Therapeutic exploitation of IPSE, a urogenital parasite‐derived host modulatory protein, for chemotherapy‐induced hemorrhagic cystitis

Abstract

Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests that IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma hematobium homolog of IL-4-inducing principle from Schistosoma mansoni eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL-4 secretion by these cells. IPSE is also an “infiltrin,” translocating into the host nucleus to modulate gene transcription. Mice were administered IL-4, H-IPSE protein or its nuclear localization sequence (NLS) mutant, with or without neutralizing anti-IL-4 antibody, or 2-mercaptoethane sulfonate sodium (MESNA; a drug used to prevent IHC), followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency, and bladdergene expression analysis were assessed. Pain behaviors were interpreted in a blinded fashion. One dose of H-IPSE was superior to MESNA and IL-4 in suppressing bladder hemorrhage in an IL-4-dependent fashion and comparable with MESNA in dampening ifosfamide-triggered pain behaviors in an NLS-dependent manner. H-IPSE also accelerated urothelial repair following IHC. Our work represents the first therapeutic exploitation of a uropathogen-derived host modulatory molecule in a clinically relevant bladder disease model and indicates that IPSE may be an alternative to MESNA for mitigating CHC.—Mbanefo, E. C., Le, L., Pennington, L. F., Odegaard, J. I., Jardetzky, T. S., Alouffi, A., Falcone, F. H., Hsieh, M. H. Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis.

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

“…We previously demonstrated that M-IPSE activates basophils in vitro through NF-AT (23). This pathway is implicated in basophil and mast cell expression of IL-4, which we have observed in vivo in mice administered H-IPSE H06 (17). Moreover, we have also noted that ifosfamide-challenged mice given H-IPSE H06 are protected from several pathogenic aspects of hemorrhagic cystitis in an IL-4-dependent fashion (17).…”

“…This pathway is implicated in basophil and mast cell expression of IL-4, which we have observed in vivo in mice administered H-IPSE H06 (17). Moreover, we have also noted that ifosfamide-challenged mice given H-IPSE H06 are protected from several pathogenic aspects of hemorrhagic cystitis in an IL-4-dependent fashion (17). Thus, we sought to demonstrate that H-IPSE H03 and H-IPSE H06 , which are both S. haematobium orthologs of M-IPSE, also stimulate IL-4-associated reporter gene expression in vitro .…”

“…Given the beneficial effects of H-IPSE H03 on ifosfamide-induced bladder wet weight increases and pain, as well as prior data indicating a direct effect of H-IPSE H03 on urothelial cells (17), we assessed the effect of H-IPSE H03 on urothelial cell IPSE H03 significantly increased cell proliferation over two successive daughter cell proliferation by co-incubating H-IPSE H03 with the MB49 (mouse urothelial) cell line. H-IPSE H03 generations compared to controls (Figure 5A; *p<0.05, **p<0.01, ***p<0.0001; n=8).…”

“…One alternative may be the interleukin-4 inducing principle from Schistosoma mansoni eggs (IPSE), the most abundant protein secreted by S. mansoni eggs. IPSE attenuates inflammation via multiple mechanisms, including binding immunoglobulins to stimulate IL-4 release, sequestering chemokines, and translocating to the nucleus to modulate transcription (17, 19). We have previously reported that similar to the S. mansoni ortholog of IPSE, M-IPSE, several S. haematobium orthologs, referred hereafter as H-IPSE, bind to IgE on mast cells and basophils and upregulate the expression of IL-4 (19).…”

“…Initial animal experiments with H-IPSE focused on the effect of systemic administration of H-IPSE H06 by tail vein injection (17). Tail vein injection of H-IPSE H06 attenuates ifosfamide-induced bladder hemorrhage in an IL-4 and NLS-dependent manner.…”