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Biomedical subjects

G F Murphy

Publications and source records attributed to G F Murphy.

At least 145 records · Page 8Linked to original sources
PubMed1987

Immunophenotypic characterization of the cutaneous exanthem of SIV-infected rhesus monkeys. Apposition of degenerative Langerhans cells and cytotoxic lymphocytes during the development of acquired immunodeficiency syndrome.

A T-cell tropic retrovirus, simian immunodeficiency virus (SIV), has recently been isolated from immunodeficient rhesus monkeys. This virus has remarkable similarities to human immunodeficiency virus (HIV), the etiologic agent of acquired immunodeficiency syndrome. Subsequent studies of simian infection with SIV have shown it to be a relevant animal model for studying the pathogenesis of AIDS in man. In both HIV-infected humans and SIV-infected monkeys, a cutaneous maculopapular eruption has been described. To date, the pathogenesis and possible relationship of these exanthema to the evolution of systemic immunosuppression have remained obscure. In this study, the mononuclear cell infiltrates that characterize skin rashes of SIV-infected rhesus monkeys were found to be composed predominantly of cells with phenotypic characteristics of cytotoxic/suppressor (T8+) lymphocytes and natural killer cells. Many of these cells expressed membrane-bound interleukin-2 receptor molecules. Double labeling and immunoelectron microscopy revealed these cells in direct contact with degenerative Langerhans cells within the epidermis and dermis. These observations suggest that the cutaneous rash associated with SIV infection may be the consequence of target cell injury of Langerhans cells by effector cells with cytotoxic potential.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Low dose cyclosporine in rheumatoid arthritis: a pilot study.

A 6 month open trial of cyclosporine (CyA) was conducted in 20 patients with active rheumatoid arthritis unresponsive to second line therapy. The dosage was monitored to achieve a serum blood level of 75-150 ng/ml. A 25% reduction in ARA joint count (baseline mean 38.2; 6 month or time of CyA withdrawal mean 28.7; p less than 0.001) was observed for all patients. Fifteen completed the 6 month CyA regimen and 5 developed toxicity requiring CyA to be permanently withdrawn. For the 15 patients completing 6 months of CyA, improvement was 36% (baseline 34.7; 6 month mean 22.2; p less than 0.001). Corresponding improvements were also observed on the other main study outcomes of pain and functional ability. Improvement occurred between 12-20 weeks, somewhat later than in other studies. Toxicity included mild hypertension (4 patients) and gastrointestinal intolerance (2). Three patients were withdrawn from CyA due to nephrotoxicity. There was a clinically significant reduction in calculated creatinine clearance but this returned to baseline within 6 months after CyA was withdrawn for all except 2 patients who took 12 months to return to baseline.

Adult↗
PubMed1987

Tonsillar epithelial dendritic cells. Demonstration by lectin binding, immunohistochemical characterization, and ultrastructure.

The association of tonsillar epithelium with lymphoid tissue suggests a functional relationship in the generation of local immune responses analogous to skin. Therefore, we investigated this epithelium for the presence of dendritic cells similar to epidermal Langerhans cells. Clusters of tonsillar epithelial dendritic cells (TEDC) were revealed by binding of the lectin peanut agglutinin, a feature not previously directly demonstrated for this cell type. Similar to epidermal Langerhans cells, TEDC showed immunoreactivity for antibodies to S-100, T6, and Ia antigens. Ultrastructurally, TEDC had features most similar to epidermal indeterminate cells. In addition, the tonsillar epithelium showed regional variation in the types of intraepithelial lymphocytes present. Surface epithelium contained T cells predominantly of helper/inducer phenotype, while the crypt epithelium contained a mixture of B cells, plasma cells, and T cells of both helper/inducer and suppressor/cytotoxic phenotypes. These findings, together with the demonstration of TEDC, suggest that the tonsillar epithelial microenvironment, like skin, provides a site of cell-cell interactions important in initiating immune responses.

Antigens, Surface↗
PubMed1987

Characterization of nonhuman primate epidermal and dermal dendritic cells with monoclonal antibodies. A study of Langerhans cells and indeterminate cells in the rhesus monkey.

