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Biomedical subjects

K D Cooper

Publications and source records attributed to K D Cooper.

At least 163 records · Page 9Linked to original sources
PubMed1987

Dose response and time course for induction of T6- DR+ human epidermal antigen-presenting cells by in vivo ultraviolet A, B, and C irradiation.

In vivo ultraviolet (UV) exposure of human skin abrogates the antigen-presenting function of T6+ DR+ Langerhans cells and induces the appearance of antigen-presenting T6- DR+ epidermal melanophages. UV-exposed epidermal cells containing T6- DR+ epidermal antigen-presenting cells, in contrast to unexposed epidermal cells containing T6+ DR+ Langerhans cells, potently activate autoreactive regulatory T cells in the absence of exogenous antigens. Autoreactive T cells may be important for regulation of other immune responses such as those which occur in photosensitive lupus erythematosus and in immune surveillance of UV-induced skin cancers. It is therefore imperative to determine the factors that govern their appearance in the skin. It was found that UVB and UVC, but not UVA, induced a dose-dependent appearance of T6- DR+ epidermal melanophages. The optimal time of appearance was 2 or 3 days after UVB and UVC exposure. In contrast, UVA was a poor inducer of T6- DR+ cells at all doses and all time points tested. Although UVA was a poor inducer of T6- DR+ epidermal cells, UVA radiation resulted in depletion of T6+ DR+ Langerhans cells from the epidermis, as did UVB and UVC radiation. This differential effect of UV wave bands on the immunocompetent cells in human skin may be related to the greater potential of UVB exposure to induce skin cancers and to exacerbate systemic lupus erythematosus.

Adult↗
PubMed1987

Inflammatory acquired oral hyperpigmentation: association with melanophages demonstrating phenotypic characteristics of antigen presenting cells and activated monocytes.

A case of a 30-year-old black woman who developed acute, extensive intraoral hyperpigmentation is reported. Its relationship to previously described entities is discussed. The condition was associated with the presence of melanophages both in the submucosa and in the oral epithelium. The melanophages displayed phenotypic markers of a population of intraepidermal melanophages previously described as potent T cell-activating, antigen presenting cells (T6- DR+ OKM5+ OKM1-) and of activated monocytes (Mo3e+), as well as other monocyte-macrophage markers (Mono 1 and My7). The distinct phenotype of these melanophages suggests that they could play an active role in the promotion of inflammatory disease.

Adult↗
PubMed1987

UVB and UVC, but not UVA, potently induce the appearance of T6- DR+ antigen-presenting cells in human epidermis.

Non-Langerhans cell, antigen-presenting T6- DR+ epidermal cells (EC) appear 3 days following broad band ultraviolet radiation exposure of human skin and are responsible for the increased antigen presentation capacity of EC seen 3 days after UV exposure. To determine the UV wavelengths that induce T6- DR+ EC, volar forearm skin of 10 human volunteers was irradiated in vivo with 4 minimal erythema doses (MED) each of pure UVA (mean 482 J cm-2), UVB (mean 0.390 J cm-2), and UVC (mean 0.397 J cm-2). The purity of the light sources was as follows: UVB, 98% of the emission was in the UVB range; UVC, 97% of the irradiance was in the UVC range; UVA, 100% of the energy had wavelengths longer than 340 nm. Three days after UV irradiation with 4 MED of each wavelength band, suction blister-derived EC suspensions were prepared from the UV-exposed and unirradiated sites. Percentages of T6+ DR+ Langerhans cells (LC) and T6- DR+ EC were quantitated. Relative to control EC, which contained 2.4 +/- 0.3% T6+ DR+ LC, the mean percentage (+/- SEM) of T6+ DR+ LC contained within UV-exposed EC was significantly decreased as follows: UVB, 0.5 +/- 0.2%; UVC, 0.9 +/- 0.1%; UVA, 0.5 +/- 0.2% (n = 10). T6- DR+ EC, absent in control EC, were induced both by UVB, 5.2 +/- 1.7% and UVC; 1.5 +/- 0.4%. Despite the use of more than 1200 times greater doses in J cm-2 of UVA than UVB and UVC, UVA was a poor inducer of T6- DR+ EC (0.5 +/- 0.2%) and in about half of these individuals, T6- DR+ EC were undetectable. The UV wavelengths for induction of T6- DR+ EC lies predominantly within the UVB band, but also to a lesser extent within the UVC band. These wavelengths appear to be analogous to both the wavelengths for generation of increased host susceptibility to UV-induced murine tumors and to the wavelengths for UV-induced systemic suppression of contact hypersensitivity. However, our data indicate that UV wavelengths for decreasing the number of T6+ DR+ LC in humans differs from the wavelengths for induction of systemic suppression of contact hypersensitivity in mice. Taken together, these data suggest that the appearance of T6- DR+ EC, but not the disappearance of T6+ DR+ LC, following UV exposure may be related to the induction of such antigen-specific suppressor T cells.

