Blockade of CD40-CD40 ligand pathway induces tolerance in murine contact hypersensitivity

Interactions between CD40 on antigen-presenting cells and its ligand (CD40L) on T cells has been implicated in T cell-mediated immune responses. Previously, we have shown that contact hypersensitivity (CHS), a cell-mediated cutaneous immune response in reaction to haptens, could be subclassified based on whether the hapten primed for Th1 or Th2 cytokines in cells isolated from draining lymph nodes. We also found that tolerance to a Th2-priming hapten could be induced only by simultane blockade of the CD40-CD40L and B7-CD28 at the time of sensitization. Here we demonstrate that blockade of CD40-CD40L signaling alone induces long-lasting unresponsiveness to the Th1 hapten 2,4-dinitrofluorobenzene (DNFB), and inhibits antigen-specific T cell proliferation in vitro. We find that CD40-CD40L signaling is required in the sensitization but not elicitation phase of DNFB-induced CHS, as treatment of mice with anti-CD40L monoclonal antibody (mAb) does not affect the response to hapten challenge in previously sensitized and untreated animals. Examination of cytokine production shows that anti-CD40L mAb decreases interferon-gamma production by draining lymph node cells from DNFB-sensitized mice, and reciprocally increases interleukin (IL)-4 production. Consistent with this Th1 to Th2 immune deviation, anti-CD40L mAb prevents the induction of IL-12 mRNA in regional lymph nodes, an event which is normally seen within 12 h following hapten sensitization. In contrast, suppression of CHS by CTLA4Ig decreased the production of all cytokines by draining lymph node cells. Together, these data show that blockade of the CD40-CD40L pathway by itself is sufficient to induce tolerance to DNFB-induced CHS, and that this is associated with blockade of IL-12 induction and Th1 to Th2 immune deviation.     

A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1)

Chemotactic factors are postulated to direct emigration of lymphocytes from the blood stream into sites of inflammation. Members of a family of chemotactic cytokines, termed chemokines, have been shown to attract lymphocytes but efficacy, i.e., the maximal percentage of attracted cells, has been low. We have identified a highly efficacious lymphocyte chemotactic activity in the supernatants of the murine bone marrow stroma cell line MS-5 which attracts 10-fold more lymphocytes in vitro than currently described lymphocyte chemoattractants. Purification of this chemotactic activity revealed identity to stromal cell-derived factor 1 (SDF-1). SDF-1 acts on lymphocytes and monocytes but not neutrophils in vitro and is both a highly efficacious and highly potent mononuclear cell attractant in vivo. In addition, SDF-1 induces intracellular actin polymerization in lymphocytes, a process that is thought to be a prerequisite for cell motility. Since SDF-1 is expressed constitutively in a broad range of tissues it may have a role in immune surveillance and in basal extravasation of lymphocytes and monocytes rather than in inflammation.     

Factors predicting a successful outcome after pharmacologic bowel compensation

OBJECTIVES: The authors determined those factors that predict a successful outcome in patients who receive pharmacologic agents to promote bowel absorption after massive intestinal resection. SUMMARY BACKGROUND DATA: Patients with the short bowel syndrome are maintained on long-term total parenteral nutrition (TPN) or more frequently considered for intestinal transplantation as part of their treatment program. The authors have administered a combination of trophic agents and a specialized diet to further enhance intestinal compensation and optimize nutrient absorption in patients with intestinal failure. METHODS: Forty-five TPN-dependent adults with a jejunal-ileal remnant < or = 50 cm and a portion of colon in continuity were treated with growth hormone, glutamine, and a modified diet for 4 weeks and observed for an average of 1.8 years. RESULTS: The average age of the patients was 43 years, the average jejunal-ileal length was 23 cm, and the average length of time the patient received TPN was 4.3 years. After 4 weeks of therapy, 26 (58%) were free of TPN support. Predictors of a favorable response included greater bowel length, lower body weight, and greater bowel length-body weight ratio. At follow-up, the percentage of patients who were not receiving TPN had fallen to 40%. CONCLUSIONS: Approximately half of a group of patients, thought to have absorptive surface area inadequate to be independent of TPN support, can maintain themselves on enteral feedings after this intestinal rehabilitation program. Because of the risk, costs, and alterations in lifestyle associated with long-term TPN or intestinal transplantation or both, it seems prudent to consider a program of bowel rehabilitation with an individual patient before embarking on another therapeutic plan.     

Long-term treatment of ulcerative colitis with ciprofloxacin: a prospective, double-blind, placebo-controlled study

BACKGROUND & AIMS: Although bacterial bowel flora may be one of the contributing factors in the pathogenesis of chronic mucosal inflammation, antibiotic treatment has no established role in ulcerative colitis. The aim of the study was to evaluate the role of ciprofloxacin in the induction and maintenance of remission in ulcerative colitis in patients responding poorly to conventional therapy with steroids and mesalamine. METHODS: Ciprofloxacin (n = 38; 500-750 mg twice a day) or placebo (n = 45) was administered for 6 months in a double-blind, randomized study with a high but decreasing dose of prednisone and maintenance treatment with mesalamine including follow-up for the next 6 months. Clinical assessment and colonoscopic evaluation were performed at 0, 3, 6, and 12 months. Treatment failure, the primary end point, was defined as both symptomatic and endoscopic failure to respond. RESULTS: During the first 6 months, the treatment-failure rate was 21% in the ciprofloxacin-treated group and 44% in the placebo group (P = 0.02). Endoscopic and histological findings were used as secondary end points and showed better results in the ciprofloxacin group at 3 months but not at 6 months. CONCLUSIONS: Addition of a 6-month ciprofloxacin treatment for ulcerative colitis improved the results of conventional therapy with mesalamine and prednisone.     

