbances which are occurring simultaneously. Recent studies in experimental animals and critically ill patients have suggested that increased apoptosis of lymphoid organs and some parenchymal tissues may contribute to the immune suppression, anergy and organ system dysfunction. Therapies aimed at inhibiting lymphoid cell apoptosis may contribute to improved outcome, and should be considered in the treatment of hospitalized patients with sepsis syndromes. Although clinical trials with anti-apoptotic agents remain distant due in large part to technical difficulties associated with their administration and tissue targeting, inhibition of lymphocyte apoptosis may be an appropriate therapeutic target for the septic patient.

Animals↗
PubMed2001

Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy.

IL-10 is a pleiotropic cytokine that acts as an important regulator of macrophage, T cell, and natural killer cell functions. Human IL-10 (hIL-10) has both stimulatory and inhibitory effects on a wide variety of cell types. Viral IL-10 (vIL-10) possesses only a subset of hIL-10's activities, predominantly its suppression of cytokine synthesis by T helper type 1 clones. In the present report, we evaluated tissue accumulation and biological activity of hIL-10 and vIL-10 in vivo in individual organs by using a first-generation adenoviral (Ad) vector administered intratracheally and intravenously. We report the observation that Ad vectors delivering vIL-10, but not hIL-10, are associated with prolonged expression in the lung (>42 days) when delivered intratracheally. In contrast, there was no prolongation in vIL-10 expression when Ad vectors were intravenously administered, although vIL-10 levels in the tissue, but not serum, were markedly increased relative to hIL-10. Moreover, we report an augmented capacity of expressed vIL-10 versus hIL-10 to suppress the acute inflammatory responses in the lung to intratracheal administration of Ad. These findings confirm fundamental differences in Ad-induced expression of vIL-10 and hIL-10 when administered to the lungs. The results further suggest that Ad vectors expressing vIL-10 may have a role as anti-inflammatory agents in the treatment of acute and chronic lung inflammation.

Adenoviridae↗
PubMed2001

Apoptosis in sepsis: a new target for therapeutic exploration.

The treatment of sepsis and septic shock remains a clinical conundrum, and recent prospective trials with biological response modifiers aimed at the inflammatory response have shown only modest clinical benefit. Recently, interest has shifted toward therapies aimed at reversing the accompanying periods of immune suppression. Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy, and organ system dysfunction. During sepsis syndromes, lymphocyte apoptosis can be triggered by the absence of IL-2 or by the release of glucocorticoids, granzymes, or the so-called 'death' cytokines: tumor necrosis factor alpha or Fas ligand. Apoptosis proceeds via auto-activation of cytosolic and/or mitochondrial caspases, which can be influenced by the pro- and anti-apoptotic members of the Bcl-2 family. In experimental animals, not only can treatment with inhibitors of apoptosis prevent lymphoid cell apoptosis; it may also improve outcome. Although clinical trials with anti-apoptotic agents remain distant due in large part to technical difficulties associated with their administration and tissue targeting, inhibition of lymphocyte apoptosis represents an attractive therapeutic target for the septic patient.

Apoptosis↗
PubMed2000

Reduced susceptibility of nonobese diabetic mice to TNF-alpha and D-galactosamine-mediated hepatocellular apoptosis and lethality.