Antigen-Presenting Cells↗
PubMed1986

Cyclosporine improves psoriasis in a double-blind study.

In a double-blind trial, 21 patients with severe plaque psoriasis were randomly assigned to receive oral cyclosporine, 14 mg/kg/d, or its vehicle. After four weeks of therapy the 11 cyclosporine recipients had the following response to treatment: two had total clearing and six improved markedly, two moderately, and one minimally; whereas ten vehicle-treated patients showed no change or minimal improvement. Vehicle-treated patients, after a switch to cyclosporine for four weeks, demonstrated impressive improvement similar to that seen in patients who initially received only cyclosporine. Moderate or marked improvement or total clearing was noted in 17 (81%) of 21 and 20 (95%) of 21 after one and four weeks of therapy, respectively. Mitotic figures and leukotriene B4 levels in lesions decreased 86% and 64%, respectively, after seven days of cyclosporine therapy. Mononuclear (including activated T cells) and polymorphonuclear leukocyte infiltrates were markedly reduced in lesions of all patients after seven days of cyclosporine therapy. These results suggest that psoriasis may have an immunologic basis mediated by activated T cells and/or other immune cells; if a long-term regimen with a favorable efficacy-side effect ratio can be determined, cyclosporine would be a significant advance in the treatment of psoriasis.

Adult↗
PubMed1986

Antigen-presenting OKM5+ melanophages appear in human epidermis after ultraviolet radiation.

Ultraviolet radiation of murine skin in vivo or epidermal cells (EC) in vitro dramatically inhibits the antigen-presenting capacity of EC in vitro and results in the inhibition of immune responses to antigen challenge. In humans, UV exposure in vivo markedly inhibits alloantigen presentation by EC in the EC-lymphocyte reaction (ELR) when EC are harvested immediately after the administration of 4 times the minimal erythema dose (4 MED), whereas EC harvested 72 h after 4 MED (UV-EC) exhibit enhanced allostimulatory capacity in the ELR. This enhanced ELR reactivity is due to the appearance, in the epidermis, of bone marrow-derived OKT6- DR+ cells which are distinct from Langerhans cells (LC) in their lack of surface OKT6 and in their ultrastructural morphology. This report focuses on the phenotype and function of T6- Dr+ UV-EC and on their relationship to known human antigen presenting cell (APC) subsets. Approximately 60% of T6- Dr+ UV-EC bore the monocyte marker defined by monoclonal antibody OKM5, but lacked determinants recognized by OKM1, Leu M1, Leu M3, Leu M4, Leu M5, and Mac1. All T6- Dr+ UV-EC bore the class II MHC antigen HLA-DQ (DC/DS), which is associated with a specialized subset of antigen-presenting monocytes capable of stimulation in the autologous mixed leukocyte reaction (AMLR). Panning of OKM5+ UV-EC resulted in a population of cells which was markedly enriched in melanophages and which exhibited potent alloantigen-presenting capacity in the ELR. Since OKM5+ T6- Dr+ UV-EC were similar to the specialized APC minor subset of OKM1- OKM5+ blood monocytes both in phenotype and in apparent phagocytic function, we examined other APC functions of UV-EC to assess the extent of this analogy. Relative to control EC (containing only LC as APC), UV-EC (containing functionally inactivated LC but many T6- Dr+ APC) induced significantly greater degrees of T-cell proliferation in the presence of either tetanus toxoid antigen or the mitogen concanavalin A. UV-EC, as well as panning-purified OKM5+ UV-EC, were also able to induce autologous T-cell proliferation in the absence of added antigen (autologous ELR), in contrast to control EC which were poor stimulators of an autologous ELR. Thus, although human EC 72 h after UV exposure are numerically and functionally depleted of LC, at least 2 additional subsets of T6- Dr+ APC appear in the epidermis.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigen-Presenting Cells↗
PubMed1985

Phosphodiesterase inhibition by Ro 20-1724 reduces hyper-IgE synthesis by atopic dermatitis cells in vitro.

