Langerhans cell sensitivity to in vitro versus in vivo loading with cyclosporine A.
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Antigen-Presenting Cells↗
Biomedical subjects
K D Cooper
Publications and source records attributed to K D Cooper.
Human dermal fibroblast interleukin-1 receptor antagonist (IL-1ra) and interleukin-1 beta (IL-1 beta) mRNA and protein are co-stimulated by phorbol ester: implication for a homeostatic mechanism.
Although the major functions of fibroblasts are to produce extracellular matrix and to maintain a structural framework for organ systems, recent studies have demonstrated that fibroblasts are active participants in inflammatory processes by synthesizing various inflammatory mediators. In this report, we provide evidence that fibroblasts may contribute to the regulation of inflammation by the synthesis of both the intracellular form and the secretory form of interleukin-1 receptor antagonists in conjunction with interleukin-1 beta production. Indirect immunofluorescence microscopy localized interleukin-1 receptor antagonist and interleukin-1 beta proteins primarily in the fibroblast cytoplasm. Polymerase chain reaction amplification of reverse-transcribed mRNA with primers specific for the intracellular form of interleukin-1 receptor antagonist detected cDNA fragments present in both unstimulated and phorbol ester-stimulated fibroblasts, identical in molecular size to that in unstimulated keratinocytes. Amplification with primers specific for the secretory form of interleukin-1 receptor antagonist, however, detected cDNA fragments in phorbol ester-stimulated fibroblasts and phytohemagglutinin-stimulated peripheral mononuclear cells, but not in unstimulated fibroblasts or keratinocytes. The amplified fibroblast cDNA sequences for both intracellular and secretory interleukin-1 receptor antagonists were confirmed by digestion with three restriction endonucleases. By ethidium bromide visualization of amplified cDNA derived from serially diluted total cellular RNA and by Southern blot hybridization analysis of amplified cDNA, we have demonstrated that fibroblast interleukin-1 receptor antagonist mRNA and interleukin-1 beta mRNA were co-stimulated by phorbol ester. Similarly, ELISA demonstrated that fibroblast cytoplasmic interleukin-1 receptor antagonist protein and interleukin-1 beta protein were co-stimulated by phorbol ester. Our data suggests that the intracellular form of interleukin-1 receptor antagonist may be important in maintaining physiologic homeostasis in fibroblasts during interleukin-1 beta induction and release.
Base Sequence↗
Expression of growth hormone receptor, insulin-like growth factor 1 (IGF-1) and IGF-1 receptor mRNA and proteins in human skin.
A cDNA corresponding to the membrane receptor for growth hormone (GH) was amplified by polymerase chain reaction (PCR) directly from human skin. The cDNA was cloned and found to have complete sequence homology to the extracellular domain of human liver GH receptor (GH-R). Northern analysis, using the cloned GH-R as probe, revealed relatively higher levels of GH-R transcripts in cultured human dermal fibroblasts compared to cultured keratinocytes or keratome biopsies. Semi-quantitative PCR analysis indicated that the level of GH-R mRNA in cultured melanocytes was similar to that in fibroblasts. The receptor protein encoded by GH-R mRNA in fibroblasts was shown by affinity cross-linking to have an apparent M(r) of 115-120 kDa, similar to that of 3T3-F442A fibroblasts used as a control. mRNA transcripts for the major mediator of GH actions, insulin-like growth factor 1 (IGF-1), were detected by PCR in fibroblasts, melanocytes, and keratome biopsies, but not in keratinocytes. In contrast, IGF-1 receptor mRNA were abundant in cultured keratinocytes and skin biopsies, as determined by Northern analysis. IGF-1 but not GH (5-50 ng/ml) promoted clonal proliferation of cultured keratinocytes. In contrast, GH (10 ng/ml) after 5 d markedly increased fibroblast cell numbers (70%, p less than 0.009) over 0.2% serum control. These data indicate that human skin cells possess the molecular elements necessary to respond to GH and raise the possibility that GH may influence skin growth in vivo.
Base Sequence↗
Skin-infiltrating lymphocytes in normal and disordered skin: activation signals and functional roles in psoriasis and mycosis fungoides-type cutaneous T cell lymphoma.
