P053 Ustekinumab decreases circulating Th1, Th17, and MAIT cells in Crohn’s disease

Abstract

Abstract Background Ustekinumab is a humanized antibody to a p40 subunit shared by the cytokines IL-12 and IL-23, which has been approved for the treatment of Crohn’s disease. While it is presumed to derive clinical efficacy by blocking the ability of these cytokines to stimulate specific T cell subsets, its actual effect upon the human immune system has not been well-described. Methods Peripheral blood mononuclear cells (PBMC) were cryopreserved from 20 Crohn’s patients before and during ustekinumab therapy. Thawed PBMC were then analyzed by flow cytometry for cell surface markers and, after overnight stimulation, intracellular cytokines. Success (n=9) or failure (n=11) of ustekinumab therapy was at the discretion of the treating physician, blinded to flow cytometry data. Results A significant decrease in IL-17A-producing Th17 (p=0.001) and CD161+/TCRVα7.2+ MAIT (p=0.005) cells was seen overall in response to ustekinumab. While no significant effect was seen overall in IFN-γ -producing CD4 (Th1) and CD8 T cells, there was a dichotomy between treatment responders and non-responders, with Th1 cells decreasing in responders (p=0.004) and increasing in non-responders (p=0.03) after ustekinumab initiation. IFN-γ+ CD8 T cells likewise increased in non-responders (p=0.01), although their decrease in responders was less significant (p=0.12). While there was no difference in the pre-treatment frequency of Th17’s or IFN-γ+ T cells between responders and non-responders, MAIT cells were significantly more common in the blood of responders (p=0.03). Conclusion While the IL-23-blocking effect of ustekinumab on Th17 and MAIT cells was seen across all recipients, its IL-12-blocking effect on IFN-γ-producing T cells was restricted to treatment-responsive patients, suggesting that its mechanism of action may differ from newer, IL-23-specific agents. Whether the frequency of MAIT cells before or a rise in IFN-γ-producing T cells during therapy can predict treatment failure warrants additional study.