Arnold Stronkhorst

CD4 antibody treatment in patients with active Crohn's disease: a phase 1 dose finding study.

BACKGROUND: T cells play an important part in Crohns disease. Immunomodulating therapies that target T cell activation may have clinical effects in Crohns disease. AIM: To investigate the toxicity and potential efficacy of anti-CD4 monoclonal antibody therapy in patients with Crohns disease. PATIENTS AND METHODS: A dose escalating pilot study was conducted in three groups of four patients with intractable Crohns disease, refractory to steroids. They received 70, 210, or 700 mg of cM-T412, a depleting anti-CD4 monoclonal antibody (mAb). RESULTS: The mean reduction in Crohns disease activity index (CDAI) was respectively 25%, 24%, and 36% at four weeks, and 24% and 52% at 10 weeks in the 210 mg and 700 mg groups. There was only a minor effect on endoscopically evaluated disease activity. Side effects were mild to moderate fever with chills and headache. No signs of opportunistic infection were seen. There was a sustained decrease in CD4 count which lasted at least four weeks in the 70 mg group (76.3 (SD 40.6)% of the baseline value), and 10 weeks in both the 210 mg group (80.8 (SD 60.9)%) and the 700 mg group (24.8 (SD 15.4)%). The primary and secondary humoral immune response was not influenced by anti-CD4 mAb treatment. CONCLUSION: This study shows the moderate potential efficacy of treatment of patients with Crohns disease using a depleting chimeric monoclonal anti-CD4 antibody.

Effect of intestinal resection on serum antibodies to the mycobacterial 45/48 kilodalton doublet antigen in Crohn's disease.

Interest in the role of mycobacterial infection in Crohns disease has been revived by the cultural detection of Mycobacterium paratuberculosis in patients with Crohns disease. This hypothesis was examined serologically using assays with high specificity for Crohns disease. The effect of intestinal resection on serum antibodies specific for Crohns disease was investigated with an immunoblot assay and an enzyme linked immunosorbent assay using the 45/48 kilodalton doublet antigen of Mycobacterium tuberculosis. Antibodies were detected in 64.7% of patients with Crohns disease (n = 17), 10% of patients with ulcerative colitis (n = 10), 5% of patients with carcinoma of the colon (n = 20), and none of 10 healthy subjects with the immunoblot assay. Statistical comparison of the Crohns disease patients with each control group resulted in p = 0.0000236. Immunoglobulin G was essentially unchanged 75 days (mean) after surgery. After more than 180 days, however, the antibody response was reduced in all of five patients studied, and was no longer demonstrable in two of them (40%). Simultaneously, the Crohns disease activity index (CDAI) decreased. Both the high specificity of this assay for Crohns disease and the diminished antibody response after intestinal resection in parallel with decreased CDAI support a mycobacterial aetiology of Crohns disease.

High detection rate of adenomas in familial colorectal cancer

Background and aims Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4–6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas. Patients and methods Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded. Results A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09). Conclusion The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.

CD4 Antibody Treatment in Crohn's Disease

Immunologic changes may play a role in the pathogenesis of Crohns disease. Whether these changes are the primary cause of the disease or secondary to the inflammatory response remains unknown. Activated T helper cells probably play a pivotal role in Crohns disease, although no causative antigen has been identified. Possible targets for immunomodulating therapy should include neutralization of the antigens, deletion of reactive activated T cells or, less specifically, interference with the antigen-presenting process. New, humanized, monoclonal antibodies that interfere with the antigen-presenting process are now available for clinical investigation. In particular, CD4 antibody treatment seems of interest, in view of the predominant role of T cells in Crohns disease. Finally, because tumor necrosis factor is necessary for granuloma formation, inhibition of this factor may be expected to improve disease activity in Crohns disease.

Cytokine induction in experimental and ulcerative colitis

In order to delineate the role of cytokines in inflammatory bowel disease, we studied induction of these mediators in an acetic acid-induced rat model for colitis. In this model, IL-1β mRNA induction was detected early after induction of acute colitis. Using in situ hybridization techniques, enterocytes were identified as the predominant source of IL-1β mRNA. TNFα mRNA was detected with in situ hybridization in cells located in the lamina propria and in the submucosa. Immunofluorescent techniques showed cells with the same localisation producing TNFα protein. Cultured human colon biopsies from patients with ulcerative colitis secreted large amounts of interleukin-1 but only modest quantities of tumor necrosis factor. Thus, interleukin-1 is synthesized in experimental as well as ulcerative colitis, and may be causally related to its pathogenesis. These findings open new possibilities for development of intervention strategies in ulcerative colitis.

Immunohistological Evidence for Mycobacteria in Crohn’s Disease

Despite an enormous amount of investigations the etiology of Crohns disease (CD) remains unknown. Exogenous factors, both of non infectious (e.g. food) and infectious (bacteria and virus) agents have been often postulated as the causatives (1–3).