Epidermal dendritic cells (Langerhans cells) present cutaneously derived antigens to T cells in the skin and draining lymph nodes and therefore are important in many afferent immune responses. The role of dermal dendritic cells on the other hand is more obscure, although it has been suggested that these cells are precursor forms of Langerhans cells. Although human cutaneous dendritic cells have been previously characterized by using monoclonal antibodies, there are no reports of comparable studies in the skin of rhesus monkeys. By using an immunoperoxidase technique with light and immunoelectron microscopy, we have evaluated 29 antibodies raised against human cell surface antigens for their reactivity to dendritic cells in the skin of rhesus monkeys. This study demonstrates that many antisera to human cell surface antigens can be used to identify cutaneous dendritic cells in this species and that the cell populations so labeled are similar ultrastructurally to those in man. These observations represent the first demonstration of immunologic markers specific for epidermal Langerhans cells in animals, and are requisite for further study of dendritic cell function in nonhuman primate models of human immunopathologic diseases.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Amelioration of acute graft vs host disease due to minor histocompatibility antigens by in vivo administration of anti-interleukin 2 receptor antibody.

Lethal acute graft vs host disease (GVHD) elicited by minor histocompatibility antigens was studied in a murine model of bone marrow transplantation (B10.BR----CBA). The severity of GVHD was reduced by both clinical and histologic parameters when transplant recipients received injections of a monoclonal antibody directed against the interleukin 2 receptor. This study suggests that anti-interleukin 2 receptor antibodies may be useful in clinical marrow transplantation and provides additional evidence that monoclonal antibodies that block T cell function in vitro may be of therapeutic value in vivo.

Animals↗
PubMed1986

Erythema nodosum leprosum: nature and extent of the cutaneous microvascular alterations.

Skin biopsy specimens from four patients with erythema nodosum leprosum, when examined as Epon-embedded, 1-micron sections, exhibited a necrotizing vasculitis involving capillaries, venules, and small-to-medium arteries and veins. In the superficial dermis, affected venules and capillaries showed endothelial cell enlargement and focal necrosis associated with perivascular infiltrates of lymphocytes. In the deep dermis and subcutaneous tissue, affected venules, arterioles, and arteries exhibited endothelial cell necrosis and matted fibrin in the vessel walls associated with perivascular infiltrates of neutrophils. Throughout the dermis, mononuclear phagocytes with vacuoles containing numerous fragmented organisms were observed. By electron microscopy, electron-dense material resembling immune complexes was observed in the walls of these vessels. These observations support the concept that erythema nodosum leprosum is an immune complex-mediated necrotizing vasculitis involving capillaries, arterioles, arteries, venules, and veins.

Adult↗
PubMed1986

Inhibition of rat skin allograft rejection by cyclosporine. In situ characterization of the impaired local immune response.

Cyclosporine (CsA) is known to induce long-term survival of skin allografts, although the cellular mechanisms responsible for this effect are not well understood. To further define the effects of CsA-induced immunosuppression, we performed a morphological and immunohistological study of acute skin allograft rejection in the rat, comparing untreated and CsA-treated animals. Three significant differences were found between grafts in CsA-treated and untreated rats. First, CsA-allografts contained fewer MRC OX-8+ cytotoxic T cells than untreated allografts. Second, although the presence and numbers of infiltrating macrophages (W3/25+, W3/13- cells) was not influenced by CsA treatment, CsA treatment blocked expression of a macrophage membrane activation antigen, defined by the monoclonal antibody A1-3, which has previously been linked with development of macrophage procoagulant activity (PCA). Third, diminution in MRC OX-8+ lymphocytes and A1-3+ macrophages in CsA allografts was associated with an absence of the widespread thrombotic and necrotizing microvascular injury typical of acute rejection in untreated rats. We conclude that prolongation of skin allograft survival by CsA is related to its ability to prevent cell mediated injury to the endothelium of graft vessels, and possibly also to inhibition of macrophage PCA with consequent reduced thrombus formation.

Animals↗
PubMed1986

Cutaneous acute graft-versus-host disease to minor histocompatibility antigens in a murine model: histologic analysis and correlation to clinical disease.

