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Psoriasis is an autoimmune disease affecting 2-4% of the Caucasian population. Inflammatory processes induce the migration of interferon (IFN) gamma 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-gamma promote intracellular IFN-gamma production by activating signal transducer and activator of transcription (STAT) 4 or 1. STAT1 activation by IFN-gamma 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.

Psoriasis is a chronic inflammatory disease of the skin and the joints. Multiple factors contribute to the initiation of psoriasis. They include specific genetic characteristics such as major histocompatibility antigens and psoriasis susceptibility genes, as well as trigger factors, namely streptococcal infections. Today, psoriasis is considered as a T-lymphocyte mediated autoimmune disease, even though the putative autoantigen remains unknown. Bacterial proteins with similarity to structural proteins of keratinocytes are potential target antigens. As in other autoimmune diseases, inflammatory cytokines of the innate immune system initiate a cascade that activates inflammation locally in the skin, in the circulation and most likely also in lymph nodes. IFN-gamma-producing CD4+ Th1-lymphocytes seem to be of central importance in the pathogenesis of psoriasis as they critically influence differentiation and functioning of antigen presenting cells, mast cells, neutrophils and endothelial cells. This inflammatory cascade simultaneously provokes neoangiogenesis in the dermis and proliferation of keratinocytes. Based on this hypothesis, cytokines or anticytokine antibodies that either inhibit T-cell mediated inflammation or transform disease-inducing, pro-inflammatory Th1-lymphocytes into a phenotype with anti-inflammatory properties were tested in psoriasis. As both approaches improved psoriasis, they strongly support the current concept that views psoriasis as a Th1-lymphocyte mediated disease.

Zusammenfassung Hintergrund: Bei Melanomen, die im Gesicht lokalisiert sind, lassen sich die am Korper ublichen Sicherheitsabstande aus funktionellen und asthetischen Grunden nicht realisieren. In der Literatur fehlen kontrollierte Studien zu Sicherheitsabstanden bei Gesichtmelanomen. Bei den Melanompatienten der Universitats-Hautklinik Tubingen (1980 – 1999) wurde retrospektiv analysiert, welche klinische Parameter und operativen Strategien die Prognose bei Gesichtsmelanomen beeinflussen. Die Bedeutung der luckenlosen histologischen Kontrolle der Exzisatschnittrander (3D-Histologie) sollte validiert werden. Patienten und Methodik: Die untersuchten 368 Melanome des Gesichts machten 9,3 % aller 3 960 Primarmelanome im klinischen Stadium I/II und 63 % der Melanome des Kopf/Hals-Bereichs aus. Ergebnisse: Operationen, die mehrzeitig durchgefuhrt wurden, eine Exzisonsbiopsie zur Diagnosesicherung gefolgt von einer spateren Nachexzision mit definitivem Sicherheitsabstand oder eine Nachexzision bei histologisch unvollstandiger Primarexzision, waren mit einer hoheren Wahrscheinlichkeit fur das rezidivfreie Uberleben verbunden (p = 0,0007), jedoch ohne prognostische Bedeutung fur das Gesamtuberleben. In der multivariaten Analyse waren Invasionslevel (p = 0,0049), Ulzeration (p = 0,011), 3D-Histologie (p = 0,027) und die Einhaltung definierter Sicherheitsabstande (Tumordicke ≤ 1,00 mm: 10 mm; > 1,00 mm 20 mm; LMM 5 mm unter Einsatz der 3D-Histologie) (p = 0,033) unabhangige signifikante Risikofaktoren fur das rezidivfreie Uberleben. Fur das Gesamtuberleben konnten Invasionslevel (p = 0,032), Ulzeration (p = 0,029), 3D-Histologie (p = 0,0047) als unabhangige signifikante Risikofaktoren identifiziert werden. In der multivariaten Analyse konnte fur den histologischen Tumortyp keine prognostische Bedeutung nachgewiesen werden. Schlusfolgerung: Aufgrund dieser Ergebnisse konnen auch reduzierte Sicherheitsabstande im Gesicht als ausreichend sicher eingeschatzt werden. Die 3D-Histologie ermoglicht eine weitere Reduzierung der Sicherheitsabstande, kann subklinische Tumorauslaufer erkennen und ist mit einer besseren Prognose bei Patienten mit Gesichtsmelanomen assoziiert. Summary Background: In treated facial melanomas, the safety margins generally applied in other body sites cannot be achieved for functional and esthetical reasons. To date there are no controlled studies on safety margins for facial melanomas. Clinical parameters and surgical strategies influencing the prognosis of patients with a facial melanoma were evaluated in a retrospective study of melanoma patients in the Department of Dermatology of the University of Tuebingen (1980 – 1999). Patients and Methods: The 368 melanomas of the face comprised 9.3 % of 3960 primary stage I and II melanomas and 63 % of the melanomas in the head and neck area. Results: Multistep procedures, excisional biopsy for histological diagnosis followed by a subsequent resection of a clinical safety margin or re-excision when the tumor extended to the margin, were associated with a higher probability for recurrence-free survival (p = 0.0007), but had no statistical influence on overall survival. In a multivariate analysis, level of invasion (p = 0.0049), ulceration (p = 0.011), 3D-histology (p = 0.027) and defined safety margins (tumor thickness ≤ 1.00 mm: 10 mm; > 1.00 mm 20 mm; lentigo maligna melanoma 5 mm with 3D-histology) (p = 0,033) were independent significant risk factors for recurrence-free survival. Level of invasion (p = 0.032), ulceration (p = 0.029), 3D-histology (p = 0.0047) were identified as independent significant risk factors for overall survival. Multivariate analysis did not show that the histological type of melanoma was of prognostic significance. Conclusion: Reduced safety margins can be employed in melanomas of the face. 3D-histology allows further reduction of safety margins, detects subclinical tumor strands and is correlated with an improved prognosis in patients with facial melanomas.

