Polarization Of Adaptive Immune Response Research Articles

Host defense peptides as immunomodulators: The other side of the coin

Host defense peptides (HDPs) exhibit a broad range of antimicrobial and immunomodulatory activities. In this sense, both functions are like different sides of the same coin. The direct antimicrobial side was discovered first, and widely studied for the development of anti-infective therapies. In contrast, the immunomodulatory side was recognized later and in the last 20 years the interest in this field has been continuously growing. Different to their antimicrobial activities, the immunomodulatory activities of host defense peptides are more effective in vivo. They offer a great opportunity for new therapeutic applications in the fields of anti-infective therapy, chronic inflammatory diseases treatment, novel vaccine adjuvants development and anticancer immunotherapy. These immune related functions of HDPs includes chemoattraction of leukocytes, modulation of inflammation, enhancement of antigen presentation and polarization of adaptive immune responses. Our attempt with this review is to make a careful evaluation of different aspects of the less explored, but attractive immunomodulatory side of the HDP functional coin.

Decreased Langerhans cell responses to IL-36γ: altered innate immunity in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease caused by human papillomaviruses (HPVs) types 6 and 11 that is characterized by the polarization of adaptive immune responses that support persistent HPV infection. Respiratory papillomas express elevated mRNA levels of IL-36γ, a proinflammatory cytokine in comparison to autologous clinically normal laryngeal tissues; however there is no evidence of inflammation in these lesions. Consistent with this, respiratory papillomas do not contain TH1-like CD4(+) T-cells or cytotoxic CD8(+) T-cells, but instead contain a predominance of TH2-like and T regulatory cells (Tregs). In addition, papillomas also are infiltrated with immature Langerhans cells (iLCs). In this study, we show that papilloma cells express IL-36γ protein, and that human keratinocytes transduced with HPV11 have reduced IL-36γ secretion. We now provide the first evidence that peripheral blood-derived iLCs respond to IL-36γ by expressing inflammatory cytokines and chemokines. When stimulated with IL-36γ, iLCs from patients with RRP had lower expression levels of the TH2-like chemokine CCL-20 as compared with controls. Patients' iLCs also had decreased steady state levels of CCL-1, which is a proinflammatory chemokine. Moreover, CCL-1 levels in iLCs inversely correlated with the severity of RRP. The combined decrease of TH1- and a TH2-like chemokines by iLCs from patients could have consequences in the priming of IFN-γ expression by CD8(+) T-cells. Taken together, our results suggest that, in RRP, there is a defect in the proinflammatory innate immune responses made by iLCs in response to IL-36γ. The consequence of this defect may lead to persistent HPV infection by failing to support an effective HPV-specific, TH1-like and/or Tc1-like adaptive response, thus resulting in the predominant TH2-like and/or Treg micromilieu present in papillomas.

Trafficking of phagocytic peritoneal cells in hypoinsulinemic-hyperglycemic mice with systemic candidiasis

BackgroundCandidemia is a severe fungal infection that primarily affects hospitalized and/or immunocompromised patients. Mononuclear phagocytes have been recognized as pivotal immune cells which act in the recognition of pathogens, phagocytosis, inflammation, polarization of adaptive immune response and tissue repair. Experimental studies have showed that the systemic candidiasis could be controlled by activated peritoneal macrophages. However, the mechanism to explain how these cells act in distant tissue during a systemic fungal infection is still to be elucidated. In the present study we investigate the in vivo trafficking of phagocytic peritoneal cells into infected organs in hypoinsulinemic-hyperglycemic (HH) mice with systemic candidiasis.MethodsThe red fluorescent vital dye PKH-26 PCL was injected into the peritoneal cavity of Swiss mice 24 hours before the intravenous inoculation with Candida albicans. After 24 and 48 hours and 7 days of infection, samples of the spleen, liver, kidneys, brain and lungs were submitted to the microbiological evaluation as well as to phagocytic peritoneal cell trafficking analyses by fluorescence microscopy.ResultsIn the present study, PKH+ cells were observed in the peritoneum, kidney, spleen and liver samples from all groups. In infected mice, we also found PKH+ cells in the lung and brain. The HH condition did not affect this process.ConclusionsIn the present study we have observed that peritoneal phagocytes migrate to tissues infected by C. albicans and the HH condition did not interfere in this process.

