Ustekinumab Improves Psoriasis without Altering T Cell Cytokine Production, Differentiation, and T Cell Receptor Repertoire Diversity

<div><p>Ustekinumab is a fully human IgG1κ monoclonal antibody targeting interleukin (IL)-12/23 p40 subunit. The role of IL-12/23-mediated pathway in the mechanism of various inflammatory disorders especially psoriasis has been well recognized. Recently the long-term efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis has been evaluated in phase 2/3 clinical trials, and the results showed no significant risk for serious adverse effects, infections, or malignancies. Ustekinumab inhibits the function of the IL-12/23 p40 subunit, and therefore it is believed that inhibition of IL-12 p40 pathway decreases IFN-γ production. The major concern for the use of ustekinumab is the possibility of increased immunosuppression due to low IFN-γ production. However, the effects of ustekinumab on CD4⁺ T cell function have not been fully investigated so far. In this study, we explored changes in cytokine production by memory CD4⁺ T cells as well as in the differentiation of naïve T cells to helper T cell (Th) 1, Th2, or Th17 cells in psoriasis patients treated with ustekinumab. The effect of the treatment on T cell receptor repertoire diversity was also evaluated. The results showed that ustekinumab improves clinical manifestation in patients with psoriasis without affecting cytokine production in memory T cells, T cell maturation, or T cell receptor repertoire diversity. Although the number of patients is limited, the present study suggests that T cell immune response remains unaffected in psoriasis patients treated with ustekinumab.</p> </div

Differentiation of naïve CD4⁺ T cells to cytokine-producing mature cells (Th1/Th2/Th17).

<p>Representative flow cytometry data are shown. (A) The percentage of CD45RA⁻CD45RO⁺IFN-γ⁺ cells in the CD4⁺ T cell population (B) The percentage of CD45RA⁻CD45RO⁺IL-4⁺ cells in the CD4⁺ T cell population (C) The percentage of CD45RA⁻CD45RO⁺IL-17⁺ cells in the CD4⁺ T cell population. T cell maturation was not influenced by ustekinumab treatment.</p

Background of five patients and five healthy controls.

<p>The PASI score of the patients was high before ustekinumab therapy, and improved dramatically after the treatment. However, the PASI score of case 5 was increased at one month after the third therapy. WBC counts and the ratio of lymphocytes in all patients and controls were preserved during all the course of the study.</p

Cytokine production by memory CD4⁺ T cells and differentiation of naïve CD4⁺ T cells to mature cytokine-producing T cells in psoriasis patients during treatment with ustekinumab and in healthy controls.

<p>(A) Memory CD4⁺ T cells were stimulated with PMA and ionomycin. Distinct cytokine production by mature cells was observed, and the production of all cytokines was not suppressed in patients with psoriasis treated with ustekinumab. (B) Naïve CD4⁺ T cells were differentiated to mature T cells (Th1/Th2/Th17). Ustekinumab treatment did not change the percentage of cytokine-producing mature T cells compared to the control group.</p

T cell receptor repertoire diversity.

<p>TCR BV subfamilies were preserved during treatment with ustekinumab as compared with normal volunteer.</p

Naturally occurring regulatory T cells.

<p>The percentage of nTreg (FoxP3⁺CD127^lowCD25^highCD4⁺ T cells/CD4⁺ T cells) was similar among the seven volunteers. Flow cytometry data from four patients and three healthy controls are shown.</p