Selective skewing of autoreactive interferon-gamma (IFN-gamma)-producing T helper cells (Th1) toward an interleukin-4 (IL-4)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without inducing general immunosuppression. In a prospective dose escalation study, we assessed treatment with human IL-4 (rhuIL-4) in 20 patients with severe psoriasis. The therapy was well tolerated, and within six weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2-0.5 microg rhuIL-4 than at < or =0.1 microg rhuIL-4 (P = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microg/kg rhuIL-4 reduced the concentrations of IL-8 and IL-19, two cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ Th1 cells; and the IFN-gamma/IL-4 ratio. In the circulation, 0.2-0.5 microg/kg rhuIL-4 increased the number of IL-4+CD4+ T cells two- to three-fold. Thus, IL-4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis, a prototypic Th1-associated autoimmune disease.

The elicitation of contact sensitivity (CS) to local skin challenge with the hapten trinitrophenyl (TNP) chloride requires an early process that is necessary for local recruitment of CS-effector T cells. This is called CS initiation and is due to the B-1 subset of B cells activated at immunization to produce circulating IgM Ab. At challenge, the IgM binds hapten Ag in a complex that locally activates C to generate C5a that aids in T cell recruitment. In this study, we present evidence that CS initiation is indeed mediated by C-activating classic IgM anti-TNP pentamer. We further demonstrate the involvement of IgM subunits derived either from hybridomas or from lymphoid cells of actively immunized mice. Thus, reduced and alkylated anti-TNP IgM also initiates CS, likely due to generated H chain-L chain dimers, as does a mixture of separated H and L chains that still could weakly bind hapten, but could not activate C. Remarkably, anti-TNP κ L chains alone mediated CS initiation that was C-independent, but was dependent on mast cells. Thus, B-1 cell-mediated CS initiation required for T cell recruitment is due to activation of C by specific IgM pentamer, and also subunits of IgM, while κ L chains act via another C-independent but mast cell-dependent pathway.

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 THelper type 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 complex in vitro protocols and regulatory hurdles. Here, we report a procedure to generate cancer-testis antigen NY-ESO-1-targeting CD4+ TH1 cells in vitro for 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.