T lymphocytes recruited into the skin can experience several different outcomes. On the one hand, they may be recruited by adhesion molecules and chemoattractants to enter the perivascular space, but never undergo activation. Other T cells undergo activation and further differentiation under the influence of the cutaneous milieu. These activated lymphocytes then coordinate specific and non-specific immune responses characteristic of inflamed tissue. We have explored two models for studying the activation and function of skin infiltrating T lymphocytes (SIL's). In the first model, we have identified a family of Langerhans cell-related professional dendritic antigen presenting cells that exist in the epidermis and dermis of normal skin, atopic skin, and mycosis fungoides skin. These have APC abilities to activate freshly recruited resting blood T cells that are distinct from another family of macrophage-related cells abnormally present in sunburned or psoriatic skin. In the second model, we examined the function of cells that have already been recruited into the skin of patients with psoriasis and mycosis fungoides. Lesional psoriasis and mycosis fungoides T cells exhibited a variety of T cell receptor gene rearrangements, conclusively demonstrating that heterogeneous populations of T lymphocytes exist in inflamed human skin. From psoriasis, clones were identified that were particularly effective at inducing normal keratinocytes to assume "psoriatic" phenotypic features and functions. Thus, lesional psoriatic SIL's could induce HLA-DR, ICAM, and CDw60 on normal keratinocytes. In addition, psoriatic SIL's induced increased keratinocyte proliferation and cytokine profile changes characteristic of psoriatic epidermis.(ABSTRACT TRUNCATED AT 250 WORDS)
Antigen-Presenting Cells↗
Interleukin-1 receptor antagonist in normal and psoriatic epidermis.
The objective of these studies was to characterize the IL-1 inhibitory activity present in normal and psoriatic epidermis from clinically stable lesions. Fractionation of normal epidermal cytosol on a molecular sizing column failed to reveal the presence of IL-1 inhibitory bioactivity. However, specific ELISAs indicated that both the IL-1 receptor antagonist (IL-1ra) and IL-1 alpha were present in overlapping peaks. Further fractionation of the normal epidermal cytosol by anion exchange chromatography separated these two molecules, revealing the IL-1 inhibitory bioactivity of the IL-1ra molecule. Similar studies on psoriatic epidermal cytosol indicated the presence of IL-1 inhibitory bioactivity and IL-1ra protein. The IL-1 inhibitory bioactivity of both normal and psoriatic cytosol was neutralized by a mAb specific for IL-1ra. The ratio of IL-1ra to IL-1 alpha proteins was significantly increased in involved psoriatic skin compared with normal skin. By Western blot analysis this IL-1ra was approximately 20 kD, slightly larger than monocyte-derived IL-1ra and equivalent to an intracellular variant of IL-1ra expressed by keratinocytes. Polymerase chain reaction indicated the presence of mRNA for both forms of IL-1ra in normal epidermis, with both forms increased in psoriatic-involved skin. Immunofluorescence studies revealed the IL-1ra protein to be concentrated in the stratum granulosum of normal skin and in the basal-midbasal layers of psoriatic epidermis. These results suggest that the balance between intracellular IL-1ra and IL-1 alpha may be an important influence on keratinocyte growth and/or differentiation, as well as on the inflammatory potential of IL-1 in injured skin.
Antibodies, Monoclonal↗
T-cell activation is potentiated by cytokines released by lesional psoriatic, but not normal, epidermis.
BACKGROUND AND DESIGN: T-cell activation appears to be critical for the maintenance of psoriatic lesions. In this study, we determined whether cytokines released by epidermal cells from psoriatic lesions are providing signals that result in propagation of intralesional T-cell activation. Supernatants were obtained from epidermal cell cultures derived from skin biopsy specimens of psoriatic patients and normal subjects. These supernatants were added to purified normal CD4+ T cells activated via T-cell receptor (immobilized anti-CD3 and fibronectin) or via other activating pathways (anti-CDw60 or UM4D4). RESULTS: Psoriatic supernatants (n = 9), but not normal supernatants (n = 7, P < .0006), potentiated T-cell stimulation with anti-CD3 and fibronectin to 172% +/- 41% over control stimulation levels. The degree of lesional psoriatic epidermal cell potentiation correlated with the clinical severity of the lesion (r = .82, P = .007). Psoriatic epidermal cytokine potentiation of T-cell activation was not limited to T-cell receptor mediated stimulation; potentiation of anti-CDw60-stimulated CD4+ T cells was also observed. Neutralizing antisera to interleukin 1 and interleukin 8, but not interleukin 6, were found to reduce only partly the observed potentiation of T-cell activation. To determine whether cyclosporine is down modulating T-cell-potentiating cytokine activity in psoriasis, we compared samples obtained during a double-blind clinical trial of intralesional cyclosporine. T-cell-potentiating activity from psoriatic lesional sites treated with cyclosporine was not significantly modulated relative to the activity derived from vehicle-treated or untreated sites. CONCLUSION: These data demonstrate that lesional psoriatic epidermal cells release a balance of cytokines that potentiate T-cell activation. Because normal epidermal cells do not potentiate T-cell activation in this system, these findings demonstrate a mechanism by which the epidermis may non-specifically potentiate and perpetuate T-cell activation in psoriatic lesions.
