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.