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Project

Effect of BCG in Endogenous and Exogenous Antigen-Induced T Helper Cell Polarized Urinary Bladder Inflammation Models

Funder: Congressionally Directed Medical Research Programs

Funding period
USD 973 K
Funding amount
Abstract
TECHNICAL ABSTRACT

Background: Interstitial cystitis (IC) is a chronic irritable condition of the urinary bladder with an unknown etiology. However, there is evidence suggesting that an antigen-induced inflammatory process is involved in the pathogenesis of this disease either via an exogenous (environmental) or endogenous (autoimmune) mechanism. One of the most surprising and intriguing new clinical developments in IC is the apparent significant and durable response of IC to instillation of the live BCG (bacillus Calmette-Guérin) vaccine into the bladder, a treatment hitherto reserved for bladder cancer. However, since the immune mechanisms for both BCG action and IC pathogenesis are unclear, BCG regimens proposed to date are largely empirical and lack a proper immunological basis for predicting and/or optimizing response to therapy.



Objective/Hypothesis: The objective of this study is to create antigen-induced T helper (Th) polarized bladder inflammation models to mimic the postulated pathogenesis of IC and investigate the potential effect of the BCG vaccine on treating the disease in these models. In accordance with previously reported characteristics of bladder inflammation in IC, we hypothesize that the bladder inflammation process in IC is associated with T helper type 2 (Th2) cytokine polarization. We propose that BCG works in IC by causing a switch from a default Th2 state to the antagonistic Th1 state. Our long-term goal is to develop effective treatment strategies to combat IC.



Specific Aims: Three specific aims will be undertaken. (1) To create an exogenous antigen-induced bladder inflammation model to determine the role of systemic Th1 and Th2 immune polarization in the development of bladder inflammation. (2) To establish a bladder autoimmune disease model by creating a novel transgenic (Tg) mouse strain that expresses OVA as a "self" antigen via promoter-specific production by the urothelium and to determine the role of the Th immune polarization in the development of this disease. (3) To assess the therapeutic effect of BCG in antigen-induced bladder inflammation.



Study Design: Two types of antigen-induced bladder inflammation models (foreign and "self") will be established and characterized to mimic the putative pathogenesis of IC. To create exogenous antigen-induced cystitis model, Th cells will be isolated from OVA-T cell receptor (TCR) Tg mice (OT-II mice), differentiated into Th1 or Th2 subsets, and adoptively transferred into syngeneic mice. Cystitis will be induced in the recipient mice by instilling OVA directly into the bladder. To create endogenous antigen-induced cystitis (autoimmune disease), a novel urothelium-specific OVA-expressing Tg mouse strain will be genetically generated using an urothelium-specific promoter (uroplakin II promoter). An autoimmune form of cystitis will be developed in these Tg mice by adoptive transfer of polarized OT-II Th cells. BCG will be evaluated for its effect on treating Th2 polarized cystitis (the hypothesized type responsible for IC) in both exogenous and endogenous antigen-induced cystitis models.



Relevance: This study will establish the antigen-induced bladder inflammation models, characterize pathological and immunological properties for both Th1 and Th2 type cystitis, and shed light on BCG's effect on treating Th2 polarized cystitis. Thus, this project will facilitate the understanding of IC pathogenesis and aid in the future development of prevention and treatment strategies for IC and other painful bladder conditions.
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • RCDC

    Interstitial Cystitis

  • RCDC

    Biotechnology

  • RCDC

    Autoimmune Disease

  • RCDC

    Immunization

  • RCDC

    Infectious Diseases

  • RCDC

    Urologic Diseases

  • RCDC

    Vaccine Related

  • HRCS HC

    Inflammatory and Immune System

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science