CD4-Positive T-Lymphocytes↗
Hyperstimulatory CD1a+CD1b+CD36+ Langerhans cells are responsible for increased autologous T lymphocyte reactivity to lesional epidermal cells of patients with atopic dermatitis.
We studied whether abnormalities in epidermal APC could be responsible for intracutaneous T cell activation in atopic dermatitis (AD). In the absence of added Ag, patients' peripheral blood T cells demonstrated significantly increased proliferation to their autologous lesional epidermal cells (mean +/- SEM = 19,726 +/- 9,754 cpm [3H]TdR uptake) relative to epidermal cells from uninvolved AD skin (2179 +/- 697 cpm) (n = 10) (p = 0.0001, log transformed data). AD T cell proliferative responses to autologous epidermal cells were dependent upon cells expressing HLA-DR, CD1a, and CD36, and not upon keratinocytes or their cytokines. Ultrastructurally, these cells ranged from typical Langerhans cells to indeterminate cells with irregular nuclear contours. Enriched populations of lesional AD Langerhans cells were highly stimulatory for autologous T cells, whereas equal numbers of Langerhans cells from non atopic epidermis were poor stimulators, even at high concentrations. The dermal perivascular dendritic cell markers CD36 and CD1b, not usually present on normal epidermal APC, were expressed by 40 and 60% of lesional AD CD1a+ epidermal Langerhans cells, respectively. Addition of anti-CD1b to cocultures of AD epidermal cells and autologous T lymphocytes augmented T cell activation, suggesting that the expression of CD1b by AD Langerhans cells may represent over expression of a molecule functionally linked to the enhanced T cell stimulatory capacity of these cells. Thus, stimulatory signals for T cells contained within AD epidermis are carried by cells in an abnormal differentiation state as indicated by expression of phenotypic characteristics of both epidermal and dermal antigen presenting cells (HLA-DR+, CD1a+, CD1b+, CD36+). We propose that activation of autologous T cells by an altered cutaneous APC population may represent a mechanism for the hyperactive and disordered cell-mediated immune response that characterizes the dermatitic lesions of AD.
Antigen-Presenting Cells↗
Ocular cicatricial pemphigoid occurring as a sequela of Stevens-Johnson syndrome.
Ocular cicatricial pemphigoid is a chronic scarring inflammation of the ocular mucosae that can lead to blindness. Although cicatricial pemphigoid has been classified clinically, histopathologically, and immunopathologically, no definite initiating factor or precipitating factor has been identified. In this report, we describe five cases of ocular cicatricial pemphigoid that developed following an acute episode of severe ocular inflammatory injury secondary to Stevens-Johnson syndrome. The time lag between the onset of Stevens-Johnson syndrome and cicatricial pemphigoid ranged from a few months to 31 years. All five patients had linear immune deposits characteristic of cicatricial pemphigoid along the basement membrane zone of mucosal biopsy specimens as detected by either direct immunofluorescence microscopy or direct immunoperoxidase staining. In two patients whose serum was tested, a Western blot assay taken of keratinocyte antigens that had undergone electrophoresis reacted with the serum and identified a 120-kd epidermal antigen detected by the IgG class antibodies. All five patients were treated with systemic immunosuppressive therapy for cicatricial pemphigoid, and we obtained objective responses. Severe ocular mucosal injury such as that which occurs in Stevens-Johnson syndrome may be a precipitating factor in the development of ocular cicatricial pemphigoid.
Adult↗
Urticaria and angioedema: diagnosis and evaluation.
