Background: Proinflammatory cytokine IL-6 has an important role in regulating the balance between Th17 cells and regulatory T cells (Tregs). We studied the immunological impact of tocilizumab (TCZ), a monoclonal antibody to IL-6R, in kidney transplant recipients with subclinical graft inflammation.
Methods: Patients were prospectively enrolled in a randomized controlled clinical trial (2014-2018). PBMCs were collected at baseline, 3, 6, 9 and 12 months from stable kidney transplant recipients on tacrolimus/MMF/±prednisone with subclinical inflammation receiving TCZ (8 mg/kg IV q4 weeks X6) or no treatment (controls). PBMCs (N=28, 14 in each arm) were analyzed with respect to the Treg population, T cell activation, and cytokine (IFN-γ and IL-17) production after ex vivo PMA/Ionomycin stimulation.
Results: Mean frequency of CD4+CD25+Foxp3+ Tregs was similar in the 2 groups at enrollment (4.3% ± 0.83 vs 5.1% ± 0.63, p= 0.37). At 6 months, the Treg frequency had increased (+47%) in TCZ group and decreased (-29%) in control group (p=0.02). Percentage of naïve, central memory, effector memory, TEMRA remained stable. Patients in TCZ group showed a profound decline in IFN-γ (-34%) and IL-17 (-59%) production by CD4+ T cells when compared to control group at 6 months. IFN-γ/ IL17 double producing CD4+ T cells also showed a significant decrease in TCZ group (-63% vs.+40%, p=0.009).
Conclusion: Tocilizumab treatment for 6 months significantly increased circulating Tregs and suppressed inflammatory cytokines (IFN-γ and IL-17). The favorable change in Treg to Th17 and Th1 balance suggests that tocilizumab is a promising option for controlling allograft inflammation.
Joey Leung– Specialist, University of California San Francisco
Qizhi Tang– Professor, University of California San Francisco
Sindhu Chandran– Associate Clinical Professor, University of California San Francisco
Crystal Hu– University of California San Francisco
Flavio Vincenti– Clinical Professor, University of California San Francisco