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The classical model of metastasis is that tumor cell dissemination occurs late in tumor development, after the primary tumor has grown, and that only then will tumor cells invade the local tissue, enter the blood or lymphatic vessels, and colonize new sites to cause metastases. However, evidence increasingly indicates that single tumor cells spread to distant sites much earlier than previously believed. In this issue of the JCI, Eyles and colleagues provide new insight into the mechanisms underlying early tumor cell dissemination, formation of metastases, and tumor immunosurveillance using transgenic mice that spontaneously develop melanomas of the uvea. The authors provide striking evidence that tumor cells start to disseminate during the initial steps of tumor development, that late appearing metastases arise from these early disseminated tumor cells, and that CD8+ T cells inhibit the growth of disseminated tumor cells, surprisingly, not by cytotoxic effects, but through cytostatic effects. [ABSTRACT FROM AUTHOR]

T cells are key players in inflammation, autoimmune diseases, and immunotherapy. Thus, holistic and noninvasive in vivo characterizations of the temporal distribution and homing dynamics of lymphocytes in mammals are of special interest. Herein, we show that PET-based T-cell labeling facilitates quantitative, highly sensitive, and holistic monitoring of T-cell homing patterns in vivo. We developed a new T-cell receptor (TCR)-specific labeling approach for the intracellular labeling of mouse T cells. We found that continuous TCR plasma membrane turnover and the endocytosis of the specific 64Cu-monoclonal antibody (mAb)-TCR complex enables a stable labeling of T cells. The TCR-mAb complex was internalized within 24 h, whereas antigen recognition was not impaired. Harmful effects of the label on the viability, DNA-damage and apoptosis-necrosis induction, could be minimized while yielding a high contrast in in vivo PET images.We were able tofollow and quantify the specific homing of systemically applied 64Cu-labeled chicken ovalbumin (cOVA)-TCR transgenic T cells into the pulmonary and perithymic lymph nodes (LNs) of mice with cOVA-induced airway delayed-type hypersensitivity reaction (DTHR) but not into pulmonary and perithymic LNs of naïve control mice or mice diseased from turkey or pheasant OVA-induced DTHR. Our protocol provides consequent advancements in the detection of small accumulations of immune cells in single LNs and specific homing to the sites of inflammation by PET using the internalization of TCR-specific mAbs as a specific label of T cells. Thus, our labeling approach is applicable to other cells with constant membrane receptor turnover. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Para-phenylenediamine-specific lymphocyte activation test: a sensitive in vitro assay to detect para-phenylenediamine sensitization in patients with severe allergic reactions. Experimental Dermatology 2010; 19: 435–441. Patients sensitized to para-phenylenediamine (PPD) by semi-permanent tattoos increasingly develop threatening allergic reactions in response to black hair dye. The gold standard to diagnose allergic contact dermatitis is to perform epicutaneous patch tests, however, iatrogenic sensitizations and severe patch test reactions to PPD have been described, the latter especially in patients with severe allergic reactions. We examined nine patients with severe allergic reactions in response to permanent hair dyes. Patch tests using the standard concentration of 1% or 0.5% PPD resulted in severe and sometimes even bullous reactions in all patients responsive to PPD. Titration revealed that at 1% of the standard concentration (0.01% PPD), patch test sensitivity decreased and only 50% of patients responded. Consequently, we established an in vitro assay to diagnose PPD allergy. Freshly isolated peripheral blood mononuclear cells (PBMC) were cultured with titrated concentrations of PPD with or without IL-2 supplementation, and cell proliferation was determined by [3H]-thymidine incorporation. Lymphocyte activation test (LAT ) detected PBMC cell proliferation specific to PPD, with at least 3.5-fold increase in [3H]-thymidine uptake in all PPD allergic patients. Most importantly, PPD –LAT without IL-2 supplementation remained negative in three out of eight PPD allergic patients. Thus, PPD-LAT with IL-2 supplementation demonstrated a sensitivity of 100%, remained unresponsive in controls not sensitized to PPD, and in one patient sensitive to other p-amino compounds. These data demonstrate that LAT with PPD can be used to detect PPD sensitization as a possible alternative to patch testing at least in patients with severe allergic reactions to PPD. [ABSTRACT FROM AUTHOR]

