Biomedical subjects

J G Krueger

Publications and source records attributed to J G Krueger.

At least 19 recordsLinked to original sources

PubMed2006

Psoriasis: genetic associations and immune system changes.

Psoriasis is a common inflammatory skin disease characterized by infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. Psoriasis is currently thought of as a T-cell mediated 'Type-1' autoimmune disease. Gene expression changes in psoriasis lesions have been well documented, and strongly support an important role for tumor necrosis factor and interferon gamma signal pathways in its pathogenesis. The strongest genetic determinant of psoriasis identified to date lies within the class I region of the multiple histocompatibility locus antigen cluster, although its low penetrance implicates a requirement for other genetic risk factors. Multiple genome-wide linkage and an increasing number of association studies have been carried out, leading to multiple linkage peaks, and the identification of potential low risk variants. A number of these variants lie within genes encoding components of the immune system. However, the functional relationships between predisposing genetic variation is unclear, and presumably involves genetic susceptibility factors affecting both immune cell activation and keratinocyte differentiation. The interaction of environmental trigger factors with genetic effects is also not understood, but provide further evidence for the complex basis of this disease.

Animals↗

PubMed2005

Psoriasis pathophysiology: current concepts of pathogenesis.

Psoriasis vulgaris is a common skin disorder characterised by focal formation of inflamed, raised plaques that constantly shed scales derived from excessive growth of skin epithelial cells. The disease is defined by a series of linked cellular changes in the skin: hyperplasia of epidermal keratinocytes, vascular hyperplasia and ectasia, and infiltration of T lymphocytes, neutrophils, and other types of leucocyte in affected skin. In a relatively short period, psoriasis vulgaris has been conceptualised as a T lymphocyte mediated autoimmune disease and new biological therapies that target T cells have just entered routine clinical practice. Similarly, rapid progress has been made towards dissecting cellular and molecular pathways of inflammation that contribute to disease pathogenesis. This short review presents current pathogenic concepts that have emerged from genetic, genomic, and cellular information obtained in basic studies and from clinical studies of selective immune targeting drugs.

Animals↗

PubMed2004

Psoriasis genomics: analysis of proinflammatory (type 1) gene expression in large plaque (Western) and small plaque (Asian) psoriasis vulgaris.

BACKGROUND: Type 1 T cells are hypothesized to be central in the immunopathogenesis of psoriasis. Through elaboration of interferon (IFN)-gamma, type 1 T cells regulate the expression of many 'downstream' inflammatory genes, including an array of chemokines that regulate leucocyte trafficking and activation in skin lesions. Accordingly, disease progression and/or severity might be controlled by the degree to which differing cytokines and chemokines are overexpressed in focal skin regions. To examine this possibility, we studied two forms of chronic psoriasis vulgaris that differ significantly in overall severity and progression: small plaque (SP) psoriasis occurring in Korean patients, and large plaque (LP) psoriasis occurring in North American patients. OBJECTIVES: To characterize LP and SP psoriasis vulgaris with respect to expression of proinflammatory genes that define the type 1 T-cell axis in skin lesions [genes encoding interleukin (IL)-12, IFN-gamma, and IFN-gamma-regulated chemokines or inflammatory mediators]. METHODS: Total cellular RNA of skin samples from groups of patients with LP or SP psoriasis was analysed by quantitative reverse transcription-polymerase chain reaction (TaqMan analysis) to compare the differences in mRNA expression of genes related to the IFN-gamma pathway. RESULTS: The mRNA expression of keratin 16, CD25, IFN-gamma, IL-12 p40, signal transducer and activator of transcription-1, inducible nitric oxide synthase, IL-8, macrophage inflammatory protein-3alpha, monocyte chemoattractant protein-1, S100A12, IFN-gamma-inducible protein of 10 kDa, IFN-inducible T-cell alpha-chemoattractant and monokine induced by IFN-gamma was increased in the lesions of both LP psoriasis and SP psoriasis. However, IL-18 mRNA expression was significantly different in the lesions of LP psoriasis in comparison with those of SP psoriasis. CONCLUSIONS: The results indicate that proinflammatory type 1 genes regulated by IFN-gamma are similarly increased in both SP and LP psoriasis, but a potential difference in IL-18 exists between these disease forms. The consistent activation of this set of genes argues for a central role of IFN-gamma as a molecular regulator of inflammation in these distinct subtypes of psoriasis vulgaris. In contrast, disease extent/severity must be controlled by yet other factors.