Because urticaria clears spontaneously in most patients, an extensive workup is not advised during the early weeks of an urticarial eruption. Whether and when to perform a screening workup or a more extensive workup depend on the degree of suspicion that the patient is ill, the urgency with which the patient presses for an answer, and the presence or absence of signs or symptoms that might lead the physician to pursue a diagnosis other than chronic idiopathic urticaria. Angioedema may occur with urticaria, and when it does, the prognosis is worse. Whereas urticaria manifests as circumscribed edema involving the superficial dermis, angioedema involves primarily the deep dermis or subcutaneous or deeper layers. Individual urticarial lesions usually disappear within 2 to 4 hours, whereas those of angioedema can persist for 72 hours. The workup for patients with chronic angioedema can be similar to that for patients with urticaria. However, several additional diagnostic possibilities should be pursued in patients with angioedema, such as hereditary angioedema caused by C1-esterase inhibitor deficiency, because anabolic steroids are effective in the treatment of these conditions.
Angioedema↗
Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells.
Determination of the cell types proliferating in the dermis of patients with psoriasis should identify those cells experiencing activation or responding to growth factors in the psoriatic dermal milieu. Toward that end, sections of formalin-fixed biopsies obtained from 3H-deoxyuridine (3H-dU)-injected skin of eight psoriatic patients were immunostained, followed by autoradiography. Proliferating dermal cells exhibit silver grains from tritium emissions. The identity of the proliferating cells could then be determined by simultaneous visualization with antibodies specific for various cell types. UCHL1+ (CD45RO+) T cells (recall antigen-reactive helper T-cell subset) constituted 36.6 +/- 3.1% (mean +/- SEM, n = 6) of the proliferating dermal cells in involved skin, whereas Leu 18+ (CD45RA+) T cells (recall antigen naive T-cell subsets) comprised only 8.7 +/- 1.5% (n = 6). The Factor XIIIa+ dermal perivascular dendritic cell subset (24.9 +/- 1.5% of proliferating dermal cells, n = 6) and Factor VIII+ endothelial cells (23.0 +/- 2.3%, n = 6) represented the two other major proliferating populations in lesional psoriatic dermis. Differentiated tissue macrophages, identified by phase microscopy as melanophages or by immunostaining with antibodies to Leu M1 (CD15) or myeloid histiocyte antigen, comprised less than 5% of the proliferating population in either skin type. In addition to calculating the relative proportions of these cells to each other as percent, we also determined the density of cells, in cells/mm2 of tissue. The density of proliferating cells within these populations was increased in involved versus uninvolved skin: UCHL1+, 9.0 +/- 1.7 cells/mm2 versus 1.8 +/- 0.6 cells/mm2, p less than 0.01; Factor XIIIa+, 6.0 +/- 0.7 cells/mm2 versus 1.5 +/- 0.5 cells/mm2, p less than 0.01; Factor VIII+, 5.5 +/- 1.4 cells/mm2 versus 0.0 cells/mm2, p less than 0.05. The presence of preferential active proliferation of a T-cell subset in lesional dermis suggests that activating signals specific for this subset are contained within the psoriatic dermis in vivo. The activation of recall antigen-reactive T cells may be a driving force behind the dendritic cell and endothelial cell proliferation. Alternatively, the selective proliferation and expansion of these two constitutive cell types (Factor XIIIa+ and Factor VIII+) may result in signals that promote activation of UCHL1+ (CD45RO+) T cells.
Cell Division↗
Elevated thymidine phosphorylase activity in psoriatic lesions accounts for the apparent presence of an epidermal "growth inhibitor," but is not in itself growth inhibitory.
An apparent tissue-specific growth inhibitor, or chalone, obtained from psoriatic lesions was tentatively identified in the 100-kDa fraction based upon inhibition of DNA synthesis, as measured by [3H]-thymidine uptake by a squamous cell carcinoma cell line, SCC 38. This fraction, however, failed to inhibit SCC 38 cell growth when assessed directly in a neutral red uptake assay. Characterization of the inhibitor of [3H]-thymidine uptake revealed it to have biochemical properties identical to thymidine phosphorylase: 1) molecular weight close to 100 kDa, 2) isoelectric point of 4.2, and 3) thymidine phosphorylase enzyme activity. Thus, we conclude that its ability to inhibit [3H]-thymidine uptake was due to thymidine catabolism rather than inhibition of DNA synthesis or growth inhibition. Examination of thymidine phosphorylase activity in keratome biopsies from psoriatic and normal skin demonstrated a twentyfold increase in activity in psoriatic lesions relative to non-lesional or normal skin. This increase in metabolism of thymidine was due to thymidine phosphorylase rather than uridine phosphorylase activity. The correlation between increased thymidine phosphorylase activity and increased keratinocyte proliferation in vitro (cultured) and in vivo (psoriasis), suggests that this enzyme may play a critical role in providing the thymidine necessary for keratinocyte proliferation.