Mast cells are still generally viewed as mediators of type I allergic or pseudoallergic reactions. Research over the past 10 years revealed that our view was too small and that mast cells are of key importance in innate immunity and also types II, III and IV adaptive immune reactions. Understanding their role in modulating and amplifying of inflammatory responses provides important insights into the pathogenesis of skin diseases such as psoriasis, atopic dermatitis, bullous pemphigoid or the control of infections. This helps us to understand the course of these diseases, their trigger mechanisms, and, the new role of agents, which can modulate the function of mast cells. These insights will help to develop new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Psoriasis is an autoimmune disease affecting 2–4% of the Caucasian population. Inflammatory processes induce the migration of interferon (IFN) γ producing Th1 lymphocytes into the skin. These play a key role in the pathogenesis of psoriasis. These Th1 lymphocytes are responsible for the pathological reactions in psoriatic skin leading to keratinocyte hyperproliferation, small vessel proliferation and neutrophilic infiltration. Antigen-presenting cells activate dermal CD4+ T lymphocytes, and various signals can support the polarization of Th1 responses. The main signal for Th1 development is interleukin (IL) 12. After binding to their receptors both IL-12 and IFN-γ promote intracellular IFN-γ production by activating signal transducer and activator of transcription (STAT) 4 or 1. STAT1 activation by IFN-γ is followed by T-bet activation, a master transcription factor for Th1 lymphocytes. In experimental models of Th1-mediated autoimmune diseases immune deviation of polarized autoreactive Th1 into anti-inflammatory Th2 responses generally improves the disease. Therefore new therapeutic approaches based on immunomodulating molecules have been developed for psoriasis, a prototypical Th1-mediated autoimmune disorder. Recently IL-4, the most effective Th2-inducing cytokine, has been shown to be safe and efficient for treating psoriasis. Improvement was associated with the induction of a Th2 phenotype of skin infiltrating lymphocytes. This review summarizes the IL-4 inducing potential of various conventional and newer systemic therapies for psoriasis. Many of these were thought to be primarily immunosuppressive. A review of the literature reveals that most of them can induce IL-4 and Th2, and that Th2 induction may be an underestimated mode of action in the therapy of Th1-mediated autoimmune disease. Further studies are needed to determine the central role of IL-4 in the control of Th1-induced autoimmune disease, namely psoriasis. [ABSTRACT FROM AUTHOR]

Immunity to infection with intracellular pathogens is regulated by interleukin 12 (IL-12), which mediates protective T helper type 1 (TH1) responses, or IL-4, which induces TH2 cells and susceptibility. Paradoxically, we show here that when present during the initial activation of dendritic cells (DCs) by infectious agents, IL-4 instructed DCs to produce IL-12 and promote TH1 development. This TH1 response established resistance to Leishmania major in susceptible BALB/c mice. When present later, during the period of T cell priming, IL-4 induced TH2 differentiation and progressive leishmaniasis in resistant mice. Because immune responses developed via the consecutive activation of DCs and then T cells, the contrasting effects of IL-4 on DC development and T cell differentiation led to immune responses that had opposing functional phenotypes. [ABSTRACT FROM AUTHOR]

Reports on the identification of early signs required to recruit memory T cells to sites of antigen-specific inflammation. Benefits of the T-cell responses in protection against pathogens; Investigation of the early steps of immune response; Benefits of the findings in understanding various disorders.

Tumor-associated antigens such as NY-ESO-1 are expressed in a variety of solid tumors but absent in mature healthy tissues with the exception of germline cells. The immune system anti-cancer attack is mediated by cell lysis or induction of growth arrest through paralysis of tumor cells, the latter of which can be achieved by tumor-specific CD4+, IFNγ-producing THelpertype 1 (TH1) cells. Translation of these immune-mediated mechanisms into clinical application has been limited by availability of immune effectors, as well as the need for complexin vitroprotocols and regulatory hurdles. Here, we report a procedure to generate cancer-testis antigen NY-ESO-1-targeting CD4+TH1 cellsin vitrofor cancer immunotherapy in the clinic. After in vitro sensitization by stimulating T cells with protein-spanning, overlapping peptide pools of NY-ESO-1 in combination with IL-7 and low dose IL-2, antigen-specific T cells were isolated using IFNγ capture technique and subsequently expanded with IL-2, IL-7 and IL-15. Large numbers of NY-ESO-1-specific CD4+T cells with a TH1 cytokine profile and lower numbers of cytokine-secreting CD8+T cells could be generated from healthy donors with a high specificity and expansion potential. Manufactured CD4+T cells showed strong specific TH1-responses with IFNγ+, TNFα+, IL-2+and induced cell cycle arrest and apoptosis in tumor cells. The protocol is GMP-grade and approved by the regulatory authorities. The tumor-antigen specific CD4+TH1 lymphocytes can be adoptively transferred as a T-cell therapy to boost anticancer immunity and this novel cancer treatment approach is applicable to both T cells from healthy allogeneic donors as well as to autologous T cells derived from cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Psoriasis is a T cell–dependent autoimmune disease of the skin and joints. Disease manifestation is orchestrated by proinflammatory CD4-positive T helper cells producing either interferon-γ (Th1) or interleukin (IL)-17 (Th17). These Th1 and Th17 cells interact with dermal dendritic cells, macrophages, mast cells, and neutrophils. Together, they cause an inflammation that mainly involves interferon-γ, tumor necrosis factor, IL-8, IL-12, IL-17, IL-19, and IL-23. New therapeutics either are directed against T cells, tumor necrosis factor, and IL-12/IL-23 or deviate immune responses into a protective IL-4–dominated Th2 phenotype. [Copyright &y& Elsevier]