Nonobese diabetic (NOD/LtJ or NOD) mice are resistant to doses of LPS and D-galactosamine that uniformly produce lethality in C57BL/6J (B6) mice (p < 0.01). Liver caspase-3-like activity, serum transaminase levels (both p < 0.05), and the numbers of apoptotic liver nuclei were also reduced in NOD compared with B6 mice treated with LPS (100 ng) and D-galactosamine (8 mg). NOD mice were also at least 100-fold more resistant to recombinant human TNF-alpha and D-galactosamine treatment than B6 mice (p < 0.001). Binding of recombinant human TNF-alpha to splenocytes from NOD mice was similar to that seen in B6 mice, suggesting that the defect in responsiveness was not due to an inability of recombinant human TNF-alpha to bind the NOD TNF type 1 (p55) receptor. Because the TNF type 1 (p55) receptor shares a common signaling pathway with Fas (CD95), NOD and B6 mice were treated with the Fas agonist antibody, Jo-2. Surprisingly, NOD mice were as sensitive as B6 mice to Fas-induced lethality and hepatic injury. In addition, primary hepatocytes isolated from NOD mice and cultured in vitro in the presence of D-galactosamine with or without TNF-alpha were found to be resistant to apoptosis and cytotoxicity when compared with B6 mice. In contrast, Jo-2 treatment produced similar increases in caspase-3 activity and cytotoxicity in primary hepatocytes from NOD and B6 mice. The resistance to LPS- and TNF-alpha-mediated lethality and hepatic injury in D-galactosamine-sensitized NOD mice is apparently due to a post-TNFR binding defect, and independent of signaling pathways shared with Fas.

Animals↗
PubMed2000

Autoregulation of human monocyte-derived dendritic cell maturation and IL-12 production by cyclooxygenase-2-mediated prostanoid production.

PG added to cell culture profoundly affect the in vitro maturation and function of monocyte-derived dendritic cells (MDC). Because unstimulated monocytes express cyclooxygenase (COX)-1, and COX-2 when activated, we examined whether MDC express these enzymes and produce prostanoids that autoregulate maturation and IL-12 production. Immature MDC (I-MDC) and mature MDC express COX-1, but, unlike monocytes, both MDC populations constitutively express COX-2. However, COX-2 regulation in both MDC populations differs from monocytes, as IL-4 does not suppress enzyme expression. COX-2 is functional in MDC as a specific inhibitor, NS-398, significantly reduces PGE(2) production. I-MDC undergoing maturation with soluble CD40 ligand (sCD40L) increase PGE(2) synthesis, but prostanoid synthesis is switched to COX-1. However, with IFN-gamma present, sCD40L-stimulated PG metabolism is redirected to COX-2, and PGE(2) synthesis increases severalfold. Endogenous PG production by MDC does not regulate CD40, CD80, CD86, or HLA DR expression; however, it does promote MDC maturation, as NS-398 significantly reduces CD83 expression in I-MDC matured with sCD40L/IFN-gamma. PG produced through COX-2 also autoregulate IL-12, but the effects are dependent on the MDC maturation state. Blocking COX-2 reduces I-MDC secretion of IL-12p40, whereas it increases IL-12p40 and p70 production by maturing MDC. COX-2-mediated PG production impacts MDC function as maturing these cells in the presence of NS-398 yields MDC that stimulate significantly more IFN-gamma in an allogeneic mixed lymphocyte response than MDC matured without this inhibitor. These studies demonstrate that MDC express both COX isoforms constitutively and produce prostanoids, which autoregulate their maturation and function.

Adjuvants, Immunologic↗
PubMed2000

Direct evidence for cytokine involvement in neointimal hyperplasia.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) are proximal inflammatory cytokines that stimulate expression of adhesion molecules and induce synthesis of other proinflammatory cytokines. In addition, TNF-alpha and IL-1 influence vascular smooth muscle cell migration and proliferation in vitro. In view of the inflammatory nature of neointimal hyperplasia (NIH), we tested the hypothesis that endogenous TNF-alpha and IL-1 modulate low shear stress-induced NIH. METHODS AND RESULTS: Mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated CCA has previously been shown to result in remodeling and NIH. Reverse transcriptase-polymerase chain reaction for TNF-alpha and IL-1alpha mRNA demonstrated both TNF-alpha and IL-1alpha mRNA in ligated CCAs, whereas normal and sham-operated CCAs had none. Mice lacking functional TNF-alpha (TNF-/-) developed 14-fold less neointimal area than WT controls (P:<0.05). p80 IL-1 type I receptor knockout (IL-1RI-/-) mice tended to develop less (7-fold, P:>0.05) neointimal area than WT controls. Furthermore, no IL-1alpha mRNA expression was detected in CCAs from TNF-/- mice; however, TNF-alpha mRNA expression was found in the IL-1RI-/- mice. Mice that overexpress membrane-bound TNF-alpha but produce no soluble TNF-alpha display an accentuated fibroproliferative response to low shear stress (P:<0.05). CONCLUSIONS: These results directly demonstrate that TNF-alpha and IL-1 modulate NIH induced by low shear stress. NIH can proceed by way of soluble TNF-alpha-independent mechanisms. Specific anti-TNF-alpha and anti-IL-1 therapies may lessen NIH.