The role of the class A scavenger receptors, SR-A and MARCO, in the immune system. Part 2. Contribution to recognition and phagocytosis of pathogens as well as induction of immune response

Recognition of pathogens by innate immune cells is mediated by pattern recognition receptors (PRR), which include the class A scavenger receptors (SR), SR-A/CD204 and MARCO. It seems that in addition to activating innate immune responses, phagocytosis and inflammation, this initial, PRR-mediated recognition also determines polarization of adaptive immune responses (Th1, Th2, Th17 or Treg). It has been demonstrated that class A SR are major PRR mediating opsonin-independent phagocytosis. SR-A- or MARCO-deficient mice exhibit impaired ability to control bacterial infections, resulting in increased mortality. Our results suggest that in addition to impaired bacterial destruction by macrophages, dysregulation of immune responses may contribute to defective antibacterial defense in class A SR-deficient mice. Using specific receptor ligation with antibodies, we showed that SR-A and MARCO regulate in an opposite manner production of IL-12 in macrophages, the cytokine playing a crucial role in Th1/Th2 polarization of adaptive immune responses. Together with the observation that expression of MARCO is increased by different Th1-polarizing factors and decreased by Th2-polarizing factors, these results suggest that changes in relative expression levels of SR-A and MARCO may be a mechanism of sustained polarization of adaptive immune responses.

Scavenger receptors and β-glucan receptors participate in the recognition of yeasts by murine macrophages

ObjectivesNumerous receptors have been implicated in recognition of pathogenic fungi by macrophages, including the β-glucan receptor dectin-1. The role of scavenger receptors (SRs) in anti-fungal immunity is not well characterized.MethodsWe studied uptake of unopsonized Saccharomycetes cerevisiae (zymosan) and live Candida albicans yeasts as well as zymosan-stimulated H2O2 production in J774 macrophage-like cells and peritoneal exudate macrophages (PEMs). The role of different receptors was assessed with the use of competitive ligands, transfected cells and receptor-deficient macrophages.ResultsThe uptake of zymosan by untreated J774 cells was mediated approximately half by SRs and half by a β-glucan receptor which was distinct from dectin-1 and not linked to stimulation of H2O2 production. Ligands of β-glucan receptors and of SRs also inhibited uptake of C. albicans by macrophages (J774 cells and PEMs). In macrophages pretreated with a CpG motif-containing oligodeoxynucleotide (CpG-ODN) the relative contribution of SRs to yeast uptake increased and that of β-glucan receptors decreased. Whereas the class A SR MARCO participated in the uptake of both zymosan and C. albicans by CpG-ODN-pretreated, but not untreated macrophages, the related receptor SR-A/CD204 was involved in the uptake of zymosan, but not of C. albicans. The reduction of zymosan-stimulated H2O2 production observed in DS-pretreated J774 cells and in class A SRs-deficient PEMs suggest that class A SRs mediate part of this process.ConclusionsOur results revealed that SRs belong to a redundant system of receptors for yeasts. Binding of yeasts to different receptors in resting versus CpG-ODN-pre-exposed macrophages may differentially affect polarization of adaptive immune responses.