The inflammasome is a protein complex cleaving the pro-inflammatory cytokines IL-1β and IL-18 into their active forms by caspase-1 activation. The cytosolic protein complex can be activated by danger signals, such as bacterial and viral components, ATP, or uric acid crystals, and reacts as a sensor of innate immunity. In the skin, sensitizing agents promote induction of specific T-cell-mediated contact hypersensitivity. They induce dendritic cell migration, a precondition for the priming of specific T cells. They are a prerequisite for the recruitment of cells into the skin that demand pro-inflammatory stimuli, such as IL-1β and IL-18. Watanabe et al. (2007, this issue) demonstrate the presence of the inflammasome complex in keratinocytes and report that this complex can be activated by contact sensitizers, such as trinitrocholorobenzene (TNCB), both in vitro and in vivo. The study documents a regulatory effect of innate immunity in a T-cell-mediated delayed-type hypersensitivity reaction.Journal of Investigative Dermatology (2007) 127, 1853–1855. doi:10.1038/sj.jid.5700815 [ABSTRACT FROM AUTHOR]

Summary Skin is constantly exposed to bacteria and antigens, and cutaneous innate immune sensing orchestrates adaptive immune responses. In its absence, skin pathogens can expand, entering deeper tissues and leading to life-threatening infectious diseases. To characterize skin-driven immunity better, we applied living bacteria, defined lipopeptides, and antigens cutaneously. We found suppression of immune responses due to cutaneous infection with Gram-positive S. aureus , which was based on bacterial lipopeptides. Skin exposure to Toll-like receptor (TLR)2-6-binding lipopeptides, but not TLR2-1-binding lipopeptides, potently suppressed immune responses through induction of Gr1 + CD11b + myeloid-derived suppressor cells (MDSCs). Investigating human atopic dermatitis, in which Gram-positive bacteria accumulate, we detected high MDSC amounts in blood and skin. TLR2 activation in skin resident cells triggered interleukin-6 (IL-6), which induced suppressive MDSCs, which are then recruited to the skin suppressing T cell-mediated recall responses such as dermatitis. Thus, cutaneous bacteria can negatively regulate skin-driven immune responses by inducing MDSCs via TLR2-6 activation. [ABSTRACT FROM AUTHOR]

In this issue, Paek et al. describe two phenomena. First, they show that intermediate concentrations of a 'transgenic' autoantigen may cause a lichen planus-like autoimmune disease. Second, and more importantly, they show that high doses of peptide antigen suppress the expression of the T-cell receptor and coreceptors, particularly CD8, and that this suppression improves this T-cell-mediated, destructive inflammatory skin disease that is similar to erosive lichen planus. [ABSTRACT FROM AUTHOR]

Summary: Immune responses may arrest tumor growth by inducing tumor dormancy. The mechanisms leading to either tumor dormancy or promotion of multistage carcinogenesis by adaptive immunity are poorly characterized. Analyzing T antigen (Tag)-induced multistage carcinogenesis in pancreatic islets, we show that Tag-specific CD4+ T cells home selectively into the tumor microenvironment around the islets, where they either arrest or promote transition of dysplastic islets into islet carcinomas. Through combined TNFR1 signaling and IFN-γ signaling, Tag-specific CD4+ T cells induce antiangiogenic chemokines and prevent αvβ3 integrin expression, tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis, without destroying Tag-expressing islet cells. In the absence of either TNFR1 signaling or IFN-γ signaling, the same T cells paradoxically promote angiogenesis and multistage carcinogenesis. Thus, tumor-specific T cells can directly survey multistage carcinogenesis through cytokine signaling. [Copyright &y& Elsevier]