Immunomodulatory effects of BCG in patients with recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis (RRP) is a rare manifestation of human papilloma virus (HPV) infection with extremely high relapse frequency, poorly understood immunopathogenesis, and lack of efficient treatment. Immunotherapy with Calgevax (BCG) in combination with CO2 surgery significantly improves the outcome of RRP. The present study investigates cellular immunity parameters in RRP patients, and the effects of 20-month Calgevax immunomodulation.

RRP patients (n = 15) subjected to combined therapy were tested before, 6, 12 and 20 months after the start of immunomodulation. Absolute counts and percentage of T, B and NK cells, effector T1 (CD8 + IFNgamma+); Th1 (CD4+IFNgamma+), Th17 (CD4+IL-17+) and regulatory (CD4+FoxP3+) T lymphocytes, as well as the in vitro stimulated secretion of IL-2, IL-4, IL-5, IL-10, IFNgamma and TNFalpha were determined by flow cytometry (FACSCanto II, BD).

While no significant changes were detected in the circulating T, B and NK subsets, RRP patients presented increased proportions of Tc1, Th1 and Th17 cells, and significantly reduced IFNgamma/IL-4 and IFNgamma/IL-10 ratios as compared to healthy controls (15% vs. 8%), (58 vs. 139 and 15 vs. 26, respectively), p < 0.05 for all comparisons. Increased Treg (9% vs. 4%), and decreased Th17 effectors share (0.7% vs. 0.4%) were observed at 12 months, while IFNgamma/IL-4 and IFNgamma/IL-10 ratios were restored after 20 months of Calgevax application.

Antiviral response closely depends on cytokine background. Calgevax potentiates Treg differentiation at the expense of proinflammatory Th17, limits hyperactivation and virus-specific T cell clones depletion, and restores a Th1 cytokine background.