Adult↗

PubMed2001

Potential role of the chemokine receptors CXCR3, CCR4, and the integrin alphaEbeta7 in the pathogenesis of psoriasis vulgaris.

Various adhesion molecules have been implicated in T lymphocyte binding to dermal vascular endothelium in psoriasis vulgaris, but the chemotactic signals that promote subsequent homing into the adjacent dermis and overlying epidermis are poorly defined. We studied chemokine receptor (CCR1-CCR5, CXCR1-CXCR3), chemokine (interferon-gamma inducible protein 10 [IP-10]), monokine induced by interferon-gamma (MIG), thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), and adhesion molecule (cutaneous lymphocyte antigen [CLA], E-selectin, lymphocyte function-associated antigen-1 [LFA-1], intercellular adhesion molecule-1 [ICAM-1], very late antigen 4 [VLA-4], vascular cell adhesion molecule-1 [VCAM-1], alphaEbeta7, and E-cadherin) expression in psoriasis by immunohistology, flow cytometry, and molecular techniques. CXCR3 and CCR4 were expressed by dermal CD3+ lymphocytes, and their chemokine ligands, IP-10, MIG, TARC, and MDC, were up-regulated in psoriatic lesions. Keratinocytes stimulated with tumor necrosis factor-alpha and interferon-gamma up-regulated expression of IP-10, MIG, and MDC mRNA, whereas dermal endothelial cells, similarly stimulated, up-regulated expression of IP-10, MDC, and TARC mRNA, suggesting that these cell types were sources of the chemokines detected in biopsies. There was enhanced expression of E-selectin, CLA, LFA-1, ICAM-1, VLA-4, VCAM-1, and alphaEbeta7 in psoriatic lesions versus nonlesional skin. Finally, intra-epidermal CLA+ and alphaEbeta7+ T lymphocytes selectively expressed the chemokine receptor CXCR3. Collectively, these data suggest that CXCR3 and CCR4 may be involved in T lymphocyte trafficking to the psoriatic dermis and that CXCR3 is selectively involved in subsequent T cell homing to the overlying epidermis.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2001

Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling.

Psoriasis is recognized as the most common T cell-mediated inflammatory disease in humans. Genetic linkage to as many as six distinct disease loci has been established but the molecular etiology and genetics remain unknown. To begin to identify psoriasis disease-related genes and construct in vivo pathways of the inflammatory process, a genome-wide expression screen of multiple psoriasis patients was undertaken. A comprehensive list of 159 genes that define psoriasis in molecular terms was generated; numerous genes in this set mapped to six different disease-associated loci. To further interpret the functional role of this gene set in the disease process, a longitudinal pharmacogenomic study was initiated to understand how expression levels of these transcripts are altered following patient treatment with therapeutic agents that antagonize calcineurin or NF-KB pathways. Transcript levels for a subset of these 159 genes changed significantly in those patients who responded to therapy and many of the changes preceded clinical improvement. The disease-related gene map provides new insights into the pathogenesis of psoriasis, wound healing and cellular-immune reactions occurring in human skin as well as other T cell-mediated autoimmune diseases. In addition, it provides a set of candidate genes that may serve as novel therapeutic intervention points as well as surrogate and predictive markers of treatment outcome.

Adult↗

PubMed2001

The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody.