Peripheral blood mononuclear leukocytes (MNL) from patients with atopic dermatitis spontaneously produce large amounts of IgE in vitro. These cells also show markedly elevated levels of cAMP phosphodiesterase (PDE) which may be responsible for the observed abnormal cAMP responsiveness. Treatment of atopic dermatitis MNL with varying concentrations of the cAMP PDE inhibitor Ro 20-1724 resulted in progressively decreasing amounts of IgE synthesis, statistically significant at the 10(-4) M and 10(-5) M concentrations. There was a close correlation between PDE inhibition and inhibition of IgE synthesis, r = 0.93, p less than 0.05. To define the cellular target of the drug, we used monoclonal antibodies directed toward MNL subsets (Lyt 3, OKT8, OKT4, monocyte-myeloid) in a modified "panning" method to perform experiments with purified subsets. With untreated subsets, removal of OKT4-positive cells significantly reduced IgE synthesis; readdition of OKT4-positive cells enhanced IgE synthesis. OKT8 cells and monocytes did not affect IgE synthesis. Pretreatment of T cell-depleted MNL with Ro 20-1724 resulted in significantly more inhibition of IgE synthesis than did pretreatment of T enriched cells prior to recombination with the reciprocal untreated subset and subsequent culture. Similarly, pretreatment of monocyte-depleted cells resulted in significantly more inhibition of IgE synthesis than pretreatment of monocyte-enriched cells prior to recombination and culture. The majority of the effect appeared to be mediated by a direct effect on the B cells. However, some inhibition of IgE synthesis was also achieved through pretreatment of T enriched cells. Since pretreatment of isolated suppressor/cytotoxic or helper/inducer T-cell subsets did not give the same degree of inhibition as with unfractionated T cells, a T-T interaction may be involved in this aspect. The imidazolidinone derivative, Ro 20-1724, significantly and consistently inhibited both the elevated cAMP phosphodiesterase activity and the elevated spontaneous IgE synthesis of MNL from patients with atopic dermatitis. These findings demonstrate a previously undescribed link between cAMP PDE levels and in vitro IgE synthesis.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1985

The role of Langerhans cells in antigen presentation.

Epidermal Langerhans cells are dendritic bone marrow-derived cells which synthesize and express Ia antigens. During the past decade, in vitro studies have demonstrated that they play a critical role in the induction of many types of T-cell responses. Specifically, Langerhans cells are effective antigen-presenting cells in allogeneic and antigen specific proliferative and cytotoxic T-cell responses. This paper reviews these functions and suggests areas of future investigations into the mechanisms involved in T-cell activation by Langerhans cells.

Antibodies, Monoclonal↗
PubMed1985

Fluorescence microscopic and flow cytometric analysis of bone marrow-derived cells in human epidermis: a search for the human analogue of the murine dendritic Thy-1+ epidermal cell.

