AIDS--clinical synopsis.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
G Stingl
Publications and source records attributed to G Stingl.
[Therapy of AIDS].
Therapeutic strategies in the management of AIDS should aim at an inhibition of the replication and spread of HIV; the reconstitution of immune functions; an effective chemotherapy of opportunistic infections and tumors; and the prevention of new opportunistic infections. At present, these goals can be only partially achieved and where beneficial therapeutic results are obtained they are only transient in nature. Antiretroviral therapy and chemotherapy of infections have, however, resulted in some, albeit temporary, improvement of the prognosis of ARC/AIDS patients. This review summarizes the principles and results of antiretroviral treatment of the HIV infection and chemotherapy of opportunistic infections in AIDS.
Acquired Immunodeficiency Syndrome↗
[HIV-1 infection: pathogenesis of immune suppression].
Although, in the course of HIV-1-infection, the functional capacities of virtually all immune cells are greatly impaired, only CD4+ cells (antigen-presenting cells, helper T cells) are directly infected by the virus. CD4+ T cells are involved, to a greater or lesser degree, in the induction of virtually all immunologic phenomena, either directly or indirectly. Thus, it is clear that the HIV-1-induced depletion and functional impairment of this critical T cell subset will result in a dysfunction/deficiency of the entire immune system and, finally, in the development of opportunistic infections and neoplasms.
Acquired Immunodeficiency Syndrome↗
[Initial clinical experiences in a large Austrian patient sample with immunodeficiency syndrome (AIDS): I. Type and course of encountered infections].
This study presents a report on the first clinical experiences gained in 68 hospitalized HIV antibody-positive patients from Austria, covering a period of twelve months. 36 patients (52.9%) belonged to risk group I or Ib (homo- or bisexual), whereas 26 (38.2%) patients were i.v. drug abusers (risk group II). 5 (7.4%) patients fulfilled the criteria of stage II of the CDC classification of HIV-associated clinical symptoms, 10 (14.7%) were classified as stage III and the remaining 53 patients (78%) as stage IV. The most frequent and also the most serious problem was the development of opportunistic infections. Multiple infections were found in 45.7% of all cases. Kaposi's sarcoma was found in 9 patients who all belonged to risk group I. During the entire observation period 10 patients died as a consequence of HIV-1-induced immunodeficiency and the resulting opportunistic infections and/or neoplasms.
Acquired Immunodeficiency Syndrome↗
Expression of C gamma 4 T cell receptors and lack of isotype exclusion by dendritic epidermal T cell lines.
Although four murine C gamma gene segments (C gamma 1, 2, 3, and 4) are known to exist, the large majority of expressed gamma-chains have been shown to be of the C gamma 1 isotype and no evidence exists for the expression of more than one receptor by gamma delta TCR-bearing cells. We investigated the nature of the TCR expressed on a number of murine dendritic epidermal T cell-derived cell lines by using both Northern blot and immunoprecipitation analyses. One of these CD3+ cell lines (T195) expresses C gamma 4, V gamma 1, and delta mRNA, and its CD3-associated TCR complex can be precipitated by both anti-C gamma 4 and anti-delta sera, indicating that this receptor is a C gamma 4/delta heterodimer. Furthermore, we show that two cell lines (Y245, Y93) express two distinct TCR gamma-chains, one derived from the C gamma 4 locus, whereas the second gamma-chain is probably derived from the C gamma 2 locus. Together with the previous demonstration of C gamma 1/delta TCR on a number of dendritic epidermal T cell lines (DETC), these results indicate that such DETC are capable of expressing a variety of gamma delta TCR and that, in some DETC, isotype exclusion of gamma-chain expression does not occur.
Animals↗
Characterization of a cell surface-expressed disulfide-linked dimer involved in murine T cell activation.
We have produced a hamster mAb, H1.2F3, which was derived by immunization with a murine TCR-gamma delta + epidermal T cell line. H1.2F3 immunoprecipitates a cell surface-expressed disulfide-linked dimer that has a m.w. of 85,000 under non-reducing conditions and consists of subunits of 35,000 to 39,000 m.w. This dimer is distinct from the CD3-associated TCR-gamma delta complex (CD3/TCR), inasmuch as H1.2F3 does not co-precipitate or co-modulate with the CD3/TCR complex and recognizes an Ag with a single-peptide backbone of 22,000 m.w. after N-Glycanase treatment. H1.2F3 is weakly reactive with a small percentage of cells from unfractionated thymus, spleen, or lymph node, but reactivity with both T and B lymphocytes is markedly enhanced by a brief period of stimulation with Con A or PMA in vitro. This enhancement requires de novo protein synthesis. Enhanced expression of the H1.2F3 Ag can also be induced in vivo by injection of Con A or anti-CD3. H1.2F3 is a potent stimulator of T, but not B, cell proliferation in the presence of PMA and FcR-bearing accessory cells. These functional and biochemical studies strongly suggest that the Ag recognized by H1.2F3 is the murine homologue of the human CD28 Ag recognized by mAb 9.3.
