Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease.

BACKGROUND & AIMS: Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohn's disease and to explore the effects of dose and schedule on platelet count and Crohn's disease activity. METHODS: A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohn's disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. RESULTS: Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. CONCLUSIONS: Short-term treatment with rhIL-11 is well tolerated in patients with active Crohn's disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohn's disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Abnormalities of the intestinal immune system in AIDS.

Significant abnormalities in the distribution of lymphocyte subsets have been noted in the intestinal mucosa of ARC and AIDS patients. Abnormalities are most striking among the CD4 helper-inducer T-cell subset and likely reflects the direct effects of HIV infection of those cells. A deficiency in CD4-positive T cells in the intestinal mucosa potentially could result in significant abnormalities in mucosal immune function, including defects both in cell-mediated immunity and in the secretory IgA system. Such alterations in mucosal immunity and mucosal defense may render AIDS and ARC subjects susceptible to enteric infections and systemic infections in which the intestinal tract is the portal of entry.

Gastrointestinal manifestations of the acquired immunodeficiency syndrome.

In addition to abnormalities in systemic immune function, patients with the acquired immunodeficiency syndrome (AIDS) and the pre-AIDS syndromes have significant abnormalities in the distribution of T-cell subsets in the intestinal tract. Such immune deficits predispose such patients to opportunistic infections and tumors, many of which involve the gastrointestinal tract. For example, Candida albicans often causes stomatitis and esophagitis. Intestinal infections with parasites (Cryptosporidium, Isospora belli, Microsporidia) or bacteria (Mycobacterium avium-intracellulare) are associated with severe diarrhea and malabsorption, whereas viruses like cytomegalovirus and herpes simplex virus cause mucosal ulcerations. Clinically debilitating chronic diarrhea develops in many AIDS patients for which no clear cause can be identified. Enteric pathogens like Salmonella and Campylobacter can be associated with bacteremias. Kaposi's sarcoma and lymphoma involving the intestinal tract are now well-recognized complications of AIDS. Although AIDS is not associated with a pathognomonic liver lesion, opportunistic infections and Kaposi's sarcoma or lymphoma may involve the liver.

Abnormalities in intestinal mucosal T cells in homosexual populations including those with the lymphadenopathy syndrome and acquired immunodeficiency syndrome.

Enteric infections are common in homosexual men. We have characterized the phenotypic distribution of small intestinal mononuclear cells among healthy homosexual men, homosexual men with lymphadenopathy syndrome, homosexual men with acquired immunodeficiency syndrome (AIDS), and a group of healthy heterosexual men. Total numbers of T lymphocytes in the small intestinal mucosa were significantly decreased in homosexual men with lymphadenopathy syndrome and AIDS. This decrease was most striking among the Leu-3a T-cell subset usually associated with helper/inducer function. The proportion of mucosal T cells reacting with Leu-2a (cytotoxic/suppressor phenotype) and lymphoid cells having the T305 antigen was significantly increased only in AIDS subjects. Both lymphadenopathy syndrome and AIDS subjects had a significant reversal of the normal mucosal helper/suppressor T-cell ratio. Mucosal helper/suppressor T-cell ratios and the distribution of mucosal mononuclear cells were normal in healthy homosexual men, although the same individuals had reversed helper/suppressor ratios among circulating T cells. Enteric infections in healthy homosexual men likely reflect sexual practices, and not a primary abnormality in intestinal mucosal immunity. In contrast, specific abnormalities in intestinal mucosal immunity may contribute to the persistent and opportunistic enteric infections that occur in AIDS.