Lymphoid cells with an affinity for the epidermis (epidermotropic lymphocytes) have been proposed to play a role in the immune functions of the epidermis. However, antigen-presenting Langerhans cells (LC) and indeterminate cells are presently the only cells in the human epidermis which have been demonstrated to originate in the bone marrow. Recent studies of murine epidermis have identified a population of bone marrow-derived cells which express Thy-1 antigen and which are present in a similar density to, but distinct from, LC. We therefore sought to identify the potential human analogue of the murine Thy-1+ epidermal cell utilizing a battery of antileukocyte reagents in immunohistochemical, flow cytometric, and cell sorting studies. A panel of antibodies failed to detect significant numbers of human Thy-1 antigen-bearing cells, T cells, B cells, monocytes/macrophages (other than LC), and natural killer cells in tissue sections, epidermal sheets, and epidermal cell (EC) suspensions. This was the case using EC suspensions either unfractionated or fractionated on Ficoll-Hypaque to enrich for leukocyte subpopulations. Since the nature of the murine Thy-1+ EC is uncertain, it is possible that antibodies directed against well-defined leukocyte subpopulations may not be of value in the detection of a potential human analogue. We therefore utilized double fluorescence staining with anti-HLe-1, an antibody which identifies all human leukocytes, and anti-HLA-Dr (Dr), which identifies epidermal LC, in order to demonstrate a potential population of HLe-1+ Dr- non-LC, bone marrow-derived cells. The vast majority of HLe-1+ cells were HLA-Dr+ LC; these were present at a density of 608 cells/mm2 in epidermal sheets. A minor population of HLe-1+ cells which did not express HLA-Dr (HLe-1+ Dr-) was observed in tissue sections, epidermal sheets, and EC suspensions. The nondendritic morphology and low density of these HLe-1+ Dr- EC in epidermal sheets (mean density of 4.2 +/- 1.6 cells/mm2) precluded their representing a strict human analogue of the murine Thy-1+ EC, since murine Thy-1+ EC are dendritic and are present in a density similar to that of LC. Purified preparations of the minor HLe-1+ Dr- EC population obtained by electronic cell sorting or panning and examined ultrastructurally were not enriched for any bone marrow-derived cell population. Thus, using currently available markers and sorting technology, we have been unable to identify a human analogue of the murine dendritic Thy-1+ epidermal cell.

Animals↗
PubMed1985

Effects of ultraviolet radiation on human epidermal cell alloantigen presentation: initial depression of Langerhans cell-dependent function is followed by the appearance of T6- Dr+ cells that enhance epidermal alloantigen presentation.

The effects of ultraviolet radiation (UV) on the immune parameters of human epidermis were studied. We determined the effects of both in vitro and in vivo UV on human epidermal cell surface markers and on epidermal immune function in the allogeneic epidermal cell-lymphocyte reaction (ELR). Epidermal cells obtained immediately after in vitro and in vivo UV exposure exhibited a dose-dependent decrease in alloantigen-presenting function in the ELR. This was not the result of a decrease in the number of T6+ Dr+ Langerhans cells but was due to their being less efficient at alloantigen presentation than equivalent numbers of Langerhans cells from unirradiated skin. The reduced stimulation in the ELR immediately after UV was not reversible by the addition of exogenous IL 1 or indomethacin and thus appeared to be due to a direct effect of UV on the alloantigen-presenting function of Langerhans cells. In contrast to this suppression of the epidermal immune function when epidermal cells were obtained immediately after UV, epidermal cells harvested 24 hr or later after in vivo UV exhibited a dose-dependent enhancement of allostimulatory capacity in the ELR that peaked 3 days after UV. The time course of the enhancement of allostimulation in the ELR after in vivo UV coincided with a decrease in the percentage of Langerhans cells and the appearance within the epidermis of T6- Dr+ cells, which are derived from the bone marrow, as evidenced by their expression of the bone marrow derivation markers HLe 1 and T200. Removal of Dr+ cells but not of T6+ cells from epidermal cell suspensions harvested 3 days after in vivo UV abrogated allostimulation in the ELR, demonstrating that the T6- Dr+ cells were responsible for the observed UV-induced enhancement of alloantigen presentation. Taken together, the results indicate that the timing and dosage of UV exposure are critical factors determining whether suppression or enhancement of epidermal immune function follows UV.

Amputation, Surgical↗
PubMed1984

Direct depletion and purification of monoclonal antibody defined cells from unfractionated human mononuclear leukocytes using antibody coated polystyrene Petri dishes.