Aging↗
T cell receptor gamma/delta chain diversity.
The TCR-gamma and -delta chains of six murine hybridomas were compared by one-dimensional SDS-PAGE and two-dimensional NEPHGE/SDS-PAGE analysis. This allowed the identification of three distinct gamma chains (gamma a, gamma b, and gamma c) and three distinct delta chains (delta a, delta b, and delta c). Four gamma/delta chain combinations (gamma a delta a, gamma b delta b, gamma b delta c, and gamma c delta a) were observed. These results indicate that multiple forms of the delta chain are expressed and suggest that the delta chains are encoded for by an Ig-like rearranging gene. This delta chain polymorphism significantly enhances the potential diversity of TCR-gamma/delta, which may be of importance for a better understanding of the putative ligand(s) recognized by this receptor.
Animals↗
Characterization of T cell receptors on resident murine dendritic epidermal T cells.
Cell lines derived from Thy-1+ dendritic epidermal cells (Thy-1+DEC) display a marked heterogeneity in T cell receptor (TcR) expression including CD3-associated alpha/beta, C gamma 1/delta or C gamma 2/delta and C gamma 4/delta TcR. In order to investigate whether this heterogeneity is primarily imposed by in vitro culture conditions or, alternatively, is already present within the epidermis, we studied TcR expression by Thy-1+DEC in situ and on freshly isolated epidermal cell suspensions greatly enriched for Thy-1+DEC. Immunolabeling experiments showed that resident Thy-1+DEC are CD45+, Thy-1+, CD3+, TcR V beta 8-, CD5-, CD4- CD8-, CD25- lymphocytes. Immunoprecipitation of lysates from 125I-surface-labeled Thy-1+DEC-enriched epidermal cells with anti-CD3 epsilon, anti-C gamma 1,2,3 and anti-C gamma 4 antibodies, respectively, and subsequent analysis of the precipitates by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed only CD3-associated 35 kDa/45 kDa gamma/delta heterodimers. The demonstration of TcR heterodimers on resident Thy-1+DEC strongly implies that these cells are functional T cells. The selective expression of C gamma 1/delta (C57BL/6) and C gamma 1/delta or C gamma 2/delta (C3H/He) TcR makes these cells useful for the study of gamma/delta TcR function.
Animals↗
The phenotypic spectrum of histiocytosis X cells.
Proliferating cells in histiocytosis X (histiocytosis X cells) share many structural and immunophenotypic features with Langerhans cells, leading to the assumption that histiocytosis X represents a proliferative disorder of Langerhans cells. Because, depending on their state of activation and/or differentiation, Langerhans cells exhibit a varying immunophenotype, we investigated whether histiocytosis X cells display a similar phenotypic heterogeneity and, if so, whether the heterogenous biological behavior of histiocytosis X is reflected by differences in the immunophenotype of the proliferating cells. In 21 patients suffering from different clinical manifestations of histiocytosis X, proliferating cells uniformly expressed class I and II alloantigens, T200, CD1, CD4, and S100 protein. In 12 of 21 cases, histiocytosis X cells additionally exhibited immunocytochemically detectable amounts of C3b and C3bi receptors and certain monocyte/macrophage antigens (CDw14, Ki-M1, Ki-M6). This immunophenotypic heterogeneity of histiocytosis X cells could not be correlated with clinical course, prognosis, and final outcome of the disease in a given patient. The capacity of histiocytosis X cells to immunophenotypically mimic various states of Langerhans cell activation and/or differentiation, however, underscores the concept of histiocytosis X as a proliferative disorder of Langerhans cell origin.
Adolescent↗
Langerhans' cells are an actual site of HIV-1 replication.
Human epidermal Langerhans' cells (LC) are HLA-DR+/DQ+, CD1+, CD4+ dendritic antigen-presenting leukocytes. Based on the observation that in certain human immunodeficiency virus type 1 (HIV-1) infected individuals, LC are the only epidermal cells to react with monoclonal antibodies against HIV-1 isolate termed human T-lymphotropic virus IIIB/83 core proteins p17 and p24, we have proposed that LC can serve as a target for HIV-1. This contention was strengthened by the ultrastructural finding of HIV-1-like particles in the close proximity of LC and by the demonstration of signs of moderate to severe LC damage. Detailed electron microscopic analysis of skin and mucosal biopsies from an AIDS patient with p17/p24-positive LC now revealed not only mature HIV-1-like virions in the extracellular space surrounding LC and in intracytoplasmic LC vacuoles, but also developmental forms of HIV-1-like particles budding from LC surface membranes. Using peripheral blood derived monocytes/macrophages as targets for HIV-1 isolation, a virus isolate, designated human T-lymphotropic virus III WR-SK/86, was recovered from skin tissue from this patient by cocultivation and identified as unique by nucleic acid hybridization analysis. These findings now conclusively show that HIV-1 replicates in and is released from LC and support the concept that antigen-presenting cells (mononuclear phagocytes, LC) can serve as a reservoir for the acquired immunodeficiency syndrome virus.
