Antiadhesion molecule therapy in inflammatory bowel disease.
Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. Some of these molecules such as MadCAM-1 are specific for the gastrointestinal endothelium, but in inflammatory bowel diseases most of the adhesion factors are up-regulated. Adhesion molecules also are involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. Recently, therapeutic compounds directed against trafficking of lymphocytes toward the gut mucosa have been designed, and are being developed as a novel class of drugs in the treatment of Crohn's disease (CD) and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Secondly, the changes in adhesion molecules and T-cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered in trials of biological therapies directed against adhesion molecules. Both antiintercellular adhesion molecule-1 (ICAM-1) and anti-alpha4 integrin strategies are being developed. Trials with the anti-ICAM-1 antisense oligonucleotide, ISIS-2302, in steroid-refractory CD have provided conflicting efficacy data. The anti-alpha4 integrin antibodies natalizumab (Antegren) and LDP-02 are in phase III and phase II trials, respectively. In the near future, these novel biological agents may prove valuable therapeutic tools in the management of refractory IBD.
Division of Gastroenterology, University Hospital Leuven, Belgium. gert.vanassche@uz.kuleuven.ac.be
Gert
G
van Assche
Paul
P
Rutgeerts
D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000628:therapy*; D007962:Leukocytes / Q000276:immunology / Q000502:physiology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D054735:Phosphorothioate Oligonucleotides; D013873:Thionucleotides / Q000494:pharmacology*
D000906:Antibodies; D015815:Cell Adhesion Molecules; D007166:Immunosuppressive Agents; D020319:Oligodeoxyribonucleotides, Antisense; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D013873:Thionucleotides; C089753:alicaforsen