Human peripheral blood mononuclear leukocytes were depleted or enriched in various monoclonal antibody-defined subsets using a simplification of the indirect " panning " technique. Unfractionated mononuclear leukocytes (MNL) were sensitized with appropriate dilutions of monoclonal antibodies to human Lyt3 , OKT4 and OKT8 antigens, and to a monocyte-myeloid line antigen. The sensitized cells were then placed on polystyrene Petri dishes coated with goat antimouse IgG to obtain a population of cells depleted and a population of cells enriched in each cell type. Direct separation of surface immunoglobulin-bearing cells was similarly achieved by coating the Petri dish with goat antihuman immunoglobulins. Results showed that MNL could be depleted to greater than 95% purity with these methods and that positively selected adherent cells could be enriched to at least 85% purity. The relative proportions of MNL subpopulations in various sorted cell populations is reported. Cells obtained by panning are functionally intact. As compared to complement lysis both marker positive and marker negative cells can be obtained and the technique requires less technical expertise than using fluorescence activated cell sorting. The modification reported here is simpler and less time consuming for human T cell subpopulation separations than previously reported panning methods since an initial sheep erythrocyte rosetting step was not used.

Animals↗
PubMed1983

Thymopoietin pentapeptide (TP-5) improves clinical parameters and lymphocyte subpopulations in atopic dermatitis.

In a double-blind prospective study, eighteen patients with atopic dermatitis (AD) were treated with thrice-weekly injections of 50 mg thymopoietin pentapeptide (TP-5) or placebo for 6 weeks. Clinical parameters, lymphocyte subsets defined by monoclonal antibodies, and serum IgE were modified. Younger patients (age less than 34) responded to TP-5 with much greater improvement in severity scores than TP-5-treated patients of age greater than 34 or than placebo-treated patients of either age group (p less than 0.05). Both absolute lymphocytes and OKT8+ cytotoxic/suppressor cells were significantly increased (p less than 0.05) in the TP-5 group, whereas they were not significantly increased in the placebo group (p greater than 0.05). Conversely, Ia+ cells were significantly increased in the placebo group (p less than 0.05), but remained the same in the TP-5 group (p greater than 0.05). Serum IgE levels were not significantly altered in either group. Thus, TP-5 had a beneficial clinical effect in AD, especially in younger patients, and increased the reduced OKT8+ cytotoxic/suppressor T cells and prevented an increase of Ia+ cells during pollen season.

Adult↗
PubMed1983

Immunoregulation in atopic dermatitis: functional analysis of T-B cell interactions and the enumeration of Fc receptor-bearing T cells.

Immune aberrations in atopic dermatitis (AD) are multiple and interrelated. We investigated immunoregulatory cell markers and functional interactions of purified T- and B-enriched cells in a pokeweed mitogen (PWM)-stimulated IgG production assay in patients with AD. Atopic mononuclear leukocytes and autologous recombinations of purified atopic T and B cells were hyporesponsive to PWM stimulation of IgG synthesis. When atopic B cells were cultured with normal T cells, they were still less responsive than normal B cells. Atopic T cells generated normal levels of suppression in three responder systems. Radioresistant T-cell help was also in the normal range whereas nonirradiated AD T cells produced slightly less help than normal T cells. We noted reduced levels of T lymphocytes with FcIgG receptors (T gamma) and found that T gamma reduction correlated inversely with log serum IgE. In the light of normal T suppression, we critically examined AD cell adherence and contamination at various steps in the T gamma assay to rule out technical causes of T gamma reduction in AD. Lowered T gamma cells in AD were not associated with circulating IgG immune complexes and subsequent blockade of the FcIgG receptors. Thus, we have identified defects in the numbers of an immunoregulatory T cell, and in the generation of PWM-responsive B cells. A model is proposed in which the alterations in atopic cyclic nucleotide metabolism of T-cell helpers could result in abnormalities of immunoregulatory T cells and PWM-recruitable B cells.

Adolescent↗
PubMed1983

Effects of thymopoietin pentapeptide (TP-5) on in vitro and in vivo IgE production by atopic dermatitis cell subsets.