BACKGROUND: Anti-CD11a (hu1124) is a humanized monoclonal antibody directed against the CD11a subunit of LFA-1. This study investigated whether treatment with anti-CD11a antibody provides clinical benefit to patients with moderate to severe plaque psoriasis. METHODS: This was a double-blind, placebo-controlled, phase II, multicenter study. In total, 145 patients with minimum Psoriasis Area and Severity Index scores of 12 and affected body surface area of 10% or more were sequentially enrolled into low-dose (0.1 mg/kg, n = 22) or high-dose (0.3 mg/kg, n = 75) groups. Within groups, patients were randomized to treatment or placebo (n = 48) in a 2:1 ratio. Drug was administered intravenously at weekly intervals for 8 weeks. RESULTS: The percentage of subjects achieving more than 50% improvement in physician's global assessment at day 56 (1 week after final dose) was 15% and 48% for placebo and 0.3 mg/kg of drug, respectively (P =.002). A physician's global assessment of excellent (>75% improvement) was greater in the 0.3 mg/kg group versus placebo (25% vs 2%, P =.0003). Average Psoriasis Area and Severity Index scores at day 56 were 13.9 +/- 7.5 (placebo) and 10.9 +/- 8.4 (0.3 mg/kg) (P <.0001). Epidermal thickness was reduced in the 0.3 mg/kg group compared with the placebo group (37% vs 19%, P =.004). Treatment was well tolerated; mild to moderate flu-like complaints were the most common adverse events. White blood cell counts and lymphocyte counts transiently increased. Depletion of circulating lymphocytes did not occur. CONCLUSIONS: Anti-CD11a antibody administered intravenously in 8 weekly doses of 0.3 mg/kg was well tolerated and induced clinical and histologic improvements in psoriasis.

Adult↗

PubMed2001

Microdialysis can detect age-related differences in glucose distribution within the dermis and subcutaneous adipose tissue.

BACKGROUND: Intrinsic (chronological) cutaneous aging is a continuous and complex process. Limitation in nutrient supply to the skin could contribute to this process. OBJECTIVE: Our study focused on the impact of age on glucose supply to human skin and its distribution within the dermis and subcutaneous adipose tissue. METHODS: An oral glucose load (100 g) was given to healthy volunteers of two age groups (24 +/- 4 and 59 +/- 10 years, n = 4 for each group). Dialysate concentrations of glucose and glycerol were monitored by microdialysis in the dermis and adipose tissue. RESULTS: Baseline tissue [glucose] did not differ significantly between the two groups. After the glucose load, dialysate [glucose] of the dermis peaked between 60 and 80 min and between 80 and 120 min in the young and old groups, respectively. In the old group, dialysate [glucose] was significantly higher in the dermis than adipose tissue at 80, 100, 120, 160 and 180 min after the load. The sum of the areas under the curve (dermis + adipose tissue) did not differ significantly between the two age groups. CONCLUSIONS: Aging is accompanied by an increased diffusion barrier for glucose between the dermis and adipose tissue.

Adipose Tissue↗

PubMed2000

Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells.

Efficient T cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s) important in T cell activation. We investigated the dependence of pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium. This study highlights the critical and proximal role of T cell activation through the B7-CD28/CD152 costimulatory pathway in maintaining the pathology of psoriasis, including the newly recognized accumulation of mature DCs in the epidermis.

Abatacept↗

PubMed2000

CD69, HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry.

Many lymphocyte-activation-associated molecules are observed by immunohistochemistry in psoriasis vulgaris lesional skin. Non-T cells in lesional skin also express these molecules. We quantitatively measured the number of T cells expressing cell surface activation-associated molecules (CD69, CD25, CD122, HLA-DR) and co-stimulatory molecules (CD28, CTLA-4, CD80, CD86), including a Type 2 T cell marker (CD30) and CD11b, by flow cytometry of skin and peripheral blood. T cells in single cell suspensions of psoriatic lesional-epidermis-expressed HLA-DR (86%), CD69 (59%), CD25 (55%), CD122 (44%), and CD28 (91%). Dermal T cells showed similar percentages except for CD69 (17%). CD69 was found directly in lesional skin biopsies by immunohistochemistry. Both CD4 and CD8 subsets from lesional skin contained large populations of CD25+ cells with a bias towards CD8 activation in the epidermis and towards CD4 activation in the dermis. CD86, CD80, CTLA-4, CD30 and CD11b were expressed by less than 23% of the T cell populations from both the epidermis and dermis. CD30+CD4+ cells were found two-fold over CD8+ T cells. These results show that the majority of lesional lymphocytes are persistently activated. We also found the majority of Type 2 associated markers primarily on the CD4+ epidermal T cell population. Psoriatic blood contained elevated levels of T cells expressing CD25, primarily within the CD8+ subset. Thus the majority of lesional T cells expressed the three primary activation markers, while psoriatic blood T cells were distinguished by an increase in CD25, specifically within the CTL population.