Animals↗
PubMed2000

Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice. Relationship with body weight change.

We investigated the long-term effects of physiological levels of leptin produced by gene therapy on body weight (BW) and expression of genes that encode orexigenic and anorexigenic peptides in the hypothalamus. Recombinant adeno-associated viral vector (rAAV), a non-pathogenic and non-immunogenic vector, encoding leptin (betaOb) was generated and administered iv to ob/ob mice lacking endogenous leptin. Whereas the lowest dose of rAAV-betaOb (6x10(9) particles) was ineffective, the middle dose (6x10(10) particles) curbed BW gain without affecting food consumption for 75 days of observation. A ten-fold higher dose (6x10(11) particles) resulted in increased blood leptin levels and suppressed both BW gain and food consumption throughout the duration of the experiment. rAAV-betaOb doses that either curbed BW without affecting food consumption or evoked BW loss and reduced food intake, decreased the expression of genes encoding the orexigenic peptides, neuropeptide Y and agouti-related peptide in the ARC, and the two doses were equally effective. Concomitantly, the expression of genes encoding the anorexigenic peptide, alpha-melanocyte stimulating hormone and cocaine-and-amphetamine regulatory transcript, was augmented with the latter gene displaying a dose-dependant response. These results document the efficacy of delivering biologically active leptin for extended periods by an iv injection of rAAV-betaOb and show that physiological leptin concentrations simultaneously exert a tonic inhibitory effect on orexigenic and a stimulatory effect on anorexigenic signaling in the hypothalamus. This intricate dynamic interplay induced by leptin regulates BW with or without an effect on food intake in leptin-deficient ob/ob mice. Further, these results suggest that gene therapy is an effective mode of delivery to the hypothalamus of those therapeutic proteins that cross the blood-brain barrier to ameliorate neuroendocrine disorders.

Agouti-Related Protein↗
PubMed2000

Neither Fas ligand nor endotoxin is responsible for inducible peritoneal phagocyte apoptosis during sepsis/peritonitis.

Regulation of the phagocyte apoptotic response appears to play a significant role in the pathophysiology of sepsis. In this regard, prior studies have shown that the onset of phagocyte apoptosis, as well as those agents that regulate it at the nidus of infection, differ significantly from those seen in circulation. The aim of this study therefore was to determine if the increase in inducible phagocyte apoptosis and caspase activities seen in the peritoneum during sepsis is due to endotoxin or Fas ligand. To study this, male C3H/HeN (endotoxin-sensitive), C3H/HeJ (endotoxin-tolerant), and C3H/HeJ-FasL(gld) (endotoxin-tolerant/FasL-deficient) mice were subjected to cecal ligation and puncture or sham operation. Twenty-four hours later, phagocytes were collected and cultured with lipopolysaccharide (LPS), then harvested for apoptosis (propidium iodide cell cycle or cell death ELISA analysis), cytokine release (ELISA), and caspase activity (fluorogenic assay) determination. The data indicate that there was a marked increase in apoptosis in LPS-stimulated phagocytes which was associated with a significant increase in caspase 3, 8, and 9 activities but a decrease in caspase 1 activity from C3H/HeN and C3H/HeJ-FasL(gld) septic mice and an increase in caspase 3 and 8 activities in phagocytes from C3H/HeJ septic mice. Furthermore, cells from septic mice, including all three strains, lost their ability to produce IL-1beta and IL-6 in response to LPS stimulation. The inability to completely suppress these changes suggests that neither endotoxin (via signaling through TLR-4 pathway) nor Fas ligand regulates the peritoneal phagocyte apoptotic responses seen during the late phase of polymicrobial sepsis/peritonitis.