It is well established that an interplay between natural killer (NK) cells and dendritic cells (DCs) gives rise to their reciprocal activation and provides a Th1-biased cytokine milieu that fosters antitumor T-cell responses. Ex vivo-differentiated DCs transferred into mice strongly stimulate endogenous NK cells to produce interferon (IFN)-γ and initiate a cascade that eventually leads to cytotoxic T-lymphocyte responses. We show that the ability of exogenous DCs to trigger this pathway obviates CD40 signaling and CD4(+) T-cell help and depends on a preceding maturation step. Importantly, this mechanism was also effective in endogenously arising tumors where IFN-γ production is compromised in contrast to transplantable tumors. In c-myc-transgenic mice developing spontaneous lymphomas, injection of unpulsed DCs caused NK-cell activation and induced CD8(+) T cells capable of recognizing the lymphoma cells. Animals treated with unpulsed DCs showed a survival benefit compared to untreated myc mice. Hence, tumor immunity induced by DC-based vaccines not only depends on specific antigens loaded on the DCs. Rather, DC vaccines generate broader immune responses, because endogenous DCs presenting tumor antigens may also become stimulated by NK cells that were activated by exogenous DCs. Thus, the DC/NK-cell/cytotoxic T lymphocyte axis may commonly have relevance for DC-based vaccination protocols in clinical settings.

The viral CC chemokine macrophage inhibitory protein-II (vMIP-II) encoded by human herpes virus 8 (HHV-8) binds to multiple chemokine receptors, however, its ability to control the initial recruitment of specific leukocyte subtypes from the peripheral circulation has not been fully clarified. Here we show that vMIP-II blocks the firm arrest and transmigration of monocytes or Th1-like T lymphocytes triggered by RANTES immobilized on activated human microvascular endothelium (HMVEC) under flow conditions. The internalization of the receptors CCR1 and CCR5 that mediate arrest and transmigration of these cells in response to RANTES was prevented by vMIP-II, supporting its role as an antagonist of CCR1 and CCR5. In contrast, vMIP-II triggered the firm arrest of eosinophils and Th2-like T cells by engaging CCR3, as confirmed by its down-regulation. Immunohistochemical analysis of HHV-8-associated Kaposi's sarcoma lesions marked by vMIP-II expression and mononuclear cell infiltration revealed a predominance of Th2-type CCR3(+) lymphocytes over Th1-type CXCR3(+)/CCR5(+) leukocytes, indicating that as a CCR3 agonist vMIP-II can drive a Th2-type immune response in vivo. Thus, our data provide evidence for a immunomodulatory role of vMIP-II in directing inflammatory cell recruitment away from a Th1-type towards a Th2-type response and thereby facilitating evasion from cytotoxic reactions.

An 11-year-old boy presented in February 2008 with a facial butterfly rash that persisted for at least one month. Lupus erythematosus was repeatedly suspected and the boy was referred for further examinations. A detailed medical history did not reveal any arthralgia, fever, malaise, exanthema, intense exposure to ultraviolet (UV) light in the period one to three weeks before onset of the rash. Physical examination revealed sharply demarcated homogenous erythema on the cheeks, forehead and nose (Fig. 1a) without scaling, but with considerable accentuation of the outer rim (Fig. 1b). Laboratory tests, including complete blood count, rheumatoid factor, antinuclear antibody (ANA) screening, creatinine kinase, erythrocyte sedimentation rate and Creactive protein (CRP), remained negative. Cefuroxime 125 mg twice a day over 10 days led to complete remission without further symptoms.

