Polarized monocyte response to cytokine stimulation

BACKGROUND: Mononuclear phagocytes (MPs) stand at the crossroads between the induction of acute inflammation to recruit and activate immune effector cells and the downmodulation of the inflammatory process to contain collateral damage. This decision is extensively modulated by the cytokine microenvironment, which includes a broad array of cytokines whose direct effect on MPs remains largely unexplored. Therefore, we tested whether polarized responses of MPs to pathogens are related to the influence of selected cytokines or represent a mandatory molecular switch through which most cytokines operate. RESULTS: Circulating CD14+ MPs were exposed to bacterial lipopolysaccharide (LPS) followed by exposure to an array of cytokines, chemokines and soluble factors involved in the immune response. Gene expression was studied by global transcript analysis. Two main classes of cytokines were identified that induced a classical or an alternative pathway of MP activation. Expression of genes affected by NFkappaB activation was most predictive of the two main classes, suggesting that this pathway is a fundamental target of cytokine regulation. As LPS itself induces a classical type of activation, the most dramatic modulation was observed toward the alternative pathway, suggesting that a broad array of cytokines may counteract the pro-inflammatory effects of bacterial components. CONCLUSIONS: This analysis is directly informative of the primary effect of individual cytokines on the early stages of LPS stimulation and, therefore, may be most informative of the way MP maturation may be polarized at the early stages of the immune response

The dual role of IL-10

Classification of cytokines as pro-versus anti-inflammatory might not apply to the pleiotropic effects of interleukin-10 (IL-10). Several reports suggest that IL-10 enhances the function of natural killer cells, which leads, through pathogen destruction, to increased antigen availability. In addition, by inhibiting the maturation of antigen-presenting cells (APCs), IL-10 preserves their ability for antigen uptake while simultaneously hampering their migration to draining lymph nodes. This review suggests that this 'antigen-loading' phase might constitute an important component of the innate immune reaction to a pathogen. Additional proinflammatory stimuli might subsequently lead to maturation of 'loaded' APCs that could migrate to draining lymph nodes or recruit and activate adaptive immune effectors locally

A genomic and proteomic-based hypothesis on the ecletic effects of systemic interleukin-2 administration in the context of melanoma-specific immunization

Among human cancers, melanoma is characterized by an almost unique predisposition to regress in response to immune therapy. Recent clinical studies suggest that the frequency of this favorable event is enhanced by combining T-cell-directed active specific immunization with the systemic administration of interleukin (IL)-2. While waiting for additional clinical experience to confirm this observation, we embraced the working hypothesis that this combination provides superior response rates than either treatment alone. In particular, we have focused our interest on the paradoxical observation that active specific immunization consistently induces circulating CD8+ T cells capable of recognizing in ex vivo assays tumor cells, but cannot induce tumor regression alone. In these settings, it appears that combining the systemic administration of IL-2 is almost an absolute requirement for the induction of clinical responses. Here, we will expand on previous speculations on the postulated mechanism(s) of action of systemic IL-2 administration and, based on original data recently derived through high-throughput transcriptional and post-translational analysis, we will suggest an explanation for the eclectic effects of IL-2 administration in the context of active specific immunization

Polarized monocyte response to cytokine stimulation

Background: Mononuclear phagocytes (MPs) stand at the crossroads between the induction of acute inflammation to recruit and activate immune effector cells and the downmodulation of the inflammatory process to contain collateral damage. This decision is extensively modulated by the cytokine microenvironment, which includes a broad array of cytokines whose direct effect on MPs remains largely unexplored. Therefore, we tested whether polarized responses of MPs to pathogens are related to the influence of selected cytokines or represent a mandatory molecular switch through which most cytokines operate. Results: Circulating CD14+ MPs were exposed to bacterial lipopolysaccharide (LPS) followed by exposure to an array of cytokines, chemokines and soluble factors involved in the immune response. Gene expression was studied by global transcript analysis. Two main classes of cytokines were identified that induced a classical or an alternative pathway of MP activation. Expression of genes affected by NF\u3baB activation was most predictive of the two main classes, suggesting that this pathway is a fundamental target of cytokine regulation. As LPS itself induces a classical type of activation, the most dramatic modulation was observed toward the alternative pathway, suggesting that a broad array of cytokines may counteract the pro-inflammatory effects of bacterial components. Conclusions: This analysis is directly informative of the primary effect of individual cytokines on the early stages of LPS stimulation and, therefore, may be most informativ

