Helper T cell bias following tuberculosis chemotherapy identifies opportunities for therapeutic vaccination to prevent relapse

Abstract

Therapeutic vaccines have promise as adjunctive treatment for tuberculosis (TB) or as preventives against TB relapse. An important development challenge is the limited understanding of T helper (Th) cell roles during these stages of disease. A murine model of TB relapse was used to identify changes in Th populations and cytokine microenvironment. Active TB promoted expansion of Th1, Th2, Th17, and Th22 cells and cytokines in the lung. Following drug therapy, pulmonary Th17 and Th22 cells contracted, Th1 cells remained elevated, while Th cells producing IL-4 or IL-10 expanded. At relapse, Th22 cells failed to re-expand in the lung despite a moderate re-expansion of Th1 and Th17 cells and an increase in Th cytokine polyfunctionality. The dynamics of Th populations further differed by tissue compartment and disease presentation. These outcomes identify immune bias by Th subpopulations during TB relapse as candidate mechanisms for pathogenesis and targets for therapeutic vaccination.

Therapeutic Modulation of Arginase with nor-NOHA Alters Immune Responses in Experimental Mouse Models of Pulmonary Tuberculosis including in the Setting of Human Immunodeficiency Virus (HIV) Co-Infection

“…To date, translational studies to evaluate the therapeutic potential of arginase inhibition in animal models of experimental TB or TB/HIV co-infection are lacking. Therefore, we evaluated in vitro and in vivo outcomes of arginase inhibition using nor-NOHA in a murine Mϕ cell line and both BALB/cJ and human immune system (HIS) mouse models that we developed to understand the pathogenesis of Mtb and coinfection of HIV/Mtb [ 36 , 37 , 38 , 39 ]. These outcomes suggest that arginase inhibition approaches may hold promise to improve TB disease outcomes as host-directed therapies accompanying antibiotic chemotherapy but require further optimization through improved bioavailability or pathway complementation.…”