Enhancement of CD4+ T Cell Function as a Strategy for Improving Antibiotic Therapy Efficacy in Tuberculosis: Does It Work?

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains a major public health problem worldwide due in part to the lack of an effective vaccine and to the lengthy course of antibiotic treatment required for successful cure. Combined immuno/chemotherapeutic intervention represents a major strategy for developing more effective therapies against this important pathogen. Because of the major role of CD4+ T cells in containing Mtb infection, augmentation of bacterial specific CD4+ T cell responses has been considered as an approach in achieving this aim. Here we present new data from our own research aimed at determining whether boosting CD4+ T cell responses can promote antibiotic clearance. In these studies, we first characterized the impact of antibiotic treatment of infected mice on Th1 responses to major Mtb antigens and then performed experiments aimed at sustaining CD4+ T cell responsiveness during antibiotic treatment. These included IL-12 infusion, immunization with ESAT-6 and Ag85B immunodominant peptides and adoptive transfer of Th1-polarized CD4+ T cells specific for ESAT-6 or Ag85B during the initial month of chemotherapy. These approaches failed to enhance antibiotic clearance of Mtb, indicating that boosting Th1 responses to immunogenic Mtb antigens highly expressed by actively dividing bacteria is not an effective strategy to be used in the initial phase of antibiotic treatment, perhaps because replicating organisms are the first to be eliminated by the drugs. These results are discussed in the context of previously published findings addressing this concept along with possible alternate approaches for harnessing Th1 immunity as an adjunct to chemotherapy.

Therapeutic Effect of Subunit Vaccine AEC/BC02 on Mycobacterium tuberculosis Post-Chemotherapy Relapse Using a Latent Infection Murine Model

“…One possible hypothesis is the reduction of ESAT6/CFP10 expression by bacteria in response to chemotherapy-induced stress. Studies have shown that direct injection of Th1-polarized ESAT-6-specific CD4 + T cell clones cannot reduce bacterial loads in chemotherapeutic Mtb -infected mice [ 38 ]. The level of MHC-II associated ESAT-6 peptide on the surface of infected cells is reduced, thereby limiting the response of these lymphocytes.…”

Vaccination inducing durable and robust antigen-specific Th1/Th17 immune responses contributes to prophylactic protection against Mycobacterium avium infection but is ineffective as an adjunct to antibiotic treatment in chronic disease

“…Given that similar results were observed in our study, approaches to boosting Th1/Th17 responses during the initial phase of antibiotic treatment against antigens that are highly expressed in actively dividing bacteria can feasibly be reconsidered. This may be attributed to the fact that the antibiotic-derived elimination of replicating bacteria might precede the targeting of Th1/Th17 responses [ 81 ]. In fact, paradoxical responses (PRs) can occasionally develop during mycobacterial infection, leading to acute inflammation and increased bacterial burden and thus to a need for further surgical treatment [ 82–86 ].…”

“…More recently, Costa et al . demonstrated that enhanced antibiotic clearance of Mtb was not achieved via either the adoptive transfer of ESAT-6- or Ag85B-specific Th1-polarized CD4 + T cells (C7 and P25 cells, respectively) or the intravenous injection of the ESAT-6 1-20 or Ag85B 280-294 peptide during the initial month of chemotherapy for the purpose of boosting Th1 responses [ 81 ]. Given that similar results were observed in our study, approaches to boosting Th1/Th17 responses during the initial phase of antibiotic treatment against antigens that are highly expressed in actively dividing bacteria can feasibly be reconsidered.…”