Animals↗
PubMed2000

TNF-alpha receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung.

Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose-dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-alpha and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. beta-Galactosidase expression in mice receiving intratracheal instillation of Adv/beta-gal (adenovirus construct expressing beta-galactosidase) was transient (less than 14 days), but a significant early increase of beta-galactosidase expression was seen in mice lacking either or both TNF-alpha receptors. Absence of TNF-alpha or the p55 receptor significantly attenuated the Ab response to both adenovirus and beta-galactosidase. Human IL-10 expression in the lung suppressed local TNF-alpha production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with beta-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-alpha signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with beta-galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with beta-galactosidase, and is nonimmunogenic in the lung.

Adenoviridae↗
PubMed2000

The induction of EAE is only partially dependent on TNF receptor signaling but requires the IL-1 type I receptor.

Experimental autoimmune encephalomyelitis develops in mice immunized with CNS antigens. To elucidate the role that specific proinflammatory cytokines play in the induction of this process we examined the development of EAE in mice with targeted disruptions of the TNF p55 or p75 or the IL-1 p80 receptors. EAE developed in mice with either one or both TNF receptors deleted although the onset of disease in mice with the p55 receptor deleted was delayed. However, mice with a deletion of the IL-1 p80 receptor failed to develop any inflammatory lesions in the CNS or evidence of clinical EAE. Thus we conclude that TNF or its receptors contribute to, but are not necessary for, the induction of EAE while the IL-1 p80 receptor is absolutely required. The p55 TNF receptor plays a role in determining the onset of disease and its severity.

Animals↗
PubMed2000

Liposome-mediated, nonviral gene transfer induces a systemic inflammatory response which can exacerbate pre-existing inflammation.

Cationic liposome and plasmid-mediated gene transfer has emerged as a novel technique for the targeted delivery of protein-based therapies in acute inflammatory diseases. However, concerns have arisen that cationic liposomes and plasmid DNA have inherent proinflammatory properties which could exacerbate pre-existing inflammatory processes. In healthy mice, intraperitoneal administration of cationic liposomes (200 nmol) complexed to plasmid DNA (100 microg) induced a proinflammatory response characterized by the induction of tumor necrosis factor alpha and interleukin-1beta mRNA expression. The plasma concentrations of the hepatic acute phase proteins interleukin-6, amyloid A, amyloid P, and seromucoid were also increased (P<0.05), and this response was seen in endotoxin-resistant (C3H/HeJ) mice. The inflammatory response associated with gene transfer increased the mortality and severity of experimentally induced sterile inflammation (pancreatitis). We conclude that systemic administration of cationic liposomes and plasmid DNA is associated with induction of the innate immune response which may exacerbate pre-existing inflammatory processes.

Amyloid↗
PubMed2000

Neuropeptide Y counteracts the anorectic and weight reducing effects of ciliary neurotropic factor.

