Studies in patients with corticosteroid contact allergy: a flawed analysis of structure-function relationships.
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Adrenal Cortex Hormones↗
Biomedical subjects
R S Kalish
Publications and source records attributed to R S Kalish.
House dust mite-responsive human T cells require both interleukin 2 (IL2) and interleukin 4 for optimal proliferation, whereas IL2 alone is sufficient for proliferation of tetanus toxoid-responsive T cells.
Production of interleukin 4 (IL4) and response to IL4 may be a key determinant of the atopic immune response. Proliferation requirements of allergen-specific T cells derived from atopics and nonatopics were determined. Peripheral blood lymphocytes were cultured with either house dust mite (HDM) or tetanus toxoid under limiting dilution conditions with interleukin 2 (IL2) alone or IL2+IL4. The relative proportion of antigen-specific T cells responding under each of these conditions was determined by proliferation. The combination of IL2+IL4 resulted in the highest proportion of responding HDM-specific T cells. Similar results were obtained with HDM-specific T cells from both atopic and nonatopic donors. These HDM and Der pI responsive cells were found to be CD4+CD8-. In contrast, tetanus toxoid-responsive T cells from both atopic and nonatopic donors grew preferentially in response to IL2 alone.
Adult↗
Sulfonamide-reactive lymphocytes detected at very low frequency in the peripheral blood of patients with drug-induced eruptions.
BACKGROUND: The role of T lymphocytes in mediating drug eruptions is uncertain. METHODS: Twenty-four patients with eruptions induced by sulfonamide-related drugs were studied to detect lymphocyte reactivity to drugs. Both the lymphocyte transformation test and limiting dilution analysis were used as assays for drug-reactive lymphocytes. Peripheral blood lymphocytes were expanded in interleukin-2 and tested for reactivity to sulfamethoxazole and furosemide. RESULTS: The lymphocyte transformation test results to sulfamethoxazole, sulfisoxazole, and furosemide were found to be generally unreliable with a high rate of false-negative and false-positive results. However, as determined by limiting dilution analysis, sulfamethoxazole-reactive lymphocytes were detected in the peripheral blood of one patient at a frequency of 1/172,000. This is within the lower range of frequencies of urushiol-reactive T cells in the peripheral blood of patients with allergic contact dermatitis to urushiol (poison ivy). Two sulfonamide-reactive lymphocyte lines were cultured from two patients. Both lines proliferated in response to sulfamethoxazole but not in response to furosemide, suggesting that furosemide does not cross-react with the sulfonamides. CONCLUSIONS: Lymphocytes reactive to sulfamethoxazole were detected at low frequencies in the peripheral blood of three patients with drug eruptions secondary to administration of sulfamethoxazole.
Adult↗
Human dermatophyte-responsive T-cell lines recognize cross-reactive antigens associated with mannose-rich glycoproteins.
Resistance to dermatophyte infections has been shown to be mediated in part by T lymphocytes. The dermatophyte antigens recognized by human T lymphocytes and their degree of cross-reactivity were analyzed. Dermatophyte-responsive T-cell lines were generated by in vitro sensitization to crude fungal extracts obtained from Trichophyton rubrum, Trichophyton tonsurans, Microsporum canis and Epidermophyton floccosum. Proliferation was measured by incorporation of 3H-thymidine. The human T-cell lines responded to fungal extracts derived from these various dermatophyte species, demonstrating the recognition of cross-reactive antigens by human T cells. However, the T cells were dermatophyte-specific as they did not respond to herpes antigen, nor did herpes-specific T cells derived from the same donors respond to dermatophyte antigens. The mannose-rich glycoprotein fraction (mannan) isolated from T. rubrum was able to induce proliferation of T-cell lines generated by stimulation with various fungal extracts. Furthermore, a T-cell line generated by stimulation with mannan derived from T. rubrum proliferated in response to extracts from various fungal species, indicating that a major cross-reactive dermatophyte T-cell antigen was present in the mannose-rich glycoprotein fraction.
Adult↗
Processing of urushiol (poison ivy) hapten by both endogenous and exogenous pathways for presentation to T cells in vitro.
The antigen processing requirements for urushiol, the immunogen of poison ivy (Toxicodendron radicans), were tested by presentation of urushiol to cultured human urushiol-responsive T cells. Urushiol was added to antigen-presenting cells (APC) either before or after fixation with paraformaldehyde. Three distinct routes of antigen processing were detected. CD8+ and CD4+ T cells, which were dependent upon processing, proliferated if urushiol was added to APC before fixation, but did not proliferate when urushiol was added to APC after fixation. Processing of urushiol for presentation to CD8+ T cells was inhibited by azide, monensin, and brefeldin A. This suggests that urushiol was processed by the endogenous pathway. In contrast, presentation of urushiol to CD4+ T cells was inhibited by monensin but not by brefeldin A. This was compatible with antigen processing by the endosomal (exogenous) pathway. Finally, certain CD8+ T cells recognized urushiol in the absence of processing. These cells proliferated in response to APC incubated with urushiol after fixation. Classification of contact allergens by antigen processing pathway may predict the relative roles of CD4+ and CD8+ cells in the immunopathogensis of allergic contact dermatitis.