Polymorphonuclear leukocytes (PMNs) characterize the pathology of T cell-mediated autoimmune diseases and delayed-type hypersensitivity reactions (DTHRs) in the skin, joints, and gut, but are absent in T cell-mediated autoimmune diseases of the brain or pancreas. All of these reactions are mediated by interferon gamma-producing type 1 T cells and produce a similar pattern of cytokines. Thus, the cells and mediators responsible for the PMN recruitment into skin, joints, or gut during DTHRs remain unknown. Analyzing hapten-induced DTHRs of the skin, we found that mast cells determine the T cell-dependent PMN recruitment through two mediators, tumor necrosis factor (TNF) and the CXC chemokine macrophage inflammatory protein 2 (MIP-2), the functional analogue of human interleukin 8. Extractable MIP-2 protein was abundant during DTHRs in and around mast cells of wild-type (WT) mice but absent in mast cell-deficient WBB6F(1)-Kit(W)/Kit(W-)(v) (Kit(W)/Kit(W)(-v)) mice. T cell-dependent PMN recruitment was reduced >60% by anti-MIP-2 antibodies and >80% in mast cell-deficient Kit(W)/Kit(W)(-v) mice. Mast cells from WT mice efficiently restored DTHRs and MIP-2-dependent PMN recruitment in Kit(W)/Kit(W)-(v) mice, whereas mast cells from TNF(-/)- mice did not. Thus, mast cell-derived TNF and MIP-2 ultimately determine the pattern of infiltrating cells during T cell-mediated DTHRs.

Bei 16 Patienten mit disseminiertem und 2 mit lokalisiertem Granuloma anulare wurde eine Bade-PUVA-Therapie durchgefuhrt, da die Lasionen auf konventionelle Therapiemasnahmen nicht ansprachen. Nach durchschnittlich 55 (11–61) Behandlungen mit einer mittleren kumulativen Dosis von 69,5 (7,1–261,5) J/cm2 wurde bei 5 Patienten eine Vollremission und bei10 eine deutliche Ruckbildung erreicht. Drei Patienten brachen die Therapie vorzeitig ab. Rezidive traten nach Beendigung der Therapie 4mal auf, 2mal fuhrte die Wiederaufnahme der Behandlung zur Abheilung. Eine Erhaltungstherapie fur einige Monate erscheint bei Patienten mit starker Rezidivneigung und besonderem Leidensdruck sinnvoll. Die potentiellen Risiken einer langerfristigen Bade-PUVA-Therapie mussen beachtet werden.

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The combination of psoralens and UVA radiation (PUVA photochemotherapy) is an established treatment for many skin disorders. UVA-induced psoralen-DNA interactions are assumed to contribute to the cutaneous anti-inflammatory and anti-proliferative effects of PUVA. PUVA-induced DNA modifications might interfere not only with DNA replication, but also with gene transcription of proinflammatory genes. We therefore studied the effect of PUVA on cell proliferation and on the transcription of the c-jun and intercellular adhesion molecule-1 genes in a promyelocytic (HL60) and a keratinocyte (HaCaT) cell line. PUVA inhibited cell proliferation increasingly with increasing 8-methoxypsoralen concentrations or UVA doses. The inhibition was observed at conditions not affecting cell viability up to 48 h after PUVA. In contrast, PUVA did not inhibit gene transcription at anti-proliferative, yet nonlethal conditions. Baseline and phorbol-ester induced c-jun mRNA expression was not inhibited, nor was baseline and IFN-gamma or phorbol-ester induced intercellular adhesion molecule-1 mRNA expression. In order to assess possible transcriptional effects of PUVA-generated reactive oxygen intermediates, the reactive oxygen intermediates-sensitive transcription factor nuclear factor kappaB was assayed in mobility shift experiments. Nuclear factor kappaB-specific binding activity was not induced 1-24 h after PUVA in extracts from PUVA-treated cells when compared with controls, whereas the pro-oxidant cytokine TNF-alpha caused a marked increase in nuclear factor kappaB binding. The presented data suggest that PUVA inhibits cell proliferation, but not transcription, at nonlethal PUVA conditions. Furthermore, the data do not support a major role for PUVA-generated reactive oxygen intermediates in the regulation of gene transcription.

A 38-year-old woman infected with human immunodeficiency virus (HIV) presented with persistent oral candidosis in which non-albicans Candida strains were the predominant yeasts in most of the examinations performed over a period of 6 years. Oral treatment with fluconazole had no effect on clinical signs of oral candidosis. In 8 of a total of 11 specimens, Candida glabrata, Candida parapsilosis and Candida tropicalis were at least suspected as the causative pathogens of oral candidosis. The non-response to fluconazole in our patient could be explained by in vitro resistance to fluconazole of detected Candida glabrata and Candida tropicalis isolates.

