Biologic therapies against inflammatory bowel disease: a dysregulated immune system and the cross talk with gastrointestinal mucosa hold the key

Abstract

Inflammatory bowel disease (IBD) is a GI tract disorder that manifests as either Ulcerative colitis (UC) or Crohn's disease (CD). The precise etiology of IBD is still not completely elucidated but research into the immunopathogenesis of IBD suggests that dysfunctions of the intestinal immune system and cross-reactivity against host epithelial cells hold the key. In both UC and CD, polarized immune activity towards Th1 (marked by upregulation of TNF-alpha, IL-1beta, IFN-gamma, IL-6) and Th17 (marked by IL-17 secretion) response is reported, while UC appears to exhibit an added contribution of Th2 responses (characterized by secretion of IL-4, IL-5, and IL-13). Additionally, other molecules involved in leukocyte trafficking (adhesion molecules), chemokines (IL-8) and tissue repair molecules (PGE(2) and its receptors) are also crucial. Emergence of these new paradigms in the pathogenesis of IBD led to a recent trend of novel biological therapies that specifically inhibit molecules involved in the inflammatory cascade. In this review, we critically discuss recent advances in the pathogenesis of IBD, drug therapies (conventional versus biologic), drug efficacy and pharmacokinetics (murine versus human versus chimeric) and their adverse effects. We also discuss emerging novel biological therapies targeting pro-inflammatory cytokines including TNF-alpha and IFN-gamma, cytokine receptors and those targeting adhesion molecules-anti-integrin and anti-ICAM antibodies. Other potential approaches using anti-inflammatory cytokines (IL-10), anti-sense oligonucleotide and probiotics are also discussed. Finally, we summarized few imperative targets whose more detailed exploration can help to pave the way for an efficacious IBD therapy.