Mechanism of immune response during immunotherapy

Tumor immunology embraces an extensive array of biological phenomena that include interactions between neoplastic cells and the innate and adaptive immune response. Among immune cells, T cells have taken the center stage because they can be easily demonstrated to specifically recognize autologous cancer cells. However, their role is limited and other components of the immune response are likely necessary for the completion of cancer rejection. Metastatic melanoma and renal cell carcinoma (RCC) are malignancies strongly predisposed to regress in response to the systemic administration of high-dose interleukin (IL)-2. Several clinical Studies in extensive cohorts of patients have shown that this treatment can induce complete or partial clinical regressions of metastatic disease in 15 to 20% of patients who receive this treatment.(1-6) Although IL-2 has direct pluti-potent effects on cells with immune and inflammatory function, it remains unexplained which cell subset is implicated in mediating tumor regression. In a quest to characterize the mechanism of action of IL-2 during the course of immunotherapy, we have investigated the early changes in transcriptional profiles of circulating mononuclear cells and microenvironment of melanoma metastases following high dose IL-2 administration (720,000 IU/kg) by serial sampling of blood cells and tumors in the form of fine needle aspirate (FNA).(7) Furthermore, studies are currently on going to characterize the proteomic profiling of RCC patients undergoing the same treatment using protein arrays (manuscript in preparation). The predominant activation of genes related to inflammation and activation of mononuclear phagocytes lead us to further characterize this cell subset in the context of stimulation with a panel of soluble factors potentially present in the circulation and tumor microenvironment

Active-specific immunization against melanoma: is the problem at the receiving end?

The recent progress in tumor immunology is a striking example of the successful application of modern biotechnology to understand the complex phenomenon of immune-mediated cancer rejection. Tumor antigens were identified and successfully utilized in active immunization trials to induce tumor antigen-specific T cells. This achievement has left, however, clinicians and researchers perplexed by the paradoxical observation that immunization-induced T cells can recognize tumor cells in standard assays but cannot induce tumor regression. A closer look at T cell physiology and tumor biology suggests that this observation is not so surprising. Here, we argue that successful immunization is one of several steps required for tumor clearance while more needs to be understood about how T cells localize and are effective within a tumor microenvironment impervious to the execution of their effector function

Unexpected impairment of TNF-α-induced maturation of human dendritic cells in vitro by IL-4

International audienceBackground: An efficient strategy for programing dendritic cells (DCs) for cancer immunotherapy is the optimiza‑ tion of their maturation so that they can efficiently stimulate cancer‑specific T cell responses. Interleukin (IL)‑4 has appeared as an essential cytokine, widely used in vitro with granulocyte macrophage‑colony stimulating factor (GM‑CSF) to differentiate monocytes into immature DCs (iDC) and to prevent macrophage formation. Conflicting data have been published regarding the effect of IL‑4 on functional DC maturation. To further understand IL‑4's effects on DC maturation and function in vitro, we choose the most commonly used maturation factor tumor necrosis factor (TNF)‑α. Methods: Human monocyte‑derived iDC were treated for 48 h with GM‑CSF and TNF‑α in the presence (IL‑4 + ‑DC) or absence (IL‑4 − ‑DC) of IL‑4 and functions of both DC populations were compared. Results: On mixed lymphocyte reaction assay, IL‑4 + ‑DC were less potent than IL‑4 − ‑DC at inducing the proliferation of allogeneic CD4 + T cells and the proportion of activated T cells expressing CD69 and/or CD25 was smaller. Interleu‑ kin‑4 reduced the cell‑surface expression of TNF‑α‑induced DC maturation markers CD83, CD86, HLA‑DR and CD25 and generated a heterogeneous population of DCs. IL‑4 + ‑DC secreted less IL‑12 and more IL‑10 than IL‑4 − ‑DC follow‑ ing activation by soluble CD40L, and IL‑4 + ‑DC‑activated T cells secreted lesser amounts of T helper (Th) 1 cytokines (IL‑2 and interferon‑γ). Importantly, IL‑4 impaired the in vitro migratory capacity of DCs in response to CCL21 and CCL19 chemokines. This effect was related to reduced expression of CCR7 at both mRNA and protein levels. Conclusion: Interleukin‑4 used with GM‑CSF and TNF‑α during the maturation of DCs in vitro impaired DC functions and disturbed the maturation effect of TNF‑α. Finally, our study reinforces the view that the quality of the DC matura‑ tion stimulus, which regulates DC migration and cytokine production, may be a decisive feature of the immunogenic‑ ity of DCs