AIDS-Related Complex↗
Neopterin as discriminating and prognostic parameter in healthy homosexuals, ARC and AIDS patients.
Urinary neopterin, a sensitive marker for activation of cell mediated immunity, is compared to clinical and laboratory data in 5 patients with AIDS, in 15 patients with ARC and in 40 male subjects without AIDS-related clinical signs attending an AIDS outpatient clinic. The sensitivity of neopterin for AIDS-related diseases was higher than that of the CD4+/CD8+ subset ratio. The differences in neopterin levels between the controls, ARC and AIDS patients were found to be more significant than the T-cell subset data. The observation that the 3 AIDS patients with the highest neopterin levels have died whereas the two others with the lower levels are still alive also underlines the prognostic potential of urinary neopterin level determinations. Measurement of urinary neopterin is thus recommended as an additional criterion for monitoring ARC and AIDS patients.
AIDS-Related Complex↗
Production of a T cell hybridoma that expresses the T cell receptor gamma/delta heterodimer.
We have produced a T cell hybridoma line by fusion of an IL-2-dependent, long-term T cell receptor (TCR) gamma/delta+ Thy-1+, bone marrow-derived, dendritic epidermal cell line to the BW5147 tumor line. The resultant hybridoma was rapidly growing, lymphokine independent, and expressed T3 in association with the TCR gamma/delta heterodimer. Several subclones of the hybridoma line produced easily detectable levels of IL-2 after stimulation by anti-T3 or Con A. The availability of these cloned cell lines should greatly facilitate further functional, biochemical, and molecular studies of the TCR delta chain.
Animals↗
Identification of a T3-associated gamma delta T cell receptor on Thy-1+ dendritic epidermal Cell lines.
The murine epidermis contains a subpopulation of bone marrow-derived lymphocytes that have a dendritic morphology and that express Thy-1 and T3 cell-surface antigens but not other markers (L3T4 or Lyt-2) characteristic of mature peripheral T lymphocytes. An alternative type of T cell receptor was earlier identified on a subpopulation of murine thymocytes with a similar phenotype (T3+, L3T4-, Lyt-2-), but not on peripheral murine T lymphocytes. Two independently derived Thy-1+, L3T4-, and Lyt-2- dendritic cell lines of epidermal origin that express a T3-associated disulfide-linked heterodimer composed of a 34-kilodalton gamma-chain and 46-kilodalton partner (the delta chain) have now been identified. Analysis of N-linked glycosylation revealed that this receptor is similar to that detected on thymocytes. These results demonstrate that Thy-1+ dendritic epidermal cell lines can express gamma delta T cell receptors in vitro and suggest that Thy-1+ dendritic epidermal cells express such receptors in vivo. The localization of these gamma delta T cell receptor-expressing cells in the epidermis may be of importance for understanding the function of these receptors.
Animals↗
Azathioprine in the treatment of pemphigus vulgaris. A long-term follow-up.
In a prospective long-term study, thirty-seven patients with severe generalized pemphigus vulgaris were treated with a combined corticosteroid-azathioprine regimen. Twenty-nine patients were available for complete follow-up lasting from 4 to 16 years after initiation of therapy. At the time of final evaluation, twenty-seven patients (93%) were alive; two deaths were unrelated to therapy; thirteen (45%) of the patients were free of disease and had not received treatment for up to 132 months; five of these patients had been off therapy for periods ranging from 60 to 132 months; eleven (38%) of the patients were clinically free of disease but still had low titers of antibodies and thus required low-dose maintenance therapy; five (17%) of the patients were well controlled but not completely free of disease. Side effects were rare and mostly related to corticosteroids. Of the original thirty-seven patients, only one death related to disease or therapy occurred and was due to pulmonary tuberculosis. It is concluded that azathioprine-corticosteroid treatment of pemphigus is highly effective and safe; it leads to long-term remissions in most patients and possibly to a cure in some.
Aged↗
Thy-1+ dendritic epidermal cells express T3 antigen and the T-cell receptor gamma chain.