Biopsy↗
Stimulated urothelial cells produce cytokines and express an activated cell surface antigenic phenotype.
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Antigens, Surface↗
Concurrent eosinophilic fasciitis and cutaneous T-cell lymphoma. Eosinophilic fasciitis as a paraneoplastic syndrome of T-cell malignant neoplasms?
Eosinophilic fasciitis has been reported to precede hematologic malignant neoplasms such as myelomonocytic leukemia, lymphocytic leukemia, and Hodgkin's lymphoma. In this case study, eosinophilic fasciitis occurred concurrently with cutaneous T-cell lymphoma (mycosis fungoides). The clinical diagnosis of eosinophilic fasciitis was based on painful sclerodermatous lesions on the extremities and trunk without acrosclerosis. There was histologic confirmation with edema and lymphocytic inflammation in the superficial muscular fascia and dermis. Deposition of immune reactants was found in the fascia and dermis. In addition, peripheral eosinophilia and circulating immune complexes were detected. The diagnosis of cutaneous T-cell lymphoma (mycosis fungoides) was based on extensive erythematous cutaneous plaques, dermal and epidermal lymphocytic atypia, loss of pan-T-cell immunologic markers, and a cutaneous lesional T-cell receptor beta-chain rearrangement by Southern blot analysis. Eosinophilic fasciitis may occur as a paraneoplastic syndrome associated with hematologic malignant neoplasms, including mycosis fungoides. Cytokines or lymphokines released by activated immunocytes, either malignant leukocytes or normal leukocytes reacting to malignant cells, may be responsible for the eosinophilia and sclerosis seen in these associated hematologic malignant neoplasms.
Aged↗
In vivo ultraviolet-exposed human epidermal cells activate T suppressor cell pathways that involve CD4+CD45RA+ suppressor-inducer T cells.
In vivo UV exposure of human epidermis abrogates the function of CD1+DR+ Langerhans cells and induces the appearance of CD1-DR+ Ag-presenting macrophages. Epidermal cells from UV-exposed skin, in contrast to epidermal cells from normal skin, potently activate autologous CD4+ T cells, and, in particular, the CD45RA+ (2H4+) (suppressor-inducer) subset. We therefore determined whether UV-exposure in humans leads to a T cell response in which suppression dominates. Autologous blood T cells were incubated with epidermal cell suspensions from in vivo UV-irradiated skin. After activation, repurified T cells were transferred in graded numbers to autologous mononuclear cells (MNC) stimulated with PWM and the resultant IgG production analyzed by ELISA. Relative to T cells activated by unirradiated control epidermal cells, T cells activated by UV-exposed epidermal cells demonstrated enhanced capacity to suppress IgG production (n = 6; p less than or equal to 0.03). Within the T cell population, CD8+ cells stimulated by UV-exposed epidermal cells could be directly activated to suppress PWM-stimulated MNC Ig production if IL-2 was provided in the reaction mixture. The suppressive activity was also transferable with purified CD4+ T cells stimulated by UV-exposed epidermal cells (n = 10; p less than or equal to 0.01), and was radiosensitive. Suppression was decreased when PWM-stimulated MNC were depleted of CD8+ T cells before mixing with CD4+ T cells activated by UV-exposed epidermal cells, suggesting indirect induction of CD8+ Ts cells contained within the responding MNC populations. Indeed, physical depletion of CD45RA+ cells resulted in total abrogation of the suppressor function contained in the CD4+ T cells. Activation of suppressor function was critically dependent on DR+ APC contained in UV-exposed epidermis. The data suggest that UV-exposure modulates cutaneous APC activity in humans, as in mice, such that the dominant immune response is tilted toward suppression. These mechanisms in normal individuals may function to dampen responses to UV-induced endogenous Ag that are pathogenic in autoimmune disorders. However, these mechanisms might also facilitate the growth of UV-induced skin cancers.
Antibody Formation↗
IL-1 activity is reduced in psoriatic skin. Decreased IL-1 alpha and increased nonfunctional IL-1 beta.
