Pierre Michetti

Development of chronic colitis is dependent on the cytokine MIF

The cytokine macrophage-migration inhibitory factor (MIF) is secreted by a number of cell types upon induction by lipopolysaccharide (LPS). Because colitis is dependent on interplay between the mucosal immune system and intestinal bacteria, we investigated the role of MIF in experimental colitis. MIF-deficient mice failed to develop disease, but reconstitution of MIF-deficient mice with wild-type innate immune cells restored colitis. In addition, established colitis could be treated with anti-MIF immunoglobulins. Thus, murine colitis is dependent on continuous MIF production by the innate immune system. Because we found increased plasma MIF concentrations in patients with Crohns disease, these data suggested that MIF is a new target for intervention in Crohns disease.

Clinical experience with infliximab therapy in 100 patients with Crohn's Disease

OBJECTIVE:The aim of this study was to assess our clinical experience with infliximab, a monoclonal antitumor necrosis factor antibody, following its approval for treatment of refractory Crohns disease (CD).METHODS:We followed 100 consecutive patients with CD (53 women and 47 men; mean age, 41 yr) who received a total of 233 infliximab (5 mg/kg) infusions. Adverse events were noted and clinical response assessed every 2 wk for 6 months after each infusion using the Harvey Bradshaw Index (HBI) for active disease, the Perianal Disease Activity Index (PDAI) for fistulous disease, and steroid withdrawal rates for steroid-sparing efficacy.RESULTS:Indications for therapy were active disease (n = 57), perianal fistulous disease (n = 33), and steroid dependency (n = 10). Significant infusion reactions occurred in 16 patients (6.9% of infusions) including anaphylactic shock in one patient. Fourteen patients experienced infectious adverse events, 13 of whom were on concurrent steroids. Sixty percent of patients with active disease experienced ≥50% HBI reduction at 2 wk; mean duration of response, 8.2 wk. Three of 26 first-time nonresponders with active disease (12%) responded to a second infusion. Sixty-nine percent of patients with fistulous disease experienced >50% reduction in their PDAI at 2 wk; mean duration of response, 10.9 wk. Four of 10 steroid-dependent patients (40%) discontinued steroid therapy, one of whom recommenced steroid therapy at 24 wk.CONCLUSIONS:Our clinical response rates mirror the efficacy reported in the controlled trials for active and fistulous disease. Steroid-sparing efficacy was seen in 40% of steroid-dependent patients. Concurrent steroids did not reduce the risk of significant infusion reactions (6.9%), but did increase the risk of infections.

Saccharomyces boulardii stimulates intestinal immunoglobulin A immune response to Clostridium difficile toxin A in mice.

ABSTRACT Saccharomyces boulardii is a nonpathogenic yeast that protects against antibiotic-associated diarrhea and recurrentClostridium difficile colitis. The administration ofC. difficile toxoid A by gavage to S. boulardii-fed BALB/c mice caused a 1.8-fold increase in total small intestinal immunoglobulin A levels (P = 0.003) and a 4.4-fold increase in specific intestinal anti-toxin A levels (P < 0.001). Enhancing host intestinal immune responses may be an important mechanism for S. boulardii-mediated protection against diarrheal illnesses.

Safety and efficacy of low dose Escherichia coli enterotoxin adjuvant for urease based oral immunisation against Helicobacter pylori in healthy volunteers