Analysis of a polymorphism in the tuberous sclerosis (TSC2) gene does not predispose to schizophrenia

The tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of malformations in various organs including the brain. A polymorphism in the TSC2 gene has been found to be increased in gangliogliomas, a lesion which is associated with disturbed neuro-glial cell migration pattern. Since these pathomorphological changes are compatible with disturbed neuronal migration in schizophrenic brains, we investigated this polymorphism in 130 families with a schizophrenic index patient. A 222-bp fragment of genomic DNA containing the TSC2 variant was analyzed by SSCP. The analysis revealed that there is no association with schizophrenia.     

Mutual and intercompartmental regulation of estrogen receptor and progesterone receptor expression in the mouse uterus

The epithelial and stromal compartments of the uterus undergo significant estrogen- and progesterone (P4)-induced changes during the estrous cycle. While in the adult mouse, epithelial proliferation and stromal inflammation are induced by estrogen, P4 is antiproliferative in the epithelium and both proliferative and anti-inflammatory in the stroma. In light of these compartmentally varying roles, we have immunohistochemically examined estrogen and P4 regulation of the expression of their receptors (ER and PR) and their epithelial target gene lactoferrin (LF) in wild-type and PR null mutant mice. We demonstrate that estrogen exerts compartment-specific effects on the expression of ER, resulting in decreased levels of stromal and glandular epithelial (GE) ER and increased luminal epithelial (LE) and myometrial ER. Estrogen also has dual effects on PR expression, decreasing levels in the LE while at the same time increasing levels in the stroma and myometrium. Estrogen and P4 together mediate their effects in part through the ability of P4 to selectively inhibit myometrial ER expression while preserving GE expression. We also demonstrate a general negative feedback by P4 on PR expression that is most prominent in the GE. Finally, we demonstrate using the estrogen- and P4-responsive epithelial target gene LF that the differential regulation of PR in the glandular and luminal epithelium results in different functional responses of these compartments to P4. Together, our data indicate that the pleiotropic effects of estrogen and P4 in the adult mouse uterus are mediated by complex hormonal interregulation of ER and PR in specific uterine compartments.     

Genetics of alcoholism: rapid development of a new high-ethanol-preferring (HEP) strain of female and male rats

A genetically based animal model of alcoholism has been developed in a relatively short period of 3 years. The new strain is characterized by an intense preference for ethanol over water as well as unique behavioral, neurochemical and other attributes. This new strain, termed high-ethanol-preferring (HEP) rats, was derived initially from selective cross-breeding of a variant strain of female Harlan Sprague-Dawley (SD) rats with the outbred Wistar line of male ethanol-preferring (P) rats. In this study, drinking patterns of both genders were obtained over 10 days by presenting water and ethanol in concentrations ranging from 3% to 30%. To expedite the development of the new strain, only three to five female and male rats served as breeders, which were chosen from all litters on the basis of their maximum g/kg intake integrated with proportion of ethanol to total fluid values. Profiles of intake of preferred concentrations of ethanol were obtained over 24 h of unlimited access as well as during 2-h intervals of limited access to ethanol. Levels of blood ethanol were measured in both female and male HEP animals during bouts of ethanol drinking in the limited access paradigm. By the sixth generation of HEP rats, ethanol consumption of the females often exceeded that of any other rat genetically bred to drink ethanol (e.g., at a concentration of 15.7%, 10.3 g/kg per day). Seven additional characteristics are notable: 1) the HEP rats prefer ethanol in the presence of a nutritious chocolate drink or nonnutrient sweetened solution (aspartame); 2) high levels of blood ethanol are associated with their drinking; 3) females drink significantly greater g/kg amounts of ethanol than HEP males and prefer a higher percent concentration of ethanol; 4) the drinking of ethanol by the female HEP animals does not fluctuate during the estrous cycle; 5) neurochemical assays show differential profiles of 5-HT, dopamine, and their metabolites in different regions of the brain; 6) measures of activity using the elevated plus maze, open field, and cork gnawing reveal differences between genders of HEP rats and SD rats; and 7) the HEP animals are without phenotypically expressed abnormalities. Finally, one cardinal principle derived from this study revealed that the breeding strategy to develop high-ethanol-drinking rats centers on the use of multiple solutions of ethanol whereby the intakes of ethanol in concentration of 9% through 20% dictate the ultimate selection of breeding pairs over successive F generations. Further, it is concluded that because of an intense rise in ethanol drinking of the F1 generation of female HEP rats well above that of the parental SD female breeders, the complex genotypic characteristic of the male P rat is predominantly responsible for evoking ethanol drinking in female offspring.     

Head circumference of rural Nigerian children--the effect of malnutrition on brain growth

OBJECTIVE: To compare head circumference measurements of the well nourished with those of the malnourished children for each sex. DESIGN: Cross sectional. SETTING: Imesi, Ile-Ife village, Nigeria. SUBJECTS: 644 children in the first six years of life. MAIN OUTCOME MEASURES: Head circumference. RESULTS: The mean head circumference values of malnourished children of both sexes fell mostly below the values for their well nourished age mates. The curve for well nourished girls fell by a little below, and for malnourished girls by over two standard deviations below Tanner's 50th percentile curve. For the boys, the curve for the malnourished children fell by over one standard deviation below the curve for their well nourished age mates. CONCLUSION: The significant reductions in head circumferences found in malnourished children may have serious implications for their future performance and achievement. Therefore, sufficient community concern and appropriate world action aimed at eradicating protein energy malnutrition is solicited.