Topical immunomodulators—progress towards treating inflammation, infection, and cancer

Hengge, UR; Benninghoff, Bernd; Ruzicka, Thomas; Goos, M.

doi:10.1016/s1473-3099(01)00095-0

Cited by 137 publications

(109 citation statements)

References 67 publications

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“…To date, in vivo studies are only available for CpG-DNA-TLR9 interaction (97), which appears to be most relevant for costimulatory cytotoxic T cell responses (108). TLR9 activation is followed by a robust Th1 humoral and cellular immune response in vivo (105,108 -112), which identified synthetic oligodeoxynucleotides containing stimulatory CpG motifs as a potential tool for the development of novel immunomodulatory treatment strategies (113,114). These include CpG-DNA as vaccine adjuvants (108,115,116), as immune modulators of atopy (117), as inductors of T cell responses against malignancy (109,118), and as modulators of the immune response during infection with intracellular microbes (119).…”

Section: Polarization Of Adaptive Immune Responses By Tlr Activationmentioning

confidence: 99%

Signaling Danger

Anders¹,

Banas

Schlöndorff³

2004

Journal of the American Society of Nephrology

342

295

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Abstract. Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy). In addition, TLR9 has been shown to be involved in antigen-induced immune complex glomerulonephritis and lupus nephritis by regulating humoral and cellular immune responses. TLR are evolutionary conserved regulators of innnate and adaptive immune reponses. It is likely that TLR are involved in many if not all types of renal inflammation. Here the authors provide an overview on the biology of TLR, summarize the present data on their expression in the kidney, and provide an outlook for the potential roles of TLR in kidney disease.

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Section: Polarization Of Adaptive Immune Responses By Tlr Activationmentioning

confidence: 99%

Signaling Danger

Anders¹,

Banas

Schlöndorff³

2004

Journal of the American Society of Nephrology

342

295

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“…TLR7 and -8 bind singlestranded RNA as natural ligands, but also confer responsiveness to guanosine derivatives and the imidazolquinolines R848 (Resiquimod) and Imiquimod [13]. The latter experimental agonists have received considerable attention recently due to their effectiveness in treating genital warts and some skin malignancies [14][15][16]. Their mechanism of action is purported to be the activation of myeloid cells (primarily dendritic cells, DC) via interaction with TLR7 and -8 [17,18].…”

Section: Introductionmentioning

confidence: 99%

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

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During vaccination or infection, adaptive and innate immune receptors of B cells are engaged by microbial antigens/ligands. A better understanding of how innate and adaptive signaling pathways interact could enlighten B lymphocyte biology as well as aid immunotherapy strategies and vaccine design. To address this goal, we examined the effects of TLR stimulation on BCR and CD40-induced B cell activation. Synergistic production of IL-6 was observed in both human and mouse primary B cells stimulated through B cell antigen receptors, CD40 and TLR7, and these two receptors also cooperated independently of BCR signals. The enhanced IL-6 production was dependent upon the activity of c-Jun kinase (JNK) and cFos. Dual stimulation through CD40 and TLR7 markedly enhanced JNK activity. The increased level of active JNK in dual-stimulated cells was accompanied by an increase in the level of active AP-1 monomers cJun and cFos. The stimulation of B cells through both CD40 and TLR7 therefore enhanced the production of cytokines through increased JNK signaling and AP-1 activity. In addition, the dual stimulation increased cFos/AP-1 species in stimulated cells, effectively expanding the repertoire of AP-1 dimers as compared to singly stimulated B cells. IntroductionNatural immune responses to microbes and responses induced by vaccination involve the cooperation of innate and adaptive immunity. B lymphocytes express receptors that allow them to respond to both antigen-specific and innate immune stimuli [1,2]. One of the key receptors involved in adaptive humoral responses is the TNF receptor superfamily member CD40. The interaction of CD40 on B cells with its ligand CD154, expressed by activated T cells, is integral to immunoglobulin production, isotype switching, and the formation of germinal centers [3], important events in the development of long-lived humoral memory. CD40 stimulation also contributes to B cell antigen presentation by the upregulation of T cell co-stimulatory molecules and production of acute phase cytokines such as . Previous studies have shown that dual stimulation of B cells through the BCR and CD40 leads to an enhancement of Ig and cytokine production [7]. However, the effects and mechanisms of interactions between innate immune receptors and BCR or CD40 expressed by B cells are not yet well defined.B cells can be activated through engagement of a variety of innate immune receptors, including Toll-like receptors (TLR). TLR are related to the Drosophila receptor Toll, important for dorsal-ventral patterning in the developing fly as well as resistance to microbes [8]. The TLR in higher organisms act as sensors of infection or 'danger' by recognizing molecular patterns associated with microbes and/or cellular damage. As natural surveyors of environmental stresses, TLR induce immune cell activity and direct the initial stages of immune responses [9]. Of the 13 TLR mammalian genes [11,12]. TLR7 and -8 bind singlestranded RNA as natural ligands, but also confer responsiveness to guanosine derivatives and the imi...

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“…Imiquimod [1-(2-methylpropyl)-1H-imidazo [4,5-c]quinolin-4-amine] belongs to the group of imidazoquinolones, synthetic local immune response modifiers that have demonstrated potent antiviral and antitumor activity (5). Imiquimod activates macrophages and other monocyte-derived immune cells via interaction with Toll-like receptor-7 (6) inducing the local production of cytokines such as IFN-␣, tumor necrosis factor ␣, and interleukin (IL)-12, resulting in an enhanced innate immune response (5,7). In addition, imiquimod induces migration and activation of skin Langerhans cells (8), all of which promote the biasing of naïve T cells to Th1 cells, which are potent producers of IFN-␥, thus leading to the enhancement of adaptive immunity.…”

Section: Introductionmentioning

confidence: 99%

Imiquimod Treatment Induces Expression of Opioid Growth Factor Receptor

Urosevic

Oberholzer

Maier

et al. 2004

Clinical Cancer Research

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Purpose: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-␣.Experimental Design: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays.Results: We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-␣ or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-␣-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P ‫؍‬ 0.041).Conclusions: In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens.

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Topical immunomodulators—progress towards treating inflammation, infection, and cancer

Cited by 137 publications

References 67 publications

Signaling Danger

Signaling Danger

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Imiquimod Treatment Induces Expression of Opioid Growth Factor Receptor

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