Abatacept↗

PubMed2000

Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis.

BACKGROUND: CD11a/CD18 comprise subunits of leukocyte function associated antigen (LFA-1), a T-cell surface molecule important in T-cell activation, T-cell emigration into skin, and cytotoxic T-cell function. OBJECTIVE: We explored the immunobiologic and clinical effects of treating moderate to severe psoriasis vulgaris with a single dose of humanized monoclonal antibody against CD11a (hu1124). METHODS: This was an open label study with a single dose of hu1124 at doses of 0.03 to 10 mg/kg. Clinical (Psoriasis Area and Severity Index [PASI]) and immunohistologic parameters (epidermal thickness, epidermal and dermal T-cell numbers, and keratinocyte intercellular adhesion molecule 1 [ICAM-1] expression) were followed. RESULTS: Treatment with hu1124, at doses higher than 1.0 mg/kg (group III), completely blocks CD11a staining for at least 14 days in both blood and psoriatic plaques. At 0.3 to 1.0 mg/kg, T-cell CD11a staining was completely blocked; however, blockade lasted less than 2 weeks (group II). Only partial saturation of either blood or plaque cellular CD11a was observed at doses of hu1124 between 0.01 and 0.1 mg/kg (group I). This pharmacodynamic response was accompanied by decreased numbers of epidermal and dermal CD3(+) T cells, decreased keratinocyte and blood vessel expression of ICAM-1, and epidermal thinning. Statistically significant drops in PASI compared with baseline were observed in group II patients at weeks 3 and 4 and in group III patients at weeks 2 through 10. No significant drop in PASI score was observed in group 1. Adverse events were mild at doses of 0.3 mg/kg or less and included mild chills, abdominal discomfort, headache, and fever. At a single dose of 0.6 mg/kg or higher, headache was the most common dose-limiting toxicity observed. CONCLUSION: Targeting CD11a may improve psoriasis by inhibiting T-cell activation, T-cell emigration into the skin, and cytotoxic T-cell function.

Antibodies, Monoclonal↗

PubMed2000

Two considerations for patients with psoriasis and their clinicians: what defines mild, moderate, and severe psoriasis? What constitutes a clinically significant improvement when treating psoriasis?

The definitions of psoriasis severity and clinically significant improvement in psoriasis are used to classify treatments, obtain Food and Drug Administration approval, and determine product labeling and reimbursement. The Medical Advisory Board of the National Psoriasis Foundation has addressed these issues because of their importance in the clinical trials that are conducted to gain FDA approval of indications. Narrow indications, which are without a sound rational basis, will-in this era of constant oversight by third party payers-affect physicians' ability to manage patients with psoriasis. Body surface area (BSA) is usually used to define severity for clinical trials. It is not optimal for defining psoriasis severity because there are some patients with low BSA involvement who have very severe psoriasis and some patients with high BSA involvement who have mild psoriasis. We conclude that a quality of life (QOL) standard is better than BSA measurement for identifying patients with severe psoriasis. The second issue is what defines clinically significant improvement for patients with psoriasis. Setting an arbitrarily high criterion of clinical efficacy for new psoriasis treatments will likely limit the development and approval of useful treatments. To maximize the availability of useful psoriasis treatments, it is our thesis that psoriasis treatments should be approved when they have been shown to produce a statistically significant level of improvement in well-designed clinical trials.

Humans↗

PubMed2000

Successful in vivo blockade of CD25 (high-affinity interleukin 2 receptor) on T cells by administration of humanized anti-Tac antibody to patients with psoriasis.

