IPSE, a parasite-derived host immunomodulatory protein, is a promising therapeutic for hemorrhagic cystitis

Abstract

1Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and 2 voiding dysfunction caused by hemorrhage and inflammation. Of currently available 3 therapies, prophylactic 2-mercaptoethanesulfonic acid (MESNA) has limited efficacy 4 and cannot treat pre-existing lesions. Therefore, novel therapeutic options to treat 5 hemorrhagic cystitis are needed. We previously reported that systemic administration of 6 the Schistosomiasis haematobium-derived protein H-IPSE H06 (IL-4-inducing principle 7 from Schistosoma mansoni eggs), is superior to 3 doses of MESNA in alleviating 8 hemorrhagic cystitis. Based on prior reports by others on S. mansoni IPSE and 9 additional work by our group, we reasoned that H-IPSE H06 mediates its effects on 1 0 hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, 1 1promoting urothelial proliferation, and translocating to the nucleus to modulate 1 2 expression of genes implicated in relieving bladder dysfunction. We speculated that 1 3 local bladder injection of the S. haematobium IPSE ortholog IPSE H03 , hereafter called H-1 4 IPSE H03 , might be more efficacious in preventing hemorrhagic cystitis compared to 1 5 systemic administration of IPSE H06 . We demonstrate herein that H-IPSE H03 is a 1 6promising therapeutic for the treatment of voiding dysfunction and bladder pain in 1 7 hemorrhagic cystitis. Namely, it attenuates ifosfamide-induced increases in bladder wet 1 8 weight in an IL-4-dependent fashion. H-IPSE H03 relieves hemorrhagic cystitis-associated 1 9 allodynia. Finally, H-IPSE H03 drives increased urothelial cell proliferation. This indicates 2 0that IPSE induces bladder healing mechanisms, which suggests that it may be a novel 2 1 non-opioid analgesic to treat bladder pain syndromes. 2 2 4 1 demonstrated fewer spontaneous pain behaviors and had a higher threshold for evoked 4 2pain responses. We speculated that direct injection of IPSE into the bladder wall would 4 3 have multiple advantages over intravenous injection, including avoidance of side effects 4 4 caused by systemic administration (although none have been identified to date), and 4 5 potentially decreased dosage to achieve a therapeutic effect. The aim of this work was 4 6