Background and aims:Escherichia coli heat labile enterotoxin (LT) at doses of 5 μg or 10 μg has adjuvant activity for oral immunisation in humans infected with Helicobacter pylori, but causes severe diarrhoea. This study was undertaken to establish a safe and effective dose of LT, to confirm the safety of recombinant urease, and to compare the immunogenicity of orally compared with enterically delivered urease. Methods: 42 healthy adults without present or past H pylori infection were randomised to receive 60 mg recombinant H pylori urease in soluble or in encapsulated form, given with doses of LT ranging from 0 μg to 2.5 μg. Four oral doses were administered at day 1, 8, 29, and 57. Specific IgG, IgA, and antibody secreting cells were measured as well as total α4β7 integrin positive lymphocyte responses. Results: Enterically delivered urease was well tolerated and no serious adverse events occurred. Mild diarrhoea (one to four loose stools) occurred after the first immunisation in 50% (6 of 12) of the volunteers exposed to 2.5 μg LT (p=0.06; paired t test, compared with baseline) but not in volunteers exposed to lower LT doses. Immune responses occurred in five (p=0.048; Fisher’s exact test), one, two, and one of six subjects exposed to 2.5 μg, 0.5 μg, 0.1 μg, and no LT, respectively. Significant CD4+, CD69+, and CD45ROhi responses occurred over time among α4β7hi lymphocytes in volunteers receiving 2.5 μg LT. Enterically delivered urease induced higher lymphocyte responses than soluble urease. Conclusions: The safety of H pylori urease is confirmed. Oral LT may conserve its adjuvant activity at low doses with minimal side effects.

Safety and efficacy of E coli enterotoxin adjuvant for urease-based rectal immunization against Helicobacter pylori.

Low dose E. coli heat-labile enterotoxin (LT), delivered orally or enterically, has been used as an adjuvant for Helicobacter pylori (H. pylori) urease in healthy adults. In this study we aim to test the safety and adjuvant efficacy of LT delivered rectally together with recombinant H. pylori urease. Eighteen healthy adults without present or past H. pylori infection were enrolled in a double blind, randomized, ascending dose study to receive either urease (60 mg), or urease (60 mg) + LT (5 or 25 microg). The immunization preparation was administered per rectum on days 0, 14 and 28. Serum, stool and saliva anti-urease and anti-LT IgG and IgA antibodies (Abs) were measured and urease-specific and LT-specific antigen secreting cells (ASCs) were counted in peripheral blood at baseline and 7 (ASC counts) or 14 days (antibody levels) after each dosing. Peripheral blood lymphoproliferation assays were also performed at baseline and at the end of the study. Rectally delivered urease and LT were well tolerated. Among the 12 subjects assigned to urease+LT, 2 (16.7%) developed anti-urease IgG Abs, 1 (8.3%) developed anti-urease IgA Abs, and 3 (25%) showed urease-specific IgA(+) ASCs. Immune responses to LT were more vigorous, especially in subjects exposed to 5 microg LT. In the urease+ 5 microg LT group, anti-LT IgG and IgA Abs developed in 60 and 80% of the subjects, respectively, while LT-specific IgG(+) and IgA(+) ASCs were detected in all subjects. The magnitude of the anti-LT response was much higher than the response to urease. No IgA anti-urease or anti-LT Abs were detected in stool or saliva and lymphocyte proliferative responses to urease were unsatisfactory. In conclusion, rectal delivery of 5 microg LT is safe and induces vigorous systemic anti-LT immune responses. Further studies are needed to determine if LT can be an effective adjuvant for rectally delivered antigens.

Vaccine against Helicobacter pylori: fact or fiction?

Antibiotic-based triple therapy is reasonably effective in treating patients with symptomatic Helicobacter pylori infection, but this approach is untenable for global control of the infection. In practice, however, anti- H pylori therapy is prescribed to an increasing number of patients, in the absence of proven benefit.1 2 Firstly, anti- H pylori treatment is increasingly offered to infected patients with non-ulcer dyspepsia and to asymptomatic carriers. This “test-and-treat” attitude is aimed at controlling the dyspeptic symptoms and at reducing long term risk of gastric malignancies in infected individuals. Secondly, anti- H pylori treatment is also advocated as a first approach in H pylori positive dyspeptic patients, in an attempt to reduce the overall management costs of these patients, without prior endoscopic documentation of the presence of an ulcer or of other complications of the infection.3 4 Even though some decision analysis and clinical studies suggest that these different approaches may be beneficial,3-5 other studies have failed to show potential benefit.6-8 nnThe increased prescription of antibiotics for H pylori infection has encouraged the emergence of antibiotic resistant strains. Indeed, the efficacy of current therapies rarely exceeds 90%, and strains isolated after treatment failure often show resistance.9 Resistance to metronidazole is already high in developed countries, and resistance to clarithromycin is increasingly evident. A survey of resistance conducted over five years in Ireland showed that resistance to metronidazole and clarithromycin increased from 32% to 46% and from 5.3% to 8.6%, respectively.10 Because metronidazole has been available for decades before being used against H pylori , this rapid evolution suggests that the selection pressure on H pylori developed once antibiotics were prescribed in association with antisecretory agents. If this speculation is correct, the number of patients treated for H pylori infection may impact directly on the development of …