Anti-Bacterial Agents↗
Unilateral linear lichenoid eruption after bone marrow transplantation: an unmasking of tolerance to an abnormal keratinocyte clone?
Chronic cutaneous graft-versus-host disease may appear clinically as a lichenoid eruption. We describe a 26-year-old man who developed a unilateral linear lichenoid eruption 7 months after allogeneic bone marrow transplantation. We believe this represents an unusual form of localized, chronic graft-versus-host disease. The possible relationship to viral infection or cellular mosaicism and the clinical, histologic, and immunologic similarities to idiopathic lichen planus are discussed.
Adult↗
Alopecia areata. Autoreactive T cells are variably enriched in scalp lesions relative to peripheral blood.
BACKGROUND AND DESIGN: Alopecia areata is a condition characterized by hair loss in association with perifollicular infiltration of T cells and antigen-presenting cells. Autoreactive T cells are postulated to amplify this abnormality by interacting with DR+ follicular epithelium. These cells may recognize either autologous major histocompatibility complex class II antigen or an autoantigen restricted by major histocompatibility complex class II. Limiting dilution analysis was used to determine the frequency of autoreactive lymphocytes in scalp biopsy specimens and peripheral blood from seven adult patients with alopecia areata. Autoreactive T cells are defined for this study as those that proliferate in response to autologous irradiated peripheral blood mononuclear cells. RESULTS: Autoreactive lymphocytes were enriched in scalp biopsy specimens relative to peripheral blood in five of seven patients. This enrichment was statistically significant in four of five patients. Five autoreactive T-cell clones derived from lesional scalp were characterized. Four of these clones were CD3+CD4+CD8- and one clone was CD3+CD4-CD8+. CONCLUSIONS: Enrichment of autoreactive cells in lesions of alopecia areata supports a role for these cells in the pathogenesis of this condition. Enrichment of autoreactive lymphocytes is also found in allergic contact dermatitis. Thus, these autoreactive lymphocytes may have a general role in inflammation.
Adult↗
Autoreactive cells in alopecia areata.
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Adolescent↗
Drug eruptions: a review of clinical and immunological features.
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Drug Eruptions↗
Recent developments in the pathogenesis of allergic contact dermatitis.
Allergic contact dermatitis is both an important clinical problem and a model system for lymphocyte-mediated pathologic changes. Elicitation of allergic contact dermatitis requires interaction of antigen with epidermal Langerhans cells, followed by migration of the Langerhans cells to the lymph nodes to present antigen to T lymphocytes. These activated T lymphocytes must then home to the antigen-exposed skin. Adhesion molecules such as LFA-1 and ICAM-1 have a role in this homing. Only a small proportion of the T lymphocytes in the skin lesion are specific for the inducing antigen. Studies of poison ivy (urushiol dermatitis) have determined this fraction to be less than one per 100 infiltrating lymphocytes. By a variety of amplification mechanisms, it is possible for this small number of antigen-specific T lymphocytes to induce the pathologic changes of allergic contact dermatitis. Improved understanding of this condition should result in increased knowledge of the pathogenesis of a variety of T lymphocyte-mediated skin conditions.
Dermatitis, Contact↗
Enrichment and function of urushiol (poison ivy)-specific T lymphocytes in lesions of allergic contact dermatitis to urushiol.
The frequencies of urushiol (poison ivy)-specific T cells were determined in the lesional skin and peripheral blood of patients with allergic contact dermatitis to urushiol. Lesions of urushiol dermatitis were biopsied and the T cells retrieved. Frequencies of Ag-specific cells were determined by limiting dilution assay. Enrichment of urushiol specific T cells was detected in lesional skin or blister fluid of five of five of these donors as well as seven of seven donors with urushiol patch tests. There was also enrichment relative to tetanus toxoid specific T cells in blood and skin of six of seven donors. The frequency of lesional T cells specific for urushiol was less than 1/100 and generally less than 1/1000. Furthermore, the frequency of urushiol specific T cells was often less than 1/10,000 in the peripheral blood during an acute eruption. Autoreactive T cells that proliferated to autologous irradiated PBMC were also enriched in skin lesions relative to blood in 5/5 urushiol patch tests. These autoreactive T cells were expanded and found to be CD4+. It has been proposed that such autoreactive T cells recognize autologous DR and may have a role in immunoregulation. Urushiol-specific T cells were expanded from limiting dilution wells of two donors and characterized. The majority of the urushiol-specific cells were CD8+, and 13/43 lines were suppressive for PWM-induced IgG synthesis.
