Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remains a significant clinical challenge due to its unclear etiology and lack of effective treatment. This study investigates the therapeutic potential of specific TRPM8-II antigen determinant clusters, hereafter referred to as “T2”, administered orally to induce immune tolerance in a mouse model of CP/CPPS.

Ninety male C57BL/6 mice were divided into nine groups: Naïve, Model, T2 (0.05, 0.5, 5, 15, 30, 50 mg/kg), and Positive. The oral tolerance groups received T2 peptide segments and serum trypsin inhibitor (STI) on days -10, -8, -6, -4, and -2. All groups except Naïve received prostate homogenate injections on days 0 and 14 to induce CP/CPPS. From days 30 to 37, the Positive group was treated with Ningmitai at 0.4 g/kg. On day 40, mice were euthanized for pathological scoring via HE staining. Pain threshold, urination frequency, and plasma levels of TNF-α and CRP were assessed.

HE staining showed extensive inflammatory cell infiltration and severe congestion in the Model and most T2 groups, except for the T2-30 mg/kg group, which showed significant improvement. ELISA indicated significant differences in cytokine levels between the T2-30 mg/kg group and both Naïve and Model groups. The T2-30 mg/kg group also showed significant increases in pelvic pain threshold and reductions in urinary frequency.

Oral administration of T2 peptide at 30 mg/kg effectively induces immune tolerance, alleviating CP/CPPS-related symptoms and pathological changes in mice. These findings suggest a potential therapeutic strategy for inducing immune tolerance in the clinical treatment of CP/CPPS.