BACKGROUND: Daclizumab is a humanized antibody to the alpha-subunit (CD25) of the interleukin 2 (IL-2) receptor that blocks normal IL-2 binding to this receptor. Because IL-2 is a major stimulus for T-cell growth, blockade of the IL-2 receptor could be useful in treating T-cell-mediated (autoimmune) diseases. OBJECTIVE: Our purpose was to determine whether adequate concentrations of antibody were achieved in circulating blood and in psoriatic skin lesions to saturate CD25 receptors. We also intended to measure clinical effect and safety of this agent when used alone (without other immunosuppressive drugs) in psoriasis. METHODS: Nineteen patients with psoriasis in two centers received daclizumab at an initial dose of 2 mg/kg, then 1 mg/kg at weeks 2, 4, 8, and 12. To determine whether CD25 was blocked in vivo, flow cytometric studies measured (1) expression of CD25 on CD3(+) T cells derived from blood and (2) immuno-histochemistry measures of CD25(+) cells done on pretreatment and posttreatment biopsy specimens. Patients were followed up clinically with photographs and Psoriasis Area and Severity Index scores. RESULTS: This study showed a consistent blockade of CD25 in peripheral blood and tissue during the first 4 weeks of therapy while the dosing was every 2 weeks. Variable desaturation of receptors began after 4 weeks, which correlated with a reversal in disease improvement. Patients with a pretreatment Psoriasis Area and Severity Index score of less than 36 showed a mean reduction in severity by 30% at 8 weeks (P =.02). During the 16 weeks of treatment, a 44.8% decrease in expression of the IL-2 receptor alpha-subunit was found. The absolute T-cell counts were calculated and showed no significant changes during the course of the study. No significant adverse events were produced by daclizumab during this study. CONCLUSION: We therefore conclude that daclizumab is a well-tolerated agent that blocks CD25 expression in peripheral blood and skin. Furthermore, it may be useful in treating psoriasis in some patients.

Adult↗

PubMed2000

Anti-CD4 monoclonal antibody treatment of moderate to severe psoriasis vulgaris: results of a pilot, multicenter, multiple-dose, placebo-controlled study.

BACKGROUND: OKTcdr4a (IMUCLONE) is a humanized anti-CD4 IgG4 monoclonal antibody that retains the binding and in vitro immunosuppressive properties of the parent murine antibody. Psoriasis is a chronic disease for which treatment with multiple doses of monoclonal antibodies is likely to be required for adequate control. OBJECTIVE: This study was performed to test the efficacy and safety of OKTcdr4a, given in sequential courses over a period of several weeks, in the treatment of moderate to severe psoriasis vulgaris. METHODS: Twenty-eight patients (45.6 +/- 10.1 years of age) were studied, with a mean pretreatment Psoriasis Area and Severity Index (PASI) score of 18.3. In the first double-blind phase of the study, patients were randomized to receive OKTcdr4a as a 225 mg/course (low dose), 750 mg/course (high dose), or placebo divided into 3 identical infusions over a 5-day period. After 42 days, patients who met the criteria for re-treatment with OKTcdr4a were re-treated with the 750 mg/course in an open phase of the study. RESULTS: After the double-blind course of treatment, the mean PASI decreased by 11% in the placebo group, by 4% in the low-dose group, and by 17% in the high-dose group at 15 days. Twenty patients met the criteria for re-treatment (ie, did not experience a decrease in PASI score of 50% at 42 days). They were re-treated with OKTcdr4a at 43 days with the 750 mg/course in the open phase of the study. By day 99, the mean PASI score decreased from 19.9 at baseline to 17 in those patients who had received either placebo or low-dose OKTcdr4a followed by high-dose OKTcdr4a. In contrast, the mean PASI score decreased from 17.4 at baseline to only 7.7 in those patients who had received high-dose OKTcdr4a for both courses. Sustained CD4 saturation was not necessary for sustained clinical response. No patients had significant changes in circulating CD4(+) T-cell counts. The infusions were well tolerated. CONCLUSION: Targeting CD4 using sequential treatments with a humanized monoclonal antibody (OKTcdr4a) may offer another therapeutic option for the treatment of moderate to severe psoriasis.