IL-1 may influence or be influenced by a number of abnormalities present in psoriasis; including keratinocyte proliferation, eicosanoid production, fibroblast activation, endothelial cell adhesiveness, T cell infiltration and activation, cyclic nucleotide metabolism, and transmembrane signal transduction mechanisms. We assessed IL-1 regulation in normal, uninvolved, and involved skin of psoriatic patients using immunofluorescence microscopy, a sensitive ELISA method to quantitate immunoreactive IL-1 beta and IL-1 alpha protein levels, the thymocyte proliferation costimulation assay, costimulation of the LBRM.33 IL-1-sensitive cell line, and Northern blotting of cellular RNA to quantitate IL-1 alpha and beta mRNA. IL-1 beta was easily detectable by immunofluorescence microscopy and found to be localized predominantly in epidermal keratinocytes, whereas IL-1 alpha was not detectable with this method. Immunoreactive IL-1 beta was found to be elevated in cytosolic extracts derived from involved psoriatic keratomes relative to keratomes of normal skin. The elevated IL-1 beta protein was accompanied by elevated levels of IL-1 beta mRNA in psoriatic skin relative to normal skin. In contrast, immunoreactive IL-1 alpha levels were markedly reduced in lesional psoriatic skin. In functional assays using both the thymocyte proliferation assay and the LBRM.33 cell line, IL-1 activity from psoriatic involved skin keratomes was markedly reduced relative to that of uninvolved psoriatic keratomes and normal skin. All activity of both normal and psoriatic skin was attributable to IL-1 alpha. The elevated IL-1 beta immunoreactive protein present in psoriatic skin was found to be functionally inactive in these assays. The inactivity of the IL-1 beta was not due to an artifact of the cytosolic method of preparation because IL-1 beta released by psoriatic skin into the media was also nonfunctional. This was in keeping with the demonstration that the IL-1 beta was nonfunctional despite existing as a processed molecule. Taken together, these data demonstrate uncoordinated regulation of IL-1 alpha and Il-1 beta in psoriasis. The profound and complex changes in this system suggest IL-1 dysregulation may be integrally involved in the inflammatory, biochemical, and proliferative processes involved in the pathophysiology of psoriasis.
Biological Assay↗
Cicatricial pemphigoid. Identification of two distinct sets of epidermal antigens by IgA and IgG class circulating autoantibodies.
A patient with severe cicatricial pemphigoid demonstrated both in vivo bound and circulating anti-basement membrane zone antibodies of the IgA and IgG classes. Complement component 3 (C3) was also deposited in the basement membrane zone of lesional skin as well as in normal-appearing buccal mucosa of the patient. However, C1q was absent, while granular deposits of two factors of the alternative complement activating pathway, properdin and properdin factor B, were present only in the basement membrane zone of lesional skin, but not in normal buccal mucosa. Deposition of alternative complement pathway reactants in the lesion suggests that complement activation by IgA was associated with lesion development. Western blot analysis of the patient's serum on electrophoresed cultured keratinocyte antigens identified two distinct sets of epidermal antigens. While IgG bound antigens of 230, 205, 140, and 90 kd, the patient's IgA antibodies bound a distinct set of antigens, 180 and 130 kd. The potential pathogenic role of IgA in cicatricial pemphigoid is discussed.
Aged↗
T cell receptor beta-chain gene rearrangement without gamma-chain gene rearrangement in cutaneous T cell lymphoma: an unusual finding.
T cells from the blood and skin of a patient with cutaneous T cell lymphoma demonstrated rearrangement of the T cell receptor beta-chain gene in the absence of rearrangement of the gamma-chain gene. To our knowledge, this has not been previously reported. This finding was unexpected in light of prevailing concepts of T cell ontogeny. Potential explanations for it are discussed.
Aged↗
Intralesional cyclosporine in the treatment of psoriasis. A clinical, immunologic, and pharmacokinetic study.
In a double-blind, vehicle-controlled study, all of six psoriatic plaques treated with intralesional cyclosporine administered three times weekly for 4 weeks showed complete clearing or incomplete but significant clearing in comparison with vehicle-treated plaques (p less than 0.01). Epidermal thickness decreased from 0.42 +/- 0.07 to 0.27 +/- 0.08 mm at 4 weeks (p less than 0.03). Biopsy specimens obtained on day 5, before any clinical improvement, revealed a significant reduction of epidermal DR+CD1- antigen-presenting cells, epidermal and dermal monocytes, and keratinocyte intercellular adhesion molecule-1 expression. By day 5 the stratum corneum reverted to normal in the plaques receiving cyclosporine. Pain at the injection site was the major side effect. Steady-state blood cyclosporine levels ranged from 20 to 30 ng/ml during the first 12 hours after injection and became undetectable at 48 hours. These data suggest that cyclosporine improves the skin of patients with psoriasis by a local mechanism of action.
Adult↗