Introduction Anti-tumour necrosis factor (TNF) α antibody treatment and corticosteroid therapy represent central strategies in the management of Crohn's disease. Yet, over 30% of patients fail to respond. Understanding the mechanism of effect for each therapy is complicated by disease heterogeneity, and the complexities of effector and regulatory immune cell responses. We characterised the biological and immunological effects of infliximab and hydrocortisone therapy in a genetically identical murine model of experimental colitis.
Methods Mice (AKR) susceptible to chronic Trichuris muris-induced colitis were infected with 300 T muris eggs. A single 5 mg/kg dose of Infliximab, or daily hydrocortisone treatment (2 mg/kg, QDS) were administered intraperitoneally once chronic colitis had established (from day 35 post-infection, p.i.). Systemic, mesenteric lymph node (MLN) and colonic effects were analysed at day 45 p.i. MLN cell cytokine bead-array and colonic gene expression (RT-qPCR) analysis were performed. Colonic histopathology, tissue Foxp3+ and macrophage recruitment were determined. Treated groups were compared to naïve and untreated-infected AKR (n=5 per group).
Results Neither treatment altered worm expulsion. Anti–TNFα Ab and corticosteroid therapy preserved colonic length, compared to untreated disease. Colonic inflammation was less severe with steroid treatment (p=0.005) and infliximab (p=0.07). An increase in MLN TH2 cytokines was suggested with both treatments. Reduced colonic TNFα, IL-1β, IFNγ and IL-12p40, and increased IL-13 expression were observed following Infliximab. Down-regulated TH1 cytokines, elevated TH2 cytokines (IL-4, IL-5, IL-13), and up-regulated colonic IL-10 expression were detected following corticosteroid treatment. Colonic Foxp3+ cell numbers increased with disease but were unaltered by either treatment. A significant reduction in tissue F4/80+ macrophages was observed with infliximab treatment alone.
Conclusion Anti–TNFα Ab and corticosteroid therapy suppress TH1-driven experimental colitis. Up-regulated transcription of TH2 and regulatory (IL-10, TGFb, Foxp3) pathway molecules was seen with corticosteroid treatment. This was not accompanied by an increased influx of Foxp3+ T-cell, suggestive that corticosteroids may alter regulatory-cell function more significantly than recruitment, in the reduction of pathology and disease activity. Anti–TNFα Ab treatment reduced colonic pro-inflammatory macrophage recruitment. With differing modalities of immunosuppression demonstrated, this model may increase understanding of why either mode of therapy can induce benefit in man even if the other has failed.
Competing interests None declared.