Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

Abstract

Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality.

Fig. 1.

Kinetics of circulating and antigen-stimulated immune responses during the course of antituberculous therapy in the presence vs. the absence of adjunctive vitamin D. Vitamin D accelerated sputum smear conversion in patients fulfilling per-protocol analysis criteria (A). Monocyte counts fell more quickly (B) and lymphocyte counts rose more quickly (C) among patients in the intervention arm of the trial. Vitamin D also accelerated treatment-induced decreases in ESR (D), circulating concentrations of CXCL9 (E), CXCL10 (F), MMP-9 (G), and LL-37 (H) and rCFP-10–stimulated supernatant concentrations of IL-1RA (I), IL-6 (J), IL-12p40/p70 (K), and TNF (L). Means ± SEM at 0, 2, 4, 6, and 8 wk of treatment are presented. Dotted lines, placebo arm; solid lines, vitamin D arm.

Fig. 2.

Immunomodulatory actions of vitamin D are not restricted to individuals with the tt genotype of the TaqI vitamin D receptor polymorphism. Vitamin D supplementation accelerates sputum culture conversion in patients with the tt genotype of the TaqI vitamin D receptor polymorphism (A), but not in those with the Tt (B) or TT (C) genotypes (P_interaction = 0.03). Vitamin D, solid line; placebo, dotted line. In contrast, the immunomodulatory actions of vitamin D are not restricted to those with the tt genotype of the TaqI polymorphism. In patients with the TT genotype, vitamin D supplementation significantly reduced 8-wk circulating concentrations of CRP (D), CXCL9 (E), CXCL10 (F), NGAL (G), and LL-37 (H); in patients with the Tt genotype, statistically significant reductions in 8-wk serum concentrations of CXCL9 (E) and IL-10 (I) were also seen in patients randomized to vitamin D (Vit D) vs. Placebo (Plac). Data for patients with the tt genotype are not presented because of small numbers entering per-protocol analysis. Line at median; TT placebo (□) n = 23, TT vitamin D (■) n = 22, Tt placebo (○) n = 21, Tt vitamin D (●) n = 19. LOD, limit of detection.