Antigens, Differentiation, T-Lymphocyte↗
T-cell receptor gamma delta bearing cells in normal human skin.
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Gene Expression↗
The use of human T-lymphocyte clones to study T-cell function in allergic contact dermatitis to urushiol.
Allergic contact dermatitis to poison ivy (Toxicodendron radicans) is believed to be mediated by T lymphocytes specific for the hapten urushiol. Activated T lymphocytes may produce pathology by a variety of mechanisms including direct cytotoxicity, production of lymphokines, recruitment of non-specific effector cells, non-specific cytotoxicity, and possibly autologous DR reactivity. The regulation and pathogenesis of this condition was studied by cloning and characterizing urushiol-specific T cells from the peripheral blood of patients with poison ivy dermatitis. Multiple CD8+ (T8+) urushiol-specific clones were derived. All clones that proliferated in response to a crude extract of T. radicans also proliferated in response to purified urushiol. Thus, urushiol appears to be the single immunogenic component of T. radicans resin. Pentadecylcatechol (PDC), which differs from urushiol only in the lack of unsaturated bonds in its lipophilic tail, stimulated only one of seven clones tested. This suggests that the double bonds in the C15 lipophilic tail of urushiol are required for antigenicity. Several of the CD8+ urushiol-specific clone suppressed pokeweed mitogen-induced IgG production in the presence of urushiol. Suppression was triggered specifically by urushiol and required MHC compatibility both for the antigen-presenting cells and the responding B cells. These suppressor clones were isolated from convalescent blood and may represent a mechanism for the termination of an allergic contact dermatitis.
Antigens↗
Non-specifically activated human peripheral blood mononuclear cells are cytotoxic for human keratinocytes in vitro.
Cultured human keratinocytes were lysed by activated PBMC in a 4-h 51Cr release assay. PBMC were activated by incubation with 50 U/ml of rIL-2 for 4 days. The cytotoxic precursors were found to be NKH1+ and included both CD2+ and CD2- phenotypes. This cytotoxicity was not genetically restricted, as cells killed both allogeneic and autologous keratinocytes without priming. Cytotoxicity was blocked by pre-incubation of effector cells with mAb against LFA-1 alpha-(TS1/22) and beta-chains (TS1/18), but not by antibodies directed against CD4, CD8, or leukocyte common Ag (T200) suggesting that LFA-1 is an important interactive molecule in this cytotoxicity. IFN-gamma is reported to upregulate ICAM-1, the ligand for LFA-1. Pre-treatment of target keratinocytes with IFN-gamma was also found to greatly increase the sensitivity of keratinocytes to lysis. This increased sensitivity to lysis was blocked by anti-LFA-1 and anti-ICAM-1, but not by anti-DR (L243), and thus was not the result of increased DR expression. Such treated targets were lysed at low levels (15 to 18%) by an Ag-specific CD8+ cytotoxic clone as well as a T cell line derived from a skin lesion of allergic contact dermatitis. In contrast, control keratinocytes were only sensitive to IL-2-activated PBMC as described above. The above findings may be relevant to a variety of conditions in which epidermal damage is associated with lymphocytic infiltrate. These conditions include graft-vs-host disease, erythema multiforme, and lupus erythematosus. DR+ keratinocytes, which may be a marker for IFN-gamma are also found in the above conditions. It is suggested that epidermal pathology may be mediated by non-specific cytotoxicity induced in the course of an immune response.
Antibodies, Monoclonal↗
Quantitation and cloning of human urushiol specific peripheral blood T-cells: isolation of urushiol triggered suppressor T-cells.
A limiting dilution assay was developed to quantitate urushiol (the antigen of poison ivy; Toxicodendron radicans) specific T cells from peripheral blood of a patient with a history of rhus (poison ivy) dermatitis. It was found that maximal sensitivity with minimal nonspecific proliferation could be produced with the use of 5 U/ml of recombinant IL2 added to the assay on day 6. This donor was found to have a frequency of urushiol specific peripheral blood T cells of (1/2935). Five interleukin 2 (IL2) dependent urushiol specific T-cell clones were generated from the peripheral blood of this patient. These T-cell clones had a CD8+ (T8+) phenotype and proliferated specifically to both extracts of Toxicodendron radicans (poison ivy) leaves and pure urushiol. Pentadecylcatechol was an inferior antigen, only stimulating proliferation of one clone. The ability of all clones to proliferate to pure urushiol, despite their having been induced with leaf extract, suggests that urushiol, or closely related catechols, represent the only allergenic constituents of Toxicodendron radicans. Lymphokine production in response to antigen varied between (0.6-5.0) units/ml of interleukin 2 (IL2) and (1.0-120) units/ml of gamma interferon. Although none of the clones showed significant cytotoxicity against NK targets, three of five lines showed considerable cytotoxicity against concanavalin A treated (lectin approximated) targets. However, cytotoxicity for rhus conjugated autologous targets was not detected. It was found that several of these CD8+ clones could suppress IgG production in the presence of rhus antigen. The isolation of these T-cells from peripheral blood several months after rhus dermatitis suggests that these clones may have a role in down regulating delayed hypersensitivity to urushiol.