Ciliary neurotrophic factor (CNTF), a cytokine of the interleukin-6 superfamily, has been shown to induce hypophagia and weight loss. Neuropeptide Y (NPY) and orexin are potent orexigenic signals in the hypothalamus. Anorexia, normally seen in response to infection, injury and inflammation, may result from diminished hypothalamic orexigenic signalling caused by persistently elevated cytokines, including CNTF. To test this hypothesis, we first examined the effects of chronic intracerebroventricular (i.c.v.) infusion of CNTF for 6-7 days on food intake and body weight as well as hypothalamic NPY and orexin gene expression in male rats. Subsequently, the effectiveness of NPY replacement to counteract the effects of CNTF by coinfusion of NPY and CNTF was evaluated. Chronic i.c.v. infusion of CNTF (2.5 microg/day) reduced body weight (14.3% vs control) at the end of 7 days. Food intake remained suppressed for 5 days postinfusion and subsequently gradually returned to the control range by day 7. Serum leptin concentrations in these rats were in the same range seen in control rats. Chronic i.c.v. infusion of higher doses of CNTF (5.0 microg/day) produced sustained anorexia and body weight loss (29% vs controls) through the entire duration of the experiment. This severe anorexia was accompanied by markedly suppressed serum leptin concentrations. Furthermore, CNTF infusion alone significantly reduced hypothalamic NPY gene expression (P < 0. 05) without affecting orexin gene expression. As expected, in fusion of NPY alone (18 microg/day) augmented food intake (191.6% over the initial control, P < 0.05) and produced a 25.1% weight gain in conjunction with a 10-fold increase in serum leptin concentrations at the end of the 7-day period. Interestingly, coinfusion of this regimen of NPY with the highly effective anorectic and body reducing effects of CNTF (5.0 microg/day) not only prevented the CNTF-induced anorexia and weight loss, but also normalized serum leptin concentrations and hypothalamic NPY gene expression. These results demonstrate that chronic central infusion to produce a persistent elevation of the cytokine at pathophysiological levels (a situation that may normally manifest during infection, injury and inflammation) produced severe anorexia and weight loss in conjunction with reduction in both serum leptin concentrations and hypothalamic NPY gene expression. Reinstatement of hypothalamic NPY signalling by coinfusion of NPY counteracted these CNTF-induced responses.

Animals↗
PubMed2000

Interleukin-10 appearance following thoraco-abdominal and abdominal aortic aneurysm repair is associated with the duration of visceral ischaemia.

OBJECTIVES: to evaluate the plasma IL-10 levels during elective operative repair of thoraco-abdominal and abdominal aortic aneurysm repair. To study whether IL-10 plasma levels are associated with the duration of cross-clamping (ischaemia) and clinical outcome. MATERIALS: fifteen consecutive patients undergoing surgery for TAAA and 10 consecutive patients undergoing surgical repair of AAA were included. METHODS: plasma concentrations of IL-10 were measured by ELISA technique. Clinical outcome of the TAAA patients was prospectively analysed. RESULTS: during aortic clamping IL-10 was produced in both populations. The plasma IL-10 peak (934+/-172 pg/ml) of the TAAA group was seen at 4 h after declamping and remained detectable after 48 h. The plasma IL-10 peak (212+/-32 pg/ml) of the AAA group was seen 30 min after declamping and fell to undetectable levels by 24 h. These data show that the peak IL-10 plasma levels in TAAA repair are significantly (p<0.05) higher compared to the peak IL-10 plasma levels as seen during AAA repair. A positive correlation was seen between cross-clamping and peak plasma IL-10 and organ dysfunction. CONCLUSIONS: IL-10 plasma concentrations appear higher, later and are longer detectable in patients undergoing TAAA. Correlations were seen with duration of cross-clamping and MSOD.

Aortic Aneurysm, Abdominal↗
PubMed2000

Cytokine signaling--regulation of the immune response in normal and critically ill states.

Cytokines are produced during the activation of innate and acquired immunity, and are the principal means for intercellular communication of a microbial invasion. Cytokines serve to initiate the inflammatory response and to define the magnitude and the nature of the acquired immune response. The response of critically ill patients to their injury and/or invading pathogens is dependent, in large part, on the pattern of cytokines which are produced. The immunologic response of critically ill patients can vary from a strongly proinflammatory response, characterized by increased production of tumor necrosis factor-alpha, interleukin (IL)-1, interferon (IFN)-gamma, and IL-12 to one predominantly of anergy, characterized by increased production of T(H)2 cytokines, like IL-10 and to IL-4. Therapeutic efforts to modify the host immune response in critical illness will require a more thorough understanding of the cytokine milieu and the factors that determine their production.

Antibody Formation↗