Graft-versus-host disease (GVHD) can occur in bone marrow-transplant recipients even when donor and host are identically matched at the major histocompatibility complex. GVHD in this context presumably arises because of differences in minor histocompatibility antigens. Murine GVHD to minor histocompatibility antigens has been studied in an effort to determine whether skin is a target of the immune response in this model system. T cell-depleted marrow cells (10(7)) from B10.BR (H-2k) mice were supplemented with varying numbers of nylon wool-enriched splenic B10.BR T cells and transplanted intravenously into irradiated (1100 R) CBA (H-2k) mice. Sequential biopsies of ear skin were obtained at weekly intervals over a 7-week period. Histopathologic evaluation revealed basal cell layer vacuolization, exocytosis, and satellitosis of mononuclear cells in the epidermis. Dyskeratosis was observed only in animals receiving T cells, and proved to be the most reliable histologic parameter of disease with the number of dyskeratotic cells per linear millimeter of epidermis correlating both with severity of clinical disease and with the number of transplanted T cells. Ultrastructural examination revealed exocytosis of mononuclear cells into the epidermis where they were frequently apposed to degenerating and necrotic keratinocytes. These data indicate that the skin is an informative target organ for study of experimental GVHD to minor histocompatibility antigens.

Acute Disease↗
PubMed1986

An erythematous maculopapular eruption in macaques infected with an HTLV-III-like virus (STLV-III).

A cutaneous maculopapular eruption has been previously described in humans infected with HTLV-III/LAV, the etiologic agent of acquired immunodeficiency syndrome. In this study, rhesus monkeys were prospectively examined after infection with an HTLV-III-like virus (STLV-III) to ascertain the incidence and clinical course of gross and histologic alterations of the skin. Between 1-3 weeks after inoculation, 83% of infected animals developed a transient cutaneous maculopapular eruption of the face, groin, and trunk. Histologically, the affected skin was characterized by a superficial perivascular infiltrate of mononuclear cells with associated endothelial cell hypertrophy and degeneration. This eruption preceded opportunistic infections, neoplasms, and other overt clinical signs commonly associated with an immunodeficiency syndrome. The findings suggest that STLV-III infection in the rhesus monkey closely simulates that which occurs in HTLV-III-infected individuals, and that the skin may represent a site of altered immunoregulation early in the course of this disease.

Animals↗
PubMed1986

Lymphocyte subsets and Langerhans' cells in toxic epidermal necrolysis. Report of a case.

Toxic epidermal necrolysis is a life-threatening disease, the pathogenesis of which remains largely unknown. Histologically, in addition to the characteristic epidermal alterations, there is a sparse mononuclear cell infiltrate in the dermis. The immunologic characteristics of this infiltrate are not well known. In a case of drug-induced toxic epidermal necrolysis with fatal outcome in a 48-year-old man, we demonstrated that the majority of the inflammatory cells were of helper/inducer T-lymphocyte subsets, having only a minority of cytotoxic/suppressor T-lymphocytes and rare cells with natural killer cell phenotype. The significance of these observations is discussed, with reference to the occurrence of lesions at epithelial sites bearing local networks of antigen-presenting cells (Langerhans' cells).

Animals↗
PubMed1986

Phenotypic transformation of macrophages to Langerhans cells in the skin.

Langerhans cells, important participants in the cutaneous cellular immune response, are markedly diminished in skin of patients undergoing allogeneic bone marrow transplantation during the first 4 weeks after this procedure. To determine the mechanism responsible for the subsequent repopulation of these cells, the authors studied the immunophenotypic and morphologic profiles of sequential skin biopsies during the posttransplantation period. Cells with surface antigens of monocytes/macrophages within the superficial dermis were gradually replaced by dermal and epidermal dendritic cells exhibiting coexpression of monocyte/macrophage and Langerhans cell surface antigens. Ultrastructural examination revealed that many of these cells contained both prominent phagolysosomes and Birbeck granules. Antigenically and structurally mature Langerhans cells were observed within the epidermis by the end of the second month after transplantation. Phenotypic transformation of phagocytic dermal macrophages to Langerhans cells appears to represent a mechanism for repopulation of Langerhans cells during the period of immunologic reconstitution in this patient population.

Antigens, Surface↗
PubMed1986

Acute cutaneous graft-versus-host disease to minor histocompatibility antigens in a murine model. Evidence that large granular lymphocytes are effector cells in the immune response.

We studied the morphologic and immunophenotypic characteristics of inflammatory infiltrates in the skin of mice with acute graft-versus-host disease induced by bone marrow transplantation between strains differing only in minor histocompatibility antigens. The strain combinations employed (B10.Br - greater than CBA) have been shown to produce a lethal graft-versus-host disease with clinical severity proportional to the number of T lymphocytes added to the donor marrow inoculum. Transplant recipients developed pronounced clinical signs of graft-versus-host disease, including copious diarrhea and weight loss, and histologic alterations in skin strikingly similar to this disease in humans. Our findings indicate that the preponderant mononuclear cell in lesional skin from these animals has phenotypic characteristics of a natural killer cell. This cell was often found in apposition with necrotic epidermal cells. The origin, function, and potential relevance of natural killer cells in lesion formation in this experimental model are discussed.

