GM-CSF Transgene-Based Adjuvant Allows the Establishment of Protective Mucosal Immunity Following Vaccination with Inactivated Chlamydia trachomatis

Abstract

Cellular and humoral immune responses induced following murine Chlamydia trachomatis infection confer almost sterile protection against homologous reinfection. On the other hand, immunization with inactivated organism induces little protective immunity in this model system. The underlying mechanism(s) that determines such divergent outcome remains unclear, but elucidating the mechanism will probably be important for chlamydial vaccine development. One of the distinct differences between the two forms of immunization is that chlamydia replication in epithelial cells causes the secretion of a variety of proinflammatory cytokines and chemokines, such as GM-CSF, that may mobilize and mature dendritic cells and thereby enhance the induction of protective immunity. Using a murine model of C. trachomatis mouse pneumonitis lung infection and intrapulmonary adenoviral GM-CSF transfection, we demonstrate that the expression of GM-CSF in the airway compartment significantly enhanced systemic Th1 cellular and local IgA immune responses following immunization with inactivated organisms. Importantly, immunized mice had significantly reduced growth of chlamydia and exhibited less severe pulmonary inflammation following challenge infection. The site of GM-CSF transfection proved important, since mice immunized with inactivated organisms after GM-CSF gene transfer by the i.p. route exhibited little protection against pulmonary challenge, although i.p. immunization generated significant levels of systemic Th1 immune responses. The obvious difference between i.p. and intrapulmonary immunization was the absence of lung IgA responses following i.p. vaccination. In aggregate, the findings demonstrate that the local cytokine environment is critical to the induction of protective immunity following chlamydial vaccination and that GM-CSF may be a useful adjuvant for a chlamydial vaccine.

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

“…delivery of a rBCG strain secreting detectable levels of GM-CSF in situ augments local immunogenicity and demonstrates significant protection against M. tuberculosis infection. GM-CSF is critical to the differentiation of myeloid cells such as DC and macrophages from haematopoietic stem cell precursors, yet in the lung it has been shown to possess unique functions in the regulation of inflammation and host defense against infectious pathogens, as well as pulmonary surfactant and alveolar cell homeostasis [23][24][25][26]. The pattern of GM-CSF production within the lung, with GM-CSF concentrations diminishing over time (Fig.…”

Immunoproteomic Discovery of Novel T Cell Antigens from the Obligate Intracellular PathogenChlamydia

“…muridarum strain Nigg was grown in HeLa 229 cells in Eagle's minimal essential medium (Invitrogen Life Technologies) supplemented with 10% FCS. Elementary bodies (EBs) were purified from HeLa cells on discontinuous density gradients of Renografin-76 (Squibb Canada) as described previously (13).…”

“…Su et al (12) previously demonstrated that DCs pulsed ex vivo with Chlamydia protected mice against chlamydial infection. Our previous work has demonstrated that expression of GM-CSF (a cytokine known to mobilize DCs) in the mouse airway significantly enhanced systemic Th1 cellular immune responses following mucosal immunization with inactivated Chlamydia muridarum (13). Subsequent in vitro observations demonstrated that DCs exposed to live or to UV-irradiated C. muridarum develop distinct phenotypes, such that DCs exposed to live Chlamydia become mature and effectively present Ag to Chlamydia-specific CD4 T cells, while DCs exposed to UV-irradiated Chlamydia were less immunologically mature (14).…”

Immunotherapeutic effects of recombinant adenovirus encoding granulocyte–macrophage colony-stimulating factor in experimental pulmonary tuberculosis

“…Moreover, it has been shown recently that recombinant BCG expressing GM-CSF is highly efficient in preventing TB in a mouse model [41], inducing a similar cytokine response that we observed when AdGM-CSF was administered 1 day before infection. In fact, administration of GM-CSF, or inducing its expression, has been useful in the treatment against other pulmonary infections such as aspergillosis [43], Chlamydia trachomatis [44] and pneumococcal pneumonia [45]. Moreover, the delivery of recombinant human GM-CSF by inhalation was shown to be beneficial in the treatment of alveolar proteinosis and it was well tolerated in healthy subjects [46].…”