Adult↗

PubMed1999

312-nanometer ultraviolet B light (narrow-band UVB) induces apoptosis of T cells within psoriatic lesions.

Narrow-band (312 nm) ultraviolet B light (UVB) is a new form of therapy for psoriasis, but its mechanism of action is unknown. In a bilateral comparison clinical study, daily exposure of psoriatic plaques to broad-band UVB (290-320 nm) or 312-nm UVB depleted T cells from the epidermis and dermis of psoriatic lesions. However, 312-nm UVB was significantly more depleting in both tissue compartments. To characterize the mechanism of T cell depletion, assays for T cell apoptosis were performed on T cells derived from UVB-irradiated skin in vivo and on T cells irradiated in vitro with 312-nm UVB. Apoptosis was induced in T cells exposed to 50-100 mJ/cm2 of 312-nm UVB in vitro, as measured by increased binding of fluorescein isothiocyanate (FITC)-Annexin V to CD3(+) cells and by characteristic cell size/granularity changes measured by cytometry. In vivo exposure of psoriatic skin lesions to 312-nm UVB for 1-2 wk also induced apoptosis in T cells as assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) reaction in tissue sections, by binding of FITC-Annexin V to CD3(+) T cells contained in epidermal cell suspensions, and by detection of apoptosis-related size shifts of CD3(+) cells. Induction of T cell apoptosis could be the main mechanism by which 312-nm UVB resolves psoriasis skin lesions.

Adult↗

PubMed1999

Clinical clearing of psoriasis by 6-thioguanine correlates with cutaneous T-cell depletion via apoptosis: evidence for selective effects on activated T lymphocytes.

BACKGROUND: Psoriasis is a common and persistent disease characterized chiefly by marked epidermal and endothelial cell proliferation and inflammation. These changes are likely a result of activated T lymphocytes infiltrating skin tissue or, in the case of psoriatic arthritis, the joints. OBJECTIVE: To test the hypothesis that the antimetabolite 6-thioguanine (Sigma-Aldrich, St Louis, Mo) might be an effective treatment for psoriasis vulgaris because of its antilymphocytic effects. METHODS: Twenty patients with moderate to severe plaque-type psoriasis were treated with 6-thioguanine for 6 months. The clinical disease was assessed by the psoriasis severity index. Biopsy specimens obtained from lesional skin before treatment and after 1 and 2 months of treatment were examined for disease-related abnormalities using histochemical and computer-assisted image analysis. Antiproliferative effects of 6-thioguanine were compared in human keratinocytes and mitogen-activated lymphocytes over a range of drug concentrations, while viability, cell-cycle, and DNA fragmentation analysis were done using flow cytometry-based assays. RESULTS: After 6 months of treatment, disease severity in 18 of 20 patients showed a significant response to 6-thioguanine: 12 patients were completely cleared of trace disease; 6 showed marked clinical improvement; and 2 did not respond. Patients showed reductions in peripheral blood lymphocytes and total leukocytes, but therapeutic response correlated best with cutaneous T-cell depletion. In vitro assays established that 6-thioguanine has major cytotoxic effects (apparently S-phase specific) on activated T lymphocytes via the induction of apoptosis. Keratinocytes and unactivated T cells, on the other hand, were largely unaffected by incubation with 6-thioguanine. CONCLUSIONS: 6-Thioguanine is effective for the treatment of moderate to severe plaque-type psoriasis, and may be safe when given for defined periods and with careful hematologic monitoring. The mechanism of action of this drug seems to be the induction of apoptosis in activated T lymphocytes.

Administration, Topical↗

PubMed1999

Suberythemogenic narrow-band UVB is markedly more effective than conventional UVB in treatment of psoriasis vulgaris.

