XI International Meeting on Paracoccidioidomycosis

XI International Meeting on Paracoccidioidomycosis

Resume:56-1

Investigação

56-1	Viability of a therapeutic vaccine in Paracoccidioidomycosis. An update
Authors:	Carlos P. Taborda (USP - Departament of Microbiology - ICB/USPIMT/LIM-53-USP - Laboratory of Medical Mycology IMT/SP - LIM 53) ; Luiz R. Travassos (UNIFESP - Department of Microbiology, Immunology and Parasitology)

Abstract

Treatment of paracoccidiodomycosis (PCM) patients with antifungal drugs is the required procedure, although there is no assurance of complete cure after prolonged periods of drug administration and relapsing disease is a common event. Attempts at immunotherapy have concentrated on the gp43 and derived peptide 10 which carries a promicuous T-CD4+ epitope. Most of the successful protection experiments using P10 were carried out in BALB/c mice using complete Freundâ€™s adjuvant. Recently, alternative ways of delivering P10 using different adjuvants such as alumen and a cationic lipid, as well as a plasmid minigene encoding P10, Salmonella enterica FliCd flagellin and P10, nanoparticles and dendritic cells pulsed with P10. The following immunization procedures were used in both prophylactic and therapeutic protocols: (A) Immunization using different adjuvants rendered the most promising results using the cationic lipid, that led to a significant reduction in the fungal burden of lungs from intratracheally infected normal and anergic animals; (B) Immunization of P10 minigene in plasmid DNA accompanied or not by IL-12 gene therapy led to significant reduction of fungal burden in the lung, spleen and liver. Increased production of IL-12 and IFN-γ with low IL-4 in lung homogenates was obtained. The DNA-based vaccine encoding P10 also generated cells with regulatory and memory phenotypes; (C) The peptide was genetically fused to the central region of flagellin FliCd or was just admixed with free flagellin and nasally administered into BALB/c mice. The treatment of mixed flagellin and P10 promoted higher protection than the fused flagellin-P10 preparation; (C) The delivery of P10, encapsulated within PLGA-DMSA polymeric blends (nanoparticles), was used associated with sulfamethoxazole and the animals had a significant decrease in the fungal burden of lungs; (D) Dendritic cells pulsed with P10 were transferred to BALB/c mice previously infected with P. brasiliensis rendering a significant reduction in the lung fungal burden. With the encouraging results obtained using different preparations of P10, the next step should be pursued in pre-clinical models aiming at toxicity and pharmacokinetics studies to select the most effective formulation for clinical trials.

Keyword: Paracoccidioides, vaccine, P10, gp43

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