Abstract 472: In vivo activation of plasmacytoid dendritic cells using TLR7-L induced an efficient antitumoral effect in a murine mammary preclinical tumor model

Abstract Dendritic cells (DC) are professional antigen presenting cells involved in both the induction and the polarization of adaptive immune response. Among them figure conventional myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC), the last ones being involved in the induction of antiviral immune response through type I interferons production. In human breast cancer, we have previously shown that pDC infiltration is an independent factor correlated with a poor prognosis. Although pDC can induce efficient T cell responses against viral or endogenous antigens, it remains unclear whether pDC are efficient for cross presentation of tumor antigens acquired from dying tumor cells. Moreover, pDC have been described in some contexts to be involved in the induction of immune tolerance by promoting regulatory T cell (Treg) differentiation. Thus herein we evaluate their ability to induce efficient antitumoral response after activation by viral signals such as TLR7L or TLR9L. First, we developed several preclinical murine mammary tumor models derived from spontaneous mammary tumors arose in transgenic mice MMTV-Her2/neu expressing the rat proto-oncogene neu under the control of MMTV promoter. Several tumor cell lines (NEU) expressing HER2/Neu were derived from these spontaneous mammary tumors and were implanted in the 4th fad pad of immunotolerant transgenic mice MMTV-Her2/neu or in immunocompetent FVB wild type mice witch developed an antibody immune response against the rat Her2/neu proto-oncogene. All NEU cell lines were highly tumorigeneic in immunotolerant mice but interestingly when implanted in FVBwt mice some were rejected, some escape by immunoediting with a selection of a NEU negative variant and one (NEU15) escape by another mechanism showing as in human breast cancer the maintenance of Her2/Neu expression despite an anti-tumoral immune response. We showed that NEU15 tumors in FVBwt mice (NEU15wt) were significantly more infiltrated by pDC and Treg than NEU15 tumors in immunotolerant transgenic mice (NEU15Tg). Secondly, we focused on this NEU15wt preclinical model and analyzed the functional status of tumor associated pDC (TApDC) and TAmDC. We showed that TApDC are altered for their capacity to secrete type I IFN in response to TLR9 engagement while preserving their ability to respond to viral signals such as Influenza and TLR7 ligands. TAmDC undergo a spontaneous maturation in culture independently of TLR engagement and secrete inflammatory cytokines (TNFα, RANTES) but also IL-10 and no IL12. In vivo immuno intervention using intra-tumoral injection of TLR-7L (50μg D13 and D20) in pre-established NEU15wt tumors allowed 50% of complete tumor rejection. IFNα production was detected in mice sera 3 hours after TLR-7L intratumoral injection. The impact of in vivo depletion of pDC on the therapeutic efficiency of TLR7L is under investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 472. doi:10.1158/1538-7445.AM2011-472

A synthetic toll-like receptor 2 ligand decreases allergic immune responses in a mouse rhinitis model sensitized to mite allergen

It has been proposed that activation of Toll-like receptors (TLRs) plays crucial roles in the polarization of adaptive immune responses. A synthetic Toll-like receptor 2 (TLR2) ligand, Pam3CSK4, has been reported to modulate the balance of Th1/Th2 responses. We evaluated the modulation effect of Pam3CSK4 on allergic immune response in a mouse rhinitis model sensitized to house dust mite allergen (HDM). Mice were sensitized and challenged with Dermatophagoides farinae allergen (Der f), and then the allergic mice were treated by Pam3CSK4. Nasal allergic symptoms and eosinophils were scored. Der f-specific cytokine responses were examined in the splenocytes and bronchoalveolar lavage fluid (BALF). Serum level of total IgE was also detected. After establishing a mouse allergic rhinitis model with HDM, we have showed that Pam3CSK4 treatment not only ameliorated the nasal allergic symptoms remarkably but also decreased the eosinophils and total inflammation cells in BALF significantly. Analysis of cytokine profile found that IFN-gamma released from either BALF or stimulated splenocytes increased markedly in Pam3CSK4-treated mice, while IL-13 decreased significantly. Moreover, serum level of total IgE was significantly lower in Pam3CSK4-treated mice than in the untreated. Thus, in an allergic rhinitis mouse model developed with HDM, Pam3CSK4 was shown to exhibit an antiallergic effect, indicating its potential application in allergic diseases.