Summary. The introduction of HIV protease inhibitors was accompanied by reduction in HIV-associated opportunistic infections. Therefore, we performed a retrospective study of HIV-infected patients to evaluate the effects of therapy with an HIV protease inhibitor (PI) on oral candidosis. This was of special interest, because an important virulence factor of Candida albicans is the secreted aspartic protease (SAP), which is assigned to the same class of aspartic proteases as HTV protease. Sixty-two patients were examined five times over a period of 2 years. There was a hint at a difference in the frequencies of C. albicans carrier state and manifest oral candidosis in favour of treatment with a PI. In addition, loss of Candida colonization and manifest oral candidosis was observed only in patients with elevation of CD4 cells upon PI. This might explain the effect, which also might go back to a direct inhibition of yeast SAP. Zusammenfassung. Die Einfuhrung von HIV-Protease-Inhibitoren bewirkte eine Reduktion HIV-assoziierter opportunistischer Infektionen. Wir haben daher in einer retrospektiven Studie an HIV-infizierten Patienten die Wirkung der HIV-Protease-Inhibitor-Therapie auf die orale Candidose untersucht. Dies war von besonderem Interesse, weil ein Hauptvirulenzfaktor von Candida albicans die sekretorische Aspartatprotease (SAP) darstellt, die zur selben Klasse der Aspartatproteasen gehort wie die HIV-Protease. Es wurden 62 Patienten funfmal uber eine Periode von zwei Jahren hinweg untersucht. Es zeigte sich ein Trend zum Haungkeitsunterschied des C. albicans-Keimtragerstatus und der manifesten oralen Candidose zugunsten der Behandlung mit Protease-Inhibitoren. Ferner wurde der Ruckgang der Candida-Besiedlung und der manifesten oralen Candidose nach Protease-Inhibitorgaben nur bei Patienten mit erhohter CD4-Zellzahl beobachtet. Diese Beobachtungen legen nahe, die Wirkung als immunologisch eher denn mikrobiologisch vermittelt zu betrachten.

Synthetic oligodeoxynucleotides containing CpG dinucleotides (CpG-ODN) mimic the immunostimulatory qualities of bacterial DNA. We asked whether immunostimulation by CpG-ODN predisposes for a commitment toward a Th1 vs a Th2 response in Leishmania major infection, a model for a lethal Th2-driven disease, in BALB/c mice. CpG-ODN induced Th1 effector T cells in vitro and conveyed protective immunity to disease-prone BALB/c mice in vivo. Conversion to a Th1-driven resistant phenotype was associated with IL-12 production and maintained the expression of IL-12R β2-chains. Most strikingly, CpG-ODN were even curative when given as late as 20 days after lethal L. major infection, indicating that CpG-ODN revert an established Th2 response. These findings imply an important role of bacterial DNA and CpG-ODN in the instruction of adaptive immune responses. They also point to the therapeutic potential of CpG-ODN in redirecting curative Th1 responses in Th2-driven disorders.

Summary Confluent and reticulated papillomatosis is a rare dermatosis of unknown etiology mostly affecting young males and females most common in adolescence. The eruption consists of confluent, flat, brown papules forming a pigmented reticulated pattern. It occurs primarily in the intermammary and epigastric regions but may spread to the axillae. A 27-yearold patient with typical clinical and histologic features of confluent and reticulated papillomatosis responded well to oral minocycline. Zusammenfassung Die Papillomatosis confluens et reticularis ist eine seltene und atiologisch unklare Dermatose des jungen Erwachsenenalters mit einem Haufigkeitsgipfel kurz nach der Pubertat. Der initiale Befall mit netzartig konfluierenden Papeln findet sich meistens intermammar und im sternoepigastrischen Bereich und kann sich rhombenformig nach kraniokaudal und zu den Achseln ausbreiten.Wir berichten uber einen 27-jahrigen Patienten mit den typischen klinischen und histologischen Befunden einer Papillomatosis confluens et reticularis, welche erfolgreich mit Minozyklin behandelt wurde.