Atopic dermatitis (AD) patients exhibit multiple immune abnormalities, including T-cell defects that may be partially correctable by the administration of thymic hormones. Our investigations confirmed that peripheral blood mononuclear leukocytes obtained from patients with AD spontaneously synthesized markedly elevated amounts of IgE in vitro. The thymic hormone thymopoietin pentapeptide (TP-5) greatly inhibited this synthesis. An antihuman pan-T cell monoclonal antibody (Lyt3) was used to separate T-cell marker-positive (T+) T cells from marker-negative (T-) B-enriched cells. TP-5 pretreatment of T+ cells resulted in significant reduction of in vitro IgE synthesis by recombined T+ and T- cells, whereas pretreatment of T- B-enriched cells resulted in a nonsignificant reduction in in vitro IgE synthesis. Thus, although pretreatment of both subsets resulted in some degree of reduction, TP-5-induced inhibition of in vitro IgE synthesis was primarily mediated via T cells. The majority of patients' untreated T+ and T4+ cells showed enhanced IgE synthesis, but only one patient's T8+ cells were capable of suppressing IgE synthesis. Thus TP-5 may either induce suppressor T-cell activity or reduce helper T-cell activity. A six-week double-blind clinical trial of TP-5 produced evidence of clinical improvement and alterations of abnormalities of OKT8+ cells, although no significant effects on serum IgE were seen.

Antigens, Ly↗
PubMed1982

Immunosuppression in a homosexual man with Kaposi's sarcoma.

The occurrence of Kaposi's sarcoma in young homosexual men is a recently reported condition. The same individuals are at risk for the development of Pneumocystis carinii pneumonia and other unusual infections. These associations suggest these persons are somehow immunocompromised. Evidence of current or prior cytomegalovirus (CMV) infection is seen in a high percentage of these and other homosexual men. CMV infections are known to induce alterations in the immunoregulatory suppressor and helper T lymphocyte populations. The CMV infection is suspect as the cause of immunosuppression in these individuals. We present a case of Kaposi's sarcoma in a homosexual men with CMV cultured from his urine and semen. He showed a marked increase in his suppressor/cytotoxic cell (OKT8-positive) population, as well as a marked decrease in his helper cell (OKT4-positive) population. Mitogen and antigen studies demonstrated absent or markedly diminished response both in vitro and in vivo. Pokeweed mitogen (PWM)-induced IgG synthesis appeared normal. This patient, as well as the majority of other reported patients with this disease, manifested the HLA-Dr5 phenotype. The immunosuppression in this patient and possibly other similar men appears to be mediated by abnormalities in the immunoregulatory T lymphocytes.

Adult↗
PubMed1982

FcIgG receptor-bearing lymphocytes and monoclonal antibody-defined T cell subsets in atopic dermatitis: effect of treatment with thymopoietin pentapeptide (TP-5).

Lymphocyte subpopulations were determined in the blood of patients with atopic dermatitis (AD) before and after treatment with the thymopoietin pentapeptide TP-5. The relative and absolute numbers of lymphocytes bearing suppressor/cytotoxic cell markers (FcIgG+E+ and T8+ cells) were significantly decreased in the untreated patients and the T4+/T8+ cell ratio was increased, indicating an imbalance between lymphocyte subpopulations in AD. Patients who had been treated for 6 weeks with TP-5 displayed no significant abnormality of any of the lymphocyte subsets studied and comparison of pre- and posttreatment values revealed that there was a statistically significant increase in T8+ cell numbers, that by contrast did not take place in placebo-treated AD patients. The treatment had no demonstrable effect on IgE serum levels or on the spontaneous in vitro production of IgE by cultured lymphocytes from the patients.

Antibodies, Monoclonal↗
PubMed1981

Heterologous desensitization of leukocytes: a possible mechanism of beta adrenergic blockade in atopic dermatitis.

Studies of mononuclear leukocytes from patients with atopic dermatitis showed depressed cyclic AMP (cAMP) responses after exposure to isoproterenol, histamine, and prostaglandin E1. Because plasma and tissue histamine levels are elevated in atopic dermatitis, we questioned whether histamine or other mediators might be responsible for cAMP abnormalities. We found that exposure of normal cells to low (10(-6)M) concentrations of histamine, isoproterenol, or prostaglandin E desensitized the cells to subsequent stimulatory concentrations of any of the agonists. This heterologous desensitization occurred within 15 min and persisted for days, with gradual recovery of cAMP responses roughly paralleling those of cells from patients with atopic dermatitis. These findings provide a possible explanation for Szentivanyi's beta adrenergic blockade theory and the depressed leukocyte cAMP response to multiple agonists in atopy.

Adrenergic beta-Antagonists↗