It has been demonstrated that human placental alkaline phosphatase (HPLAP) attenuates the lipopolysaccharide (LPS)-mediated inflammatory response, likely through dephosphorylation of the lipid A moiety of LPS. In this study, it is demonstrated that also alkaline phosphatase derived from calf intestine (CIAP) is able to detoxify LPS. In mice administered CIAP, 80% of the animals survived a lethal Escherichia coli infection. In piglets, previous to LPS detoxification, the pharmacokinetic behavior of CIAP was studied. CIAP clearance was shown to be doseindependent and showed a biphasic pattern with an initial t 1/2 of 3 to 5 min and a second phase t 1/2 of 2 to 3 h. Although CIAP is cleared much faster than HPLAP, it attenuates LPS-mediated

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In this clinically relevant septic shock model, alkaline phosphatase administration improved gas exchange, decreased interleukin-6 concentrations, and prolonged survival time.

Lipopolysaccharide (LPS) contributes importantly to morbidity and mortality in sepsis. Bovine intestinal alkaline phosphatase (BIAP) was demonstrated to detoxify LPS through dephosphorylation. LPS injection combined with BIAP reduced inflammation and improved survival in various experimental settings. In this study, single-dose intravenous administration of BIAP (0.15 IU/g) was applied in a murine cecal ligation and puncture (CLP) model of polymicrobial sepsis. Saline was given as control (S group). Treatment with BIAP prior to CLP (prophylaxis; BIAP-P group) or shortly after (early treatment; BIAP-ET group) reduced cytokine concentrations in plasma and peritoneal lavage fluid (PLF). Tumor necrosis factor-alpha peak levels decreased from 170 pg/ml (S) to 57.5 (BIAP-P) and 82.5 (BIAP-ET) in plasma and in PLF from 57.5 pg/ml (S) to 35.3 (BIAP-P) and 16.8 (BIAP-ET) (all, P < 0.05). Peak interleukin-6 levels in plasma decreased from 19.3 ng/ml (S) to 3.4 (BIAP-P) and 11.5 (BIAP-ET) and in PLF from 32.6 ng/ml (S) to 13.4 (BIAP-P) and 10.9 (BIAP-ET) (all, P < 0.05). Macrophage chemoattractant protein 1 peak levels in plasma decreased from 2.0 ng/ml (S) to 1.0 (BIAP-P) and 0.7 (BIAP-ET) and in PLF from 6.4 (S) to 2.3 (BIAP-P) and 1.3 ng/ml (BIAP-ET) (all, P < 0.05). BIAP-treated groups showed decreased transaminase activity in plasma and decreased myeloperoxidase activity in the lung, indicating reduced associated hepatocellular and pulmonary damage. Survival was not significantly altered by BIAP in this single-dose regimen. In polymicrobial secondary peritonitis, both prophylactic and early BIAP treatment attenuates the inflammatory response both locally and systemically and reduces associated liver and lung damage.Secondary peritonitis can ultimately lead to sepsis with shock and/or organ failure and is associated with high morbidity and mortality (30 to 40%) (5). Both secondary peritonitis and sepsis are characterized by an excessive inflammatory response (7, 28). Activation of cytokines and other inflammatory mediators in these conditions are induced by endotoxins, such as lipopolysaccharide (LPS), which is an important contributor to morbidity and mortality (28). LPS is a component of the outer leaflet of gram-negative bacteria. It is a complex and negatively charged molecule composed of a polysaccharide chain (O-specific chain) and a toxic lipid moiety (lipid A). The two phosphate groups of lipid A are essential for its immunostimulatory characteristics (2, 7). Intravenous (i.v.) injection of LPS leads to a generalized inflammatory response (29). The dephosphorylation product of lipid A, monophosphoryl lipid A, is a nontoxic derivative that does not evoke major inflammatory response (2) and is known to induce tolerance (1, 34). Therefore, LPS (and, in particular, lipid A) is a potential therapeutic target in sepsis (7, 11). Many sepsis therapies have aimed to block the effect of LPS by using antisera (6, 35) and anti-LPS antibodies (20) or by binding LPS with LPS-binding protein (8) or high-density lipoprotein (1...

The onset or exacerbation of psoriasis, a T-cell-dependent skin disease with autoimmune features, can be triggered by drugs such as antimalarials and beta-blockers. Xenobiotics may also play a role in idiopathic psoriasis. It has been hypothesized that different metabolic efficiencies caused by variant alleles of xenobiotic metabolizing enzymes could lead to the accumulation of xenobiotics or their reactive metabolites in target organs. Subsequently, neoantigens or cryptic peptides could be presented and initiate an aggressive T cell response. In this context, we analyzed a broad array of xenobiotic metabolizing enzymes in up to 327 Caucasian psoriasis patients and compared them to 235 control persons. Alleles tested include four phase I and three phase II enzymes. Significantly more carriers of the variant alleles of CYP1A1 (alleles *2A and *2C) were found in healthy controls than in patients, suggesting a protective role for these alleles. No significant difference between patients and controls could be found, however, for the other phase I alleles 1B1*1 and 1B1 *3, 2C19*1A and 2C19*2A, and 2E1*1A and 2E1*5B. Of the variant alleles coding for phase II enzymes only GSTM1, but not GSTT1 or NQOR, correlated with a risk to contract psoriasis. Some combinations of phase I and phase II enzymes suggested protective or risk-associated effects. Interestingly, heterozygosity for CYP2C19 alleles *1A and *2A was associated with increased risk for "late onset" psoriasis, whereas this genotype was protective for psoriatic arthritis. This is the first large-scale study on these enzymes and the results obtained support the concept that different activities of metabolizing enzymes can contribute to disease etiology and progression.

A 32-year-old patient developed an anaphylactic reaction minutes after oral intake of acetaminophen-containing tablets (Doregrippin)). Scratch testing of the whole preparation was positive in contrast with the negative results obtained with pure acetaminophen. Therefore, scratch tests with the remaining drug components were performed and showed polyvinylpyrrolidone (PVP) to be the aetiological agent. Furthermore, specific IgE antibodies against PVP were demonstrated using a dot blot technique, thus ruling out a pseudo-allergic reaction. This case underlines the necessity to consider not only the active ingredient, but also additives as the causative agent.

Although the ability of CD4 + CD25 + T suppressor (Ts) cells to prevent experimental autoimmune diseases has been described, nothing is known concerning their role and mechanism of action in xenobiotic-induced autoimmunity. Procainamide, mercuric chloride, and gold(I) are three xenobiotics that can induce autoimmune reactions in humans and rodents. After the induction of IgG1 antinuclear autoantibodies (ANA) in mice treated with either of the above xenobiotics, adoptive transfer of their CD4 + CD25 + T cells completely prevented ANA formation in recipients treated with the same xenobiotic; transfer of CD8 + T cells was ineffective. Furthermore, xenobiotic-primed CD4 + CD25 + T cells could also partially prevent ANA formation in recipients treated with a different xenobiotic. CD4 + CD25 -T cells from xenobiotic-treated donors failed to suppress, but induced de novo IgG1 ANA formation in untreated recipients. Our findings suggest that during xenobiotic treatment T cell reactivity may spread from xenobiotic-induced, nucleoprotein-related neoantigens to peptides of the unaltered nucleoproteins.