Purpose. To estimate disease activity in patients with systemic sclerosis using contrast-enhanced MRI of the skin. Material and Methods. In a pre-study, sequences of a low-field (0.2 T) scanner (Artoscan, Esaote, Genova, Italy) were optimized for detection of intravenous contrast (0.1 mmol/l Gd-DTPA) in six patients with the autoimmune disease systemic scleroderma. Based on the results of the pre-study, 17 patients with scleroderma (7 sclerotic/10 active inflammatory disease) were scanned using gradient-spoiled 3D GRE sequences (FA 90 °, TR 100 ms, TE 18 ms), which had been established as most sensitive for intravenous contrast. Contrast enhancement of the skin was determined quantitatively by contrast-to-noise ratios (CNR), comparing post- to pre-contrast and dynamic scans (for 6 min, 1 acquisition/min). Patients in the chronic state with sclerodactylia and active inflammation of the hands were considered separately and compared to a control group (n = 10) matched according to age. Results. CNR increase after intravenous contrast was significantly higher in patients with active disease (86 ± 16 % increase) than sclerosing disease (29 ± 3 %, p < 0.05) and the control group (4 ± 2 %, p < 0.05). The dynamic examination showed a significantly slower decrease after the peak rise in the first minute in patients with active disease (CNR 15.4 ± 0.7 to 14.2 ± 1.4) than in those with chronic disease (14.1 ± 0.5 to 11.3 ± 0.9, p < 0.05). Discussion. Capillary leakage is the most likely explanation for the increased enhancement in patients with active scleroderma. Using sequences optimized for contrast detection, disease activity in the course of scleroderma and response to therapy can be determined by MRI in the future.

Fractionated irradiation with X-rays or megavoltage is an important therapeutic option in the palliative treatment of Kaposi's sarcoma. We report on three HIV patients demonstrating bullous cutaneous eruptions in the irradiation field. Three homosexual men (age 45-60 y) stage of disease CDC 3C, were treated with fractionated soft X-rays with the scheme conventionally used by us (total dose 30 Gy, single doses 3 Gy). Immediately to three days after completion of treatment large blisters appeared within the irradiation field, resolving after 2-4 weeks, leaving post-inflammatory hyperpigmentation. The cause of this rare reaction to soft X-ray therapy, potentially suggesting an individually altered radiation sensitivity, is so far unknown. Controlled prospective studies applying different fractionation schemes will be necessary to better elucidate this issue.

Summary Narrow band (311 nm) ultraviolet B (NB-UVB) has been shown to be a safe and effective treatment for psoriasis and other inflammatory skin diseases. We have therefore employed NB-UVB in the treatment of small plaque parapsoriasis (SPP) since 1996. All patients (16/16) responded with complete remission of the disease after a mean number of 32.8 exposures and a mean total dose of 35.4 J/cm2. Unwanted side-effects were rare (3.3%) and always mild. Relapse of the disease occurred after an average of 29 weeks in those patients who came for follow-up visits. Therefore, NB-UVB is an effective, comparably safe and convenient alternative to psoralen and ultraviolet A therapy or other treatment modalities in the suppression of SPP.

Data from different laboratories and theoretical considerations challenge our current view on anticancer immunity. Immune cells are capable of destroying cancer cells under in vitro and in vivo conditions. Therefore, cellular immunity is considered to control cancers through mechanisms that kill cancers. Yet, therapeutic anticancer immune responses rarely delete cancers. If efficient, they rather establish a life with stable disease. This raises the question of whether killing is the sole mechanism by which immune therapy attacks cancers. Here, we show that, besides cancer eradication by cytotoxic lymphocytes, other modes of action are operative and strictly required for cancer control. We show that T helper-1 cells arrest cancer growth by driving cancers into a state of stable or permanent growth arrest, called senescence. Such immune cells establish cytokine-producing walls around developing cancers. When producing interferon-γ and tumor necrosis factor, this cytokine-induced tumor immune-surveillance keeps the cancer cells in a permanently non-proliferating state. Simultaneously, antiangiogenic chemokines cut their connections to the surrounding tissues. This strategy significantly reduces tumor burden and prolongs life of cancer-bearing animals. As human cancers also undergo senescence, the current data suggest tumor-immune surveillance through cytokine-induced senescence, instead of tumor eradication, as the more realistic and primary goal of cancer control.

