Abstract
Paracoccidioidomycosis (PCM) is an endemic mycosis in Latin American caused by the thermodimorphic fungi of the genus Paracoccidioides spp. Notably, a Th1 immune response is required to control PCM. In this context, dendritic cells (DCs) seem to be essential players in capture, processing and presentation of Paracoccidioides antigens to naïve T cells and their further activation. We have previously demonstrated that differentiated DCs from bone marrow cells, pulsed with the immunoprotective peptide 10 (P10), effectively control experimental PCM immunocompetent and immunosuppressed mice. However, this procedure may not be infeasible or it is limited for the therapy of human patients. Therefore, we have sought a less invasive but equally effective approach that would better mimics the autologous transplant of DC in a human patient. Here, we isolated and generated monocyte differentiated dendritic cells (MoDCs) from infected mice, pulsed them with P-10, and used them in the therapy of PCM in syngeneic mice. Similar to the results using BMDCs, the P10-pulsed MoDCs stimulated the proliferation of CD4+ T lymphocytes, induced a mixed production of Th1/Th2 cytokines and decreased the fungal burden in murine lungs in the setting of PCM. The process of differentiating MoDCs derived from an infected host, and subsequently used for therapy of PCM is much simpler than that for obtaining BMDCs, and represents a more reasonable approach to treat patients infected with Paracoccidioides. The results presented suggest that P10-primed MoDC may be a promising strategy to combat complicated PCM as well as to significantly shorten the lengthy requirements for treatment of patients with this fungal disease.
Highlights
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by the thermally dirmophic fungus of the Paracoccidioides genus and it is one of the most important systemic diseases in the Latin America, where it occurs from Mexico to Argentina
We had previously shown that Bone Marrow-derived Dendritic Cells (BMDC) derived from healthy mice and primed with peptide 10 (P10) were effective in the therapy of both immunocompetent (Magalhães et al, 2012) and immunosuppressed (Silva et al, 2017) murine models of PCM
In order to develop a more clinically achievable approach that would better mimic the therapy of PCM using autologous transplant of dendritic cells (DCs) in human patients, we decided to investigate the efficacy of monocyte differentiated dendritic cells (MoDCs) primed with P10 in a murine model
Summary
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by the thermally dirmophic fungus of the Paracoccidioides genus and it is one of the most important systemic diseases in the Latin America, where it occurs from Mexico to Argentina (reviewed by Taborda et al, 2015). DCs are strategically injected in a different anatomical sites and they migrate through non-lymphoid peripheral tissues, continuously examining the environment for foreign compounds and abnormal cells, including invasive microorganisms, to capture, prosecute and present antigens to activate T cells (Shortman and Naik, 2007). They are considered “professional APCs” (Banchereau and Steinman, 1998; Janeway and Medzhitov, 2002; Romani et al, 2004). These DCs have been termed “inflammatory DCs” (iDCs) or “monocyte-derived DCs” (MoDCs) (Mildner et al, 2013; Segura and Amigorena, 2013), which share a similar expression of MHC-II, CD11b, and CD11c with BMDCs, but differentially express CD64, the Fc-gamma receptor 1 (FcgRI) (Tamoutounour et al, 2012; Plantinga et al, 2013)
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