M Cell-Mediated Antigen Transport and Monoclonal IgA Antibodies for Mucosal Immune Protection

The normal, healthy intestinal epithelium serves as a barrier to entry of most large macromolecules and particles, including microorganisms. An important component of this barrier is the presence on the mucosal surface of specific secretory IgAs against enteric pathogens. Paradoxically, the generation of a secretory immune response to protect against colonization and entry of microorganisms requires transport of microorganisms across the epithelial barrier and entry into organized lymphoid tissue, where presentation of antigen and stimulation of IgAcommitted lymphoblasts can occur. The major route of antigen transport across the intact epithelial barrier for stimulation of a secretory immune response is through transepithelial transport by intestinal M cells (for review see REF. 1). M cells are specialized epithelial cells present in the epithelium overlying lymphoid follicles. They can be identified morphologically by the lack of the well-organized brush border and thick glycocalyx which characterize adjacent enterocytes, and by the presence of a large basal invaginated pocket containing

Mesalamine-associated thrombocytopenia

ABSTRACTWe describe a case of a 25-yr-old woman with ulcerative colitis who developed marked thrombocytopenia during treatment and upon rechallenge with oral mesalamine. In contrast to its parent drug, sulfasalazine, which has often been reported to cause serious blood disorders, particularly agranulocytosis, mesalamine has rately been implicated as a cause of serious blood disorders. Although previous cases of hematological toxicity have been described in patients taking mesalamine, none of these patients were rechallenged in an effort to prove causality between 5-aminosalicyclic acid and the hematological abnormality as well as outrule the possible “autoimmune” contribution of inflammatory bowel disease to the hematological toxicity of these agents. This report demonstrates that mesalamine has the potential, like sulphasalazine, to cause marked thrombocytopenia in an idiosyncratic fashion. All patients receiving mesalamine therapy, either orally or topically should have regular, complete blood profiles.

MEDICAL THERAPY OF SPECIFIC CLINICAL PRESENTATIONS

A pluridisciplinary approach that integrates medical therapy with surgery and other aspects of patient care, such as nutritional and psychosocial support, is essential to the management of patients with inflammatory bowel disease (IBD). Despite new medical therapies, such as 5-amino-salicylic acid compounds, steroids, and immunomodulators, the treatment of patients with IBD remains challenging. Success depends on the appropriate use of the available medications in relation to the severity and localization of the disease. The introduction of novel immunomodulating agents such as antitumor necrosis factor alpha is likely to have a major influence on the current therapeutic strategies. This article describes the use of the available medications in the most common clinical presentations of IBD.

Laparoscopically assisted ileocolectomy for Crohn's disease through a pfannenstiel incision.

Recently, laparoscopically assisted bowel resections have been shown to be less morbid than the traditional laparotomy, especially for benign conditions such as Crohns disease. While reports describing laparoscopically assisted bowel resections use a small midline or right transverse incision, we describe a novel laparoscopically assisted approach employing a Pfannenstiel incision for Crohns patients. We attempted the Pfannenstiel incision since it is well known to be associated with less postoperative pain, decreased ileus and hospital stay, and low rates of wound infection and incisional hernia, compared with midline or right transverse incisions. Furthermore, we found that the Pfannenstiel incision offers additional advantages that may be uniquely suited for Crohns patients. First, the cosmetic position of the incision is particularly attractive to the young population affected by Crohns. Second, the Pfannenstiel incision preserves fresh tissue in the midline, right, and left lower quadrants in the event that reoperation or stoma placement are required in the future owing to recurrent disease. We describe our technique in 10 consecutive patients undergoing ileocolectomy for Crohns disease. Our patients experienced minimal morbidity and were pleased with the cosmetic results of their incisions.