The aim of this study was to evaluate the impact of different anesthetics on 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) uptake in carcinomas and arthritic ankles. To determine the amount of [18F]FLT uptake in subcutaneous CT26 colon carcinomas or arthritic ankles, spontaneously room air/medical air-breathing mice were anesthetized with isoflurane, a combination of medetomidine/midazolam, or ketamine/xylazine. Mice were kept conscious or anesthetized during [18F]FLT uptake before the 10-minute static positron emission tomographic (PET) investigations. [18F]FLT uptake in CT26 colon carcinomas and arthritic ankles was calculated by drawing regions of interest. We detected a significantly reduced (4.4 ± 0.9 %ID/cm3) [18F]FLT uptake in the carcinomas of ketamine/xylazine-anesthetized mice compared to the [18F]FLT-uptake in carcinomas of medetomidine/midazolam- (7.0 ± 1.5 %ID/cm3) or isoflurane-anesthetized mice (6.4 ± 1.5 %ID/cm3), whereas no significant differences were observed in arthritic ankles regardless of whether mice were anesthetized or conscious during tracer uptake. The time-activity curves of carcinomas and arthritic ankles yielded diverse [18F]FLT accumulation related to the used anesthetics. [18F]FLT uptake dynamics are different in arthritic ankles and carcinoma, and the magnitude and pharmacokinetics of [18F]FLT uptake are sensitive to anesthetics. Thus, for preclinical in vivo [18F]FLT PET studies in experimental tumor or inflammation models, we recommend the use of isoflurane anesthesia as it yields a stable tracer uptake and is easy to handle.

Background Atopic dermatitis (AD) is a T cell–mediated inflammatory skin disease, with T H 2 cells initiating acute flares. This inflamed skin is immediately colonized with Staphylococcus aureus , which provides potent Toll-like receptor (TLR) 2 ligands. However, the effect of TLR2 ligands on the development of T H 2-mediated AD inflammation remains unclear. Objective We investigated the progression of T H 2 cell–mediated dermatitis after TLR2 activation. Methods Using models for acute AD with T H 2 cells initiating cutaneous inflammation, we investigated the consequences of TLR2 activation. Dermatitis, as assessed by changes in ear skin thickness and histology, was analyzed in different BALB/c and C57BL/6 wild-type and knockout mouse strains, and immune profiling was carried out by using in vitro and ex vivo cytokine analyses. Results We show that T H 2 cell–mediated dermatitis is self–limiting and depends on IL-4. Activation of TLR2 converted the limited T H 2 dermatitis to chronic cutaneous inflammation. We demonstrate that the concerted activation of TLR2 and IL-4 receptor on dendritic cells is sufficient for this conversion. As an underlying mechanism, we found that the combinatorial sensing of the innate TLR2 ligands and the adaptive T H 2 cytokine IL-4 suppressed anti-inflammatory IL-10 and consequently led to the exacerbation and persistence of dermatitis. Conclusion Our data demonstrate that innate TLR2 signals convert transient T H 2 cell–mediated dermatitis into persistent inflammation, as seen in chronic human AD, through IL-4–mediated suppression of IL-10. For the first time, these data show how initial AD lesions convert to chronic inflammation and provide another rationale for targeting IL-4 in patients with AD, a therapeutic approach that is currently under development.

Epidermolysis bullosa (EB) is a heterogeneous group of inherited diseases characterized by the formation of blisters in the skin and mucosa. There is no cure or effective treatment for these potentially severe and fatal diseases. Over the past few years, several reports have proposed different molecular strategies as new therapeutic options for the management of EB. From classical vector-based gene therapy to cell-based strategies such as systemic application of bone marrow stem cells or local application of fibroblasts, a broad range of molecular approaches have been explored. This array also includes novel methods, such as protein replacement therapy, gene silencing and the use of induced pluripotent stem cells (iPCs). In this review, we summarize current concepts of how inherited blistering diseases might be treated in the future and discuss the opportunities, promises, concerns and risks of these innovative approaches.

Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-γ and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-γ- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-)Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.

A HIV-infected patient in stage CDC 3A with porphyria cutanea tarda (type I) was treated with chloroquin for some months and this led to full remission. The patient course is compared with earlier reports on HIV-infected patients with porphyria cutanea tarda. Possible provocation factors for porphyria cutanea tarda in HIV infection are considered. The increased prevalence of porphyria cutanea tarda in HIV infection, the interaction of HIV and UV irradiation as a prediposing factor for porphyria cutanea tarda and the photosensitivity present in HIV infection are discussed.

The aim of this work was to study the feasibility of measuring cell proliferation noninvasively in vivo during different stages of experimental arthritis using the PET proliferation tracer 3′-deoxy-3′-18F-fluorothymidine (18F-FLT). Methods: We injected mice with serum containing glucose-6-phosphate-isomerase–specific antibodies to induce experimental arthritis, and we injected control mice with control serum. Animals injected with 18F-FLT 1, 3, 6, and 8 d after the onset of disease were analyzed in vivo by PET, PET/CT, or PET/MR imaging followed by autoradiography analysis. The 18F-FLT uptake in the ankles and forepaws was quantified on the basis of the PET images by drawing standardized regions of interest. To correlate the in vivo PET data with cell proliferation, we performed Ki-67 immunohistochemistry of diseased and healthy joints at the corresponding time points. Results: Analysis of the different stages of arthritic joint disease revealed enhanced 18F-FLT uptake in arthritic ankles (2.2 ± 0.2 percentage injected dose per gram [%ID/g]) and forepaws (2.1 ± 0.3 %ID/g), compared with healthy ankles (1.4 ± 0.3 %ID/g) and forepaws (1.5 ± 0.5 %ID/g), as early as 1 d after the glucose-6-phosphate-isomerase serum injection, a time point characterized by clear histologic signs of arthritis but only slight ankle swelling. The 18F-FLT uptake in the ankles (3.5 ± 0.3 %ID/g) reached the maximum observed level at day 8. Ki-67 immunohistochemical staining of the arthritic ankles and forepaws revealed a strong correlation with the in vivo 18F-FLT PET data. PET/CT and PET/MR imaging measurements enabled us to identify whether the 18F-FLT uptake was located in the bone or the soft tissue. Conclusion: Noninvasive in vivo measurement of cell proliferation in experimental arthritis using 18F-FLT PET is a promising tool to investigate the extent of arthritic joint inflammation.

Through the release of distinct sets of cytokines, Th1 and Th2 cells exert characteristic and often mutually exclusive or antagonistic immune effector functions. In the present report, we document and discuss several findings on the induction mechanisms of these cellular subtypes and present recent findings on their respective functions in vivo. The preferential induction of Th1 or Th2 cytokine patterns in mature CD4+ T cells is generally attributed to the action of cytokines. In addition, there is evidence that prolonged T-cell receptor occupancy may induce the development of the Th2 phenotype. Prolonged occupancy of the T-cell receptor provides enough autocrine inter-leukin-4 to permit induction of the Th2 phenotype. Both Thl and Th2 cells may be derived from a single mature CD4+ T cell, providing strong evidence for post-thymic modulation of the T-cell cytokine profile and rendering the possibility of predetermined cytokine patterns in T cells unlikely. CD4+ Th1 cells mediate the tumor necrosis factor– and interferon-γ– dependent classic delayed type hypersensitivity reaction. We found that Th2 cells were also capable of mediating local inflammatory reactions that depended on their prototypic lymphokine interleu-kin-4, and, in high tumor necrosis factor-producing mouse strains, upon tumor necrosis factor-α. Both Th-cell subsets induced cellular infiltrates that were not distinguishable on histologic grounds. In contrast to the widely accepted belief that only Th1 cells can mediate delayed hypersensitivity reactions, our results demonstrate that T cells with either lymphokine profile can cause tissue inflammation with leukocytic infiltrates. J Invest Dermatol 105:8S-13S, 1995