The murine epidermis is a heterogeneous epithelium composed of keratinocytes, melanocytes, Langerhans cells, and a recently described subpopulation (2-3%) of bone-marrow-derived leukocytes with a dendritic morphology and the cell surface phenotype Thy-1+, L3T4-, Lyt-2-. Previous studies have demonstrated that cell lines derived from freshly explanted Thy-1+ dendritic epidermal cells (DEC) have abundant mRNA for rearranged T-cell receptor (TCR) gamma-chain genes. Analysis of Thy-1+ DEC in situ, freshly isolated cell suspensions of Thy-1+ DEC, and long-term Thy-1+ DEC lines demonstrated that 100% of the Thy-1+ DEC reacted with a monoclonal antibody to the epsilon chain of the murine T3 complex and that 40-60% of resident Thy-1+ DEC were also reactive with an antiserum to the TCR gamma chain. Two Thy-1+ DEC lines expressed a disulfide-linked 70-kDa molecule that could be precipitated with an anti-gamma-chain antiserum and could be coprecipitated with an antiserum to the T3 delta chain; the molecule appeared as a single 34-kDa band under reducing conditions. The phenotype of Thy-1+ DEC (T3+, L3T4-, Lyt-2-, TCR gamma chain+) thus resembles that of the recently described subpopulation of murine and human lymphocytes that have been identified in the thymus, peripheral blood, and fetal blood.
Animals↗
Thy-1+ dendritic epidermal cells belong to the T-cell lineage.
The murine epidermis contains a population of dendritic, Thy-1+ cells (Thy-1+ DEC). Although it is now clear that these cells are of bone marrow origin, extensive morphological, histochemical, and cell-membrane marker studies have not definitively placed them in any known hematopoietic differentiation pathway. Based on the observation that Thy-1+ DEC can be propagated in vitro with Con A and interleukin 2, we have established three cell lines (Tehy 184, Tehy 245, and Yety 245) that can be continuously grown in medium with lectin-lymphokine-rich culture supernatants of rat spleen cells. With the exception of the loss of reactivity with anti-asialo-GM1 antibodies (Tehy 184 and Tehy 245) and the gain of interleukin 2 receptor expression, the cultured cell lines bear the same surface characteristics as freshly isolated Thy-1+ DEC: Thy-1+, Ly-5+, Lyt-1-, Lyt-2-, L3T4-, Ia-, sIg-. Using Southern and RNA gel blot analysis, we now demonstrate that these Thy-1+ DEC-derived cell lines exhibit various patterns of rearrangements in the gene complexes encoding the T-cell receptor (related) beta and gamma chains and contain mature and/or incomplete transcripts from the T-cell receptor alpha- and beta-chain genes, as well as transcripts from the receptor-related gamma-chain genes. Tehy 184 cells, the only cells containing both mature alpha- and beta-chain transcripts, react positively with the F23.1 monoclonal antibody, which recognizes the product of a subset of T-cell receptor beta-chain variable region gene segments. This antibody precipitates a surface protein of 84-88 kDa from these cells that after reduction separates into two 40- to 44-kDa chains, characteristic of Ti alpha/beta heterodimers. These data strongly suggest that Thy-1+ DEC belong to the T-cell lineage and point to the epidermis as a site either of immature thymocyte migration or of extrathymic T-cell differentiation.
Animals↗
Epidermal Langerhans cells--a target for HTLV-III/LAV infection.
Langerhans cells (LC) are bone marrow-derived, Ia+, CD1+, CD4+, ATPase+ dendritic antigen-presenting cells within the human epidermis. Since the CD4 molecule has been implicated as a receptor structure for HTLV-III/LAV (human T-cell leukemia virus/lymphadenopathy-associated virus), we asked whether LC from HTLV-III/LAV-seropositive individuals display signs of HTLV-III/LAV infection. In skin biopsies from 7/40 HTLV-III/LAV-infected persons (1 asymptomatic carrier, 2 patients with acquired immunodeficiency syndrome (AIDS)-related complex and 4 patients with AIDS), LC were the only epidermal cells to react with a monoclonal antibody specific for the HTLV-III core protein p17. A varying percentage of p17+ LC were morphologically altered with blunt dendrites and poorly demarcated cellular contours. In one of these biopsies, the presence of LC-associated viral particles characteristic of HTLV-III/LAV as well as cytopathic changes in approximately one-third of the LC population were demonstrated by electron microscopy. These results strongly suggest that LC may harbor HTLV-III/LAV. The infection of LC with this retrovirus may have deleterious consequences for the immunologic functions of this cell system and may thus contribute to both the acquisition of immunodeficiency and the infectious and neoplastic complications of AIDS.
Acquired Immunodeficiency Syndrome↗
Langerhans' cells: a distinctive member of bone marrow-derived dendritic cells.
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Animals↗