Acute Disease↗
PubMed1985

Association of basal-lamina defects with epidermal and dermal T6-positive cells: evidence of Langerhans-cell migration.

We observed the apparent migration of Langerhans cells across the basal lamina of normal human skin by immunoelectron microscopy using monoclonal anti-T6 antibody. This technique made it possible to visualize cytoplasmic processes of Langerhans cells not normally detectable by routine transmission electron microscopy, and therefore facilitated the documentation of the migratory process. Although events early in the migratory sequence were not observed, perhaps as the result of the evanescent nature of this phase, the association of Langerhans cells with focal disruptions in the epidermal basal lamina was documented. The basal lamina adjacent to these Langerhans cells was electron lucent, granular in character, and thinned, or intact, suggesting sequential reassembly after disruption. This study provides ultrastructural documentation supporting the hypothesis of ongoing migration of Langerhans cells across epidermal membranes, and suggests that this process is mediated by the disruption and reconstitution of the epidermal basal lamina.

Adult↗
PubMed1985

Localization of tryptase to human cutaneous mast cells and keratinocytes by immunofluorescence and immunoperoxidase cytochemistry with monoclonal antitryptase antibody.

A monoclonal antibody (H4) against tryptase purified from human pulmonary mast cells was prepared and used as an immunoreactive marker for the cellular localization of tryptase in normal human skin and in lesional skin from subjects with systemic mastocytosis. Mast cells had characteristic metachromatic staining of cytoplasmic granules with Giemsa reagent and were detected in small numbers about superficial vessels in the papillary dermis of nonlesional skin and in large numbers about deep as well as superficial vessels of lesional skin. By both direct immunofluorescence with fluorescein isothiocyanate-H4 and indirect immunoperoxidase cytochemistry with H4, all mast cells were selectively stained. The reactivity was confined to the cytoplasm and was granular in character. In addition, keratinocytes in epidermal tissue and in cell suspensions stained diffusely with H4 antibody. A tryptase-like activity that cleaved tosyl-L-arginine methyl ester (0.003 U/10(6) cells) and was not inhibited by soy bean and lima bean trypsin inhibitors was detected in sonicated suspensions of purified epidermal keratinocytes. Monoclonal antitryptase antibody represents an immunologic probe for the presence of tryptase, a preformed mediator of human mast cells, in tissues and cells.

Aged↗
PubMed1985

Cytotoxic T lymphocytes and phenotypically abnormal epidermal dendritic cells in fixed cutaneous eruptions.

Fixed cutaneous eruptions are erythematous plaques or bullae that recur, often after drug ingestion, at precisely the same cutaneous sites. The study of this condition may provide insight into the mechanisms responsible for regionally localized, immunologically mediated dermatoses. Biopsy specimens from both advancing borders and established centers of fixed eruptions were studied by immunofluorescence microscopy, light microscopy (1-micron sections), and transmission electron microscopy, and with a panel of monoclonal antibodies to Langerhans cells and subsets of T lymphocytes. The dermal inflammatory infiltrates of the advancing edges of the lesions were composed predominantly of OKT4/Leu-3a-positive lymphoid cells in perivascular array. In more established regions (the centers of the lesions), the majority of mononuclear cells were OKT8-positive lymphocytes disposed along the dermal-epidermal junction and migrating into the epidermis through focal defects in the basement membrane. In these areas, keratinocyte reactivity for anti-HLA-DR antibody and the apposition of intraepidermal lymphocytes to degenerating keratinocytes were observed. T6-positive epidermal dendritic cells were observed in normal numbers in the epidermis, although extensive study failed to reveal characteristic Langerhans cell granules within these cells. It is concluded that fixed cutaneous eruptions are characterized by an early vascular phase involving lymphocytes with helper/inducer phenotypes, and a later epidermal phase involving cytotoxic/suppressor cells. Potential effector cells with the phenotypic characteristics of cytotoxic T cells appear to represent important mediators of the epidermal damage characteristic of fixed cutaneous eruptions. Morphologically abnormal epidermal dendritic cells may contribute to regionally altered antigen presentation and may thus be relevant to the recurrence of lesions at identical cutaneous sites.

Adult↗