Local induction of bladder Th1 responses to combat urinary tract infections

Abstract

Given the high frequency of urinary tract infections (UTIs) and their recurrence, there is keen interest in developing effective UTI vaccines. Currently, most vaccine studies, including those in humans, involve parenteral vaccination aimed at evoking and sustaining elevated levels of systemic antibody directed at the uropathogens. In view of recent reports of aberrant Th2-biased bladder immune responses to infection, we hypothesized that immunizing mice intravesically with antigens from uropathogenic Escherichia coli (UPEC) combined with a Th1-skewing adjuvant could correct this defect and promote protection against UTIs. Here we report that compared with mice immunized subcutaneously with this vaccine combination, intravesically immunized mice were markedly more protected from UTIs because of their distinctive ability to recruit Th1 cells into the bladder. This mode of vaccination was effective even in mice that experienced multiple UTIs and displayed pronounced aberrant bladder immune responses. Thus, intravesical vaccination with one or more UPEC antigens to induce bladder Th1 responses represents a superior strategy to combat UTIs, especially in UTI-prone subjects.

Multimodal Single‐Cell Analyses Outline the Immune Microenvironment and Therapeutic Effectors of Interstitial Cystitis/Bladder Pain Syndrome

“…The immune response of T cells was heavily skewed toward Th2 immune responses during other diseases. [ 14 ] However, the role of T cells in the IC/BPS was largely unknown. We first explored the intrinsic structure and functional subtypes of the T/NK cell populations (Figure S3A , Supporting Information).…”

Bladder-draining lymph nodes support germinal centre B cell responses during urinary tract infection in mice

“…Insufficient antigen uptake from the bladder to nearby lymph nodes would also affect antigen presentation and subsequent activation of adaptive immune cells. As increased bladder damage has been reported to lead to a stronger response (30,37), we reasoned that administering a second UPEC inoculation, as performed in previous studies (15,38,39), might enhance antigen uptake and presentation. The modest GC B cell responses could theoretically also be the result of adaptive immune suppression via cytokines, which is a widely cited reason for a lack of a strong adaptive response in the bladder (8,(40)(41)(42)(43).…”

Immunomodulation therapy offers new molecular strategies to treat UTI

“…These observations are supported by the results of a study that showed that bladder infection triggers a robust T H 2 cell response, causing re-epithelialization with a limited capacity to clear infection 255 . Furthermore, immunization with UPEC antigens combined with the T H 1-skewing adjuvant CpG was observed to protect mice from developing both single-episode and recurrent UTIs compared with untreated mice 256 . Intravesical vaccination provided a substantially better response than subcutaneous vaccination and was accompanied by an increase in local T H 1 cells.…”