Catechols↗
Human T cells can be directed to lyse tumor targets through the alternative activation/T11-E rosette receptor pathway.
We investigated the ability of human T cells to be directed to lyse murine and human tumor targets by antibodies (Ab) to the T11-E rosette (CD2) receptor. We found that the human cytotoxic T lymphocyte clone TBI-6, which is specific for the Epstein-Barr virus-transformed cell line, CM-EBV, could be directed to lyse the Fc receptor-positive murine tumor P388D1, by the combination of anti-T11(2) plus anti-T11(3) Ab. This activation and lysis was demonstrable only with an Fc receptor expressing tumor target and only with those Ab or with anti-T3 (CD3) Ab but not with other anti-T11 Ab or other Ab directed against surface structures on the clone. We therefore constructed heterodimeric Ab consisting of anti-T11(2) or anti-T11(3) Ab and the J5 anti-common acute lymphoblastic leukemic antigen (anti-CALLA) Ab. The purity and retained functional properties of the dimers were demonstrated by sodium dodecyl sulfate-polyacrylamide gels, fluorescence-activated cell sorter analysis on relevant cells, and by the ability of these conjugates to activate human peripheral blood lymphocytes to proliferate. These heterodimeric Ab conjugates were shown to be able to direct the lysis of CALLA+ targets by TBI-6. The specificity of this lysis was demonstrated by the inability of these heterodimers to direct the lysis of CALLA- targets by the cytotoxic T lymphocyte clone, and by the ability of excess free J5, but not an irrelevant Ab of the same isotype, to block this type of lysis. The potential clinical significance of these reagents is discussed.
Antibodies, Monoclonal↗
Generation of CD8 (T8) cytotoxic cells has a preferential requirement for CD4+2H4- inducer cells.
CD8 (T8) cells are capable of both suppression and cytotoxicity. However, we have found that the activation of CD8 cytotoxic cells has a preferential requirement for a different CD4 (T4) subset from that previously reported for the activation of CD8 suppressor cells. We have recently characterized two monoclonal antibodies which subdivide CD4 cells into inducers of help for antibody production (CD4+ 4B4+) and inducers of CD8 mediated suppression (CD4+2H4+). We now report that CD4+4B4+2H4- cells also preferentially induce CD8-mediated cytotoxicity. Human peripheral blood T cells were fractionated into CD8, CD4, CD4+2H4+, and CD4+2H4- populations by both the adherence to antibody-coated plates and the fluorescence-activated cell sorter. The cells were cultured 6 days with irradiated allogeneic non-T cells and a cytotoxicity assay was then performed using cryopreserved non-T cells as targets. It was found that the combination of CD4+2H4- cells and CD8 cells resulted in greater cytotoxicity than either CD4 + CD8, or CD4+2H4+ + CD8. The combination of CD4+2H4+ cells with CD8 cells resulted in minimal cytotoxicity, which was similar to that generated by CD8 cells alone. These results were confirmed using anti-4B4 to positively select the reciprocal CD4 subset. Furthermore, the cytotoxicity induced by CD4+2H4- cells was alloantigen specific and Class I major histocompatibility complex restricted. As both CD4+2H4+ and CD4+2H4- cells proliferate equally well to alloantigen and produce similar levels of interleukin 2 (IL-2), it is likely that the generation of CD8 cytotoxic cells requires a signal in addition to IL-2.
Antibodies, Monoclonal↗
Requirements for the construction of antibody heterodimers for the direction of lysis of tumors by human T cells.
We constructed a series of MAb heterodimers consisting of the J5 (anti-common acute lymphoblastic leukemia antigen [CALLA]) antibody and antibodies to a variety of structures present on the surface of activated human T cells, including CD3 antigen (T cell receptor-associated glycoproteins), CD2 antigen (T11/E-rosette receptor), CD25 antigen (IL-2 receptor), and the transferrin receptor. We tested the ability of these heterodimers to direct a CD2 + CD3 + CD8 + CD4 - CD25 + transferrin receptor + MHC-restricted human cytolytic T lymphocyte (CTL) clone to lyse a CALLA + human tumor in vitro. Only heterodimers containing an anti-CD3 antibody or activating antibodies to CD2 could direct the clone to lyse these human tumor targets, even when the clone was additionally activated with anti-CD3 or anti-CD2 antibodies. Our findings may have implications in the design of strategies for the use of such reagents in the treatment of human neoplasia.
Antibodies↗