The Severity of Experimental Autoimmune Cystitis Can be Ameliorated by Anti-CXCL10 Ab Treatment

Abstract

BackgroundInterstitial cystitis (IC), more recently called painful bladder syndrome (PBS) is a complex disease associated with chronic bladder inflammation that primarily affects women. Its symptoms include frequent urinary urgency accompanied by discomfort or pain in the bladder and lower abdomen. In the United States, eight million people, mostly women, have IC/PBS. New evidence that autoimmune mechanisms are important in the pathogenesis of IC/PBS triggered interest.Methodology/Principal FindingsSWXJ mice immunized with a homogenate of similar mice’s urinary bladders develop an autoimmune phenotype comparable to clinical IC with functional and histological alterations confined to the urinary bladder. Using the murine model of experimental autoimmune cystitis (EAC), we found that serum levels of CXCR3 ligand and local T helper type 1 (Th1) cytokine are elevated. Also, IFN-γ-inducible protein10 (CXCL10) blockade attenuated overall cystitis severity scores; reversed the development of IC; decreased local production of CXCR3 and its ligands, IFN-γ, and tumor necrosis factor-α (TNF-α); and lowered systemic levels of CXCR3 ligands. Urinary bladder CD4+ T cells, mast cells, and neutrophils infiltrates were reduced following anti-CXCL10 antibody (Ab) treatment of mice. Anti-CXCL10 Ab treatment also reversed the upregulated level of CXCR3 ligand mRNA at urinary bladder sites. The decreased number and percentage of systemic CD4+ T cells in EAC mice returned to normal after anti-CXCL10 Ab treatment.Conclusion/SignificanceTaken together, our findings provide important new information about the mechanisms underlying EAC pathogenesis, which has symptoms similar to those of IC/PBS. CXCL10 has the potential for use in developing new therapy for IC/PBS.

Increased CXCR3 Expression of Infiltrating Plasma Cells in Hunner Type Interstitial Cystitis

“…Due to the crucial role of the CXCR3 pathway, it has attracted attention as a therapeutic target with potential clinical application in various chronic inflammatory disorders 25 . In another autoimmune murine cystitis model using mice comparable to human IC, anti-CXCL10 antibody reduced the up-regulated level of CXCR3 and its ligands, and ameliorated the severity of cystitis 26 . Immunosuppressant therapies such as a steroidal, molecular-targeted therapy, or anti-chemokine therapy are potentially effective for HIC patients.…”

Serum Cytokine Profiling in Cats with Acute Idiopathic Cystitis

“…However, urine IL‐12 was increased in human patients with overactive bladder syndrome . Increased RNA expression of IL‐12 (p40) in bladder tissues also was identified in mice with experimental autoimmune cystitis . Interestingly, human patients receiving intravesicular instillation of IL‐12 for treatment of superficial bladder transitional cell carcinoma had adverse effects that were similar to IC/PBS such as pain, dysuria, or increased frequency .…”

Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives

“…During the early stage of EAC development, investigators used homogenized bladder tissues for immunization to induce EAC in rodents. This EAC type has been developed in Balb/cAN, 109,110 SWXJ(H‐2 q.s ) 111,112 and C57BL/6 mice, 113,114 as well as in Lewis rats 115,116 . In these models, bladders histologically showed thickened lamina propria, perivascular lymphocytic infiltration, increased urothelial permeability, increased vascularity and glomerulations, and detrusor MC accumulation.…”

“…The successful induction of cystitis by adoptive transfer showed the capacity of primed immune cells to recognize and respond to normal bladder tissues. These EAC models have been applied in therapeutic studies, including the use of angiotensin II type 1 receptor antagonist, 110 anti‐CXCL10 antibody 112 and NK1R antagonist 114 . All treatments showed favorable effects on reducing cystitis and associated symptoms in the EAC models.…”