Chronic pelvic pain is the hallmark of patients with Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), a category of prostatitis that is a significant source of morbidity in American men. A microbial etiology for CP/CPPS has long been postulated but a cause and effect relationship has been difficult to demonstrate due to the chronic nature of the syndrome, the often-delayed diagnosis, and the confounding presence of bacteria in prostates of healthy men. We recently identified a clinical E. coli strain named CP1 from a patient with chronic pelvic pain that was capable of faithfully replicating the chronic pain state in a mouse model of bacterial prostatitis. The CP1 strain infected the prostate of NOD and B6 mice, resulting in an inflammatory response in both strains but inducing the chronic pain state only in NOD mice. Chronic pain persisted even in the absence of detectable bacterial colonization. Our preliminary studies show that the pain is transferable using CD4+ T cells and is associated with a predominant Th1/Th17 immune response. In contrast, CP1 infection in the non-pain permissible B6 mice induced CD4 T cells with an IL-4 response and elevated levels of FoxP3+ CD25+ regulatory T cells. Infection with NU14, a non-pain inducing E. coli strain also resulted in elevated levels of FoxP3+ CD25+ regulatory T cells in both the NOD and B6 mice, suggesting an association between the presence of regulatory T cells and absence of pelvic pain. These studies lead us to hypothesize that bacterial-induced chronic pelvic pain is mediated by IFN-? and IL-17 secreting CD4+ T cells and suppressed by regulatory T cells in the prostate. We will address our hypothesis using the following specific aims: 1. identifying the functional role of Th1/Th17 T cells in chronic pelvic pain. 2. Defining the mechanism of T cell trafficking to the injured prostate. 3. Identifying strategies to promote self-tolerance in the prostate. These studies are expected to result in an understanding of specific mechanisms of chronic pelvic pain in CPPS as well as identification of novel methodologies to effect pain reduction and disease resolution in CPPS patients.

Public Health Relevance

Chronic pelvic pain is the hallmark of patients with chronic pelvic pain syndrome (CPPS), a category of prostatitis that is a significant source of morbidity in American men. The cause of CPPS is unknown and there is an urgent need for understanding the disease mechanism to drive targeted therapy. This project will attempt to define the mechanism behind CPPS and test novel methods to achieve disease resolution.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK094898-01A1
Application #
8438510
Study Section
Special Emphasis Panel (ZRG1-DKUS-L (03))
Program Officer
Kirkali, Ziya
Project Start
2013-04-01
Project End
2017-01-31
Budget Start
2013-04-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$336,038
Indirect Cost
$118,538
Name
Northwestern University at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Wong, Larry; Done, Joseph D; Schaeffer, Anthony J et al. (2015) Experimental autoimmune prostatitis induces microglial activation in the spinal cord. Prostate 75:50-9
Roman, Kenny; Done, Joseph D; Schaeffer, Anthony J et al. (2014) Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome. Pain 155:1328-38