RDP58 inhibits T cell-mediated bladder inflammation in an autoimmune cystitis model

Abstract

Interstitial cystitis (IC) is a chronic inflammatory condition of the urinary bladder with a strong autoimmune component. Currently, the major challenge in IC treatment is the development of effective therapies. RDP58 is a novel D-amino acid decapeptide with potent immunosuppressive activity. In this study, we investigated whether RDP58 was effective as an intravesical agent for treating bladder autoimmune inflammation in a transgenic mouse model (URO-OVA mice). URO-OVA mice were adoptively transferred with syngeneic activated splenocytes of OT-I mice transgenic for the OVA-specific CD8 + TCR for cystitis induction and treated intravesically with RDP58 at days 0 and 3. Compared with controls, the RDP58-treated bladders showed markedly reduced histopathology and expressions of mRNAs and proteins of TNF-α, NGF and substance P. To determine whether the inhibition of bladder inflammation by RDP58 was due to the interference with effector T cells, we treated the cells with RDP58 in vitro. Cells treated with RDP58 showed reduced production of TNF-α and IFN-γ as well as apoptotic death. Collectively, these results indicate that RDP58 is effective on treating T cell-mediated experimental autoimmune cystitis and may serve as a useful intravesical agent for the treatment of autoimmune-associated bladder inflammation such as IC.

Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study

“…URO-OVA mice developed bladder inflammation at day 7 after cystitis induction as described previously [25,33,34]. The inflamed bladders exhibited prominent cellular infiltration, edema, and hyperemia (Fig 1A, top panel; Table 1, score: 3+) as well as increased mast cell counts (Fig 1B; S3 Fig).…”

“…We previously demonstrated that the URO-OVA model was responsive to intravesical treatment with anti-inflammatory agents such as dimethyl sulfoxide [33] and RDP58 [34]. We observed that both agents inhibited bladder inflammation through suppressing T cell activity and/or viability in the animal model.…”

Uroplakin Peptide-Specific Autoimmunity Initiates Interstitial Cystitis/Painful Bladder Syndrome in Mice

“…URO-OVA/OT-I mice, derived by crossing URO-OVA mice with transgenic mice that express an OVA-specific CD8+ T cell receptor (OT-I mice), spontaneously develop autoimmune cystitis [43]. However, OVA is not an endogenous antigen of bladder, and the bladder urodynamic changes and pain correlates of the IC/PBS phenotype have not been characterized in those transgenic models [43], [44]. A spontaneous model of IC/PBS was described in cats [48], however this has not been studied extensively in the scientific community due its unknown etiology and the high costs of maintaining and handling cats, which require involvement of a veterinarian [15].…”

TLRs, future potential therapeutic targets for RA

“…MLN-0415, an IKKβ inhibitor developed by Millennium to target the NF-κB pathway, was discontinued at phase I, because of its adverse effects. RDP-58, a decapeptide that targets IRAK complex formation, is in phase II clinical trials for Crohn’s disease and ulcerative colitis [139, 140]. …”