BACKGROUND: Narrow-band UVB (NB-UVB) is a new phototherapy option for psoriasis. Action spectrum studies previously done with different UVB wavelengths suggest that suberythemogenic doses of NB-UVB could be highly effective in treating psoriasis vulgaris. Even so, no comparative studies with suberythemogenic doses of NB versus conventional UVB have been performed previously. OBJECTIVE: Our purpose was to compare conventional broad-band UVB (BB-UVB) with NB-UVB at suberythemogenic doses for the treatment of psoriasis vulgaris. METHODS: Eleven patients were treated using a split-body approach for 6 weeks on a three-times-a-week basis. Outcomes were evaluated by means of Psoriasis Severity Index scores and quantitative histologic measures. RESULTS: We were able to induce clinical clearing in 81.8% of patients after NB-UVB, but in only 9.1% of patients after BB-UVB (P < .01). Biopsy specimens obtained at the end of treatment revealed that keratin 16 staining was absent in 75% of patients on the NB side compared with none on the BB side, suggesting a reversal of regenerative epidermal hyperplasia by NB-UVB. CONCLUSION: NB-UVB is superior to UVB-BB in reversing psoriasis at suberythemogenic doses when given three times per week. This schedule was well tolerated by all patients.

Adult↗

PubMed1999

The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients.

Psoriasis vulgaris is a skin disease potentially mediated by pro-inflammatory cytokines produced by type 1 lesional T cells. The capability of individual T cells to produce these cytokines in lesional skin is not known. In this study we measured the ability of lesional and peripheral blood T cells to produce intracellular interferon-gamma, tumor necrosis factor-alpha, interleukin-2, interleukin-4, and interleukin-10 proteins as detected by flow cytometric analysis. Cytokine synthesis was induced by activation with ionomycin/phorbol myristate acetate (in the presence of Brefeldin A, which inhibits the exocytosis of these cytokines). After stimulation, we found relatively high percentages of epidermal CD8 and CD4 T cells capable of producing interferon-gamma, tumor necrosis factor-alpha, and interleukin-2, whereas few T cells, < 11%, expressed interleukin-4 or interleukin-10. Hence both CD8+ and CD4+ T cells are capable of type 1 effector functions (TC1 and TH1, respectively). This activation scheme was repeated on peripheral blood T cells from psoriatic patients versus healthy controls, where we also found a type 1 bias. In order to evaluate quantitatively the type 1 cytokine bias, we compared the frequency of type 2 interleukin-4 producing versus type 1 interferon-gamma producing T cells in our assay and found a shift towards type 1 producing cells. This shift reveals a type 1 differentiation bias in both lesional areas and in the peripheral blood, which may indicate an imbalance within the T cell population, which is contributing to the chronic or sustained immunologic activation of T cells found in this disease.

Adult↗

PubMed1999

PUVA-induced lymphocyte apoptosis: mechanism of action in psoriasis.

Psoralen plus ultraviolet A (PUVA), utilizing oral 8-methoxypsoralen (8-MOP), is a widely utilized and effective treatment for psoriasis vulgaris. Previous studies have suggested that PUVA's mechanism of action in psoriasis is a result of its direct lymphotoxic effects. Trimethylpsoralen (TMP), a potentially safer compound, has been found to be effective in psoriasis during bath water delivery. In this study we examined the relative antilymphocytic effects of TMP and 8-MOP through both flow cytometry and tissue analysis on lesional skin during clinical treatment. Based on FACS analysis on phytohemagglutinin-activated lymphocytes, we found TMP to be nearly 10,000 fold more lymphotoxic compared to 8-MOP. In addition, lymphocytes treated with 8-MOP or TMP with UVA displayed DNA degradation patterns typical of apoptotic cell death. These findings were consistent with our investigation of treated psoriatic skin, with virtual elimination of epidermal CD3+ T-cells following bath water treatment with TMP or 8-MOP. These results support the theory that the therapeutic effects of PUVA stem from its toxic effects on activated lymphocytes. If further investigation supports TMP's lack of carcinogenicity, this potent lymphotoxic treatment may prove to be one of the safest and most effective treatments for psoriasis.

Apoptosis↗