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T H Finkel

Publications and source records attributed to T H Finkel.

At least 37 records · Page 2Linked to original sources
PubMed1997

Possible transmission of parvovirus B19 from intravenous immune globulin.

To look for genetic changes in human parvovirus B19 that might be associated with chronic infection, we sequenced B19 DNA obtained from serum specimens collected over an approximately 1-year period from a patient with systemic vasculitis. A comparison of the nucleotide sequences of the VP1/VP2 gene from four specimens revealed an abrupt change in the B19 genotype that coincided with initiation of intravenous immune globulin (IVIG) therapy. We suspect that one or more of the lots of IVIG administered to the patient were contaminated with B19. If true, this finding suggests that investigators must be careful in linking B19 infection to disease based on detection of B19 DNA in persons who have received multiple unit blood products.

Antibodies, Viral↗
PubMed1996

Triggering through CD40 promotes interleukin-4-induced CD23 production and enhanced soluble CD23 release in atopic disease.

The pathogenesis of atopic disease is closely linked to the overproduction of IgE. CD23 and CD40 are two cellular receptors involved in the regulation of IgE production and both receptors are elevated in atopic disease. We have examined the role of CD40 in the regulation of CD23 and soluble CD23 production in healthy and atopic donors. Triggering of the B cell CD40 receptor directly enhances interleukin (IL)-4-mediated up-regulation of CD23 at both the protein and the mRNA level. When atopic donors were studied, the synergistic effect of CD40 triggering on the IL-4-induced up-regulation of CD23 and soluble CD23 (sCD23) was enhanced and there was a relative skewing toward production of sCD23. These studies implicate the CD40 receptor in the hyperproduction of CD23 and sCD23 in atopic disease and suggest that abnormalities may exist in the cellular pathways leading to sCD23 production.

Antibodies, Monoclonal↗
PubMed1996

Apoptosis in HIV-1 Infection.

We have studied apoptosis in lymph node and peripheral blood mononuclear cells (PBMCs) from HIV-infected children and adults and SIV-infected rhesus macaques. In lymph nodes, we found that apoptosis and productive infection occurred only rarely in the same cell. There was, however, a direct correlation between the numbers of apoptotic and productively-infected cells. In HIV-infected children, we found a direct correlation between disease severity and percentage CD4+ T cell apoptosis (p = 0.001). Both CD4+ and CD8+ T cell apoptosis were directly related to CD4+ T cell depletion (p = 0.006 and p = 0.01, respectively). In addition, we found a trend towards diminished CD4+ T cell apoptosis on anti-retroviral agents. These findings suggest that apoptosis of uninfected cells may be important in HIV pathogenesis and that measurement of apoptosis may be a useful marker of disease activity.

Adult↗
PubMed1995

Tyrosine-phosphorylated T cell receptor zeta chain associates with the actin cytoskeleton upon activation of mature T lymphocytes.

The multichain T cell antigen receptor (TCR) is composed of an antigen binding (alpha/beta) domain and associated signal-transducing complexes, the CD3 (gamma, delta, and epsilon) and the zeta chains. The zeta chain (TCR zeta) plays a key role in signal transduction. We show here that TCR ligation induces association of tyrosine-phosphorylated TCR zeta with the detergent-insoluble cell fraction. The microfilament poison, cytochalasin D, disrupts this association and enhances the coprecipitation of actin with TCR zeta after receptor ligation. This microfilament association is specific to TCR-associated polypeptides containing at least one intact immunoreceptor tyrosine-based activation motif (ITAM). Mapping studies using transfectants and chimeric TCR zeta chain constructs suggest that the third ITAM is necessary and sufficient for association, if the distal tyrosine is intact. This cytoskeletal association is directly correlated with IL-2 production, and ligation of TCR on immature thymocytes does not induce TCR zeta-cytoskeleton association. These data thus provide direct evidence of a developmentally regulated activation-dependent interaction between a lymphocyte antigen receptor and the actin cytoskeleton.

Actins↗
PubMed1995

Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.

Although 13 years have passed since identification of human immunodeficiency virus-1 (HIV-1) as the cause of AIDS, we do not yet know how HIV kills its primary target, the T cell that carries the CD4 antigen. We and others have shown an increase in the percentage of apoptotic cells among circulating CD4+ (and CD8+) T cells of HIV-seropositive individuals and an increase in frequency of apoptosis with disease progression. However, it is not known if this apoptosis occurs in infected or uninfected T cells. We show here, using in situ labelling of lymph nodes from HIV-infected children and SIV-infected macaques, that apoptosis occurs predominantly in bystander cells and not in the productively infected cells themselves. These data have implications for pathogenesis and therapy, namely, arguing that rational drug therapy may involve combination agents targeting viral replication in infected cells and apoptosis of uninfected cells.

Animals↗
PubMed1994

Thymic development in human CD4 transgenic mice. Positive selection occurs after commitment to the CD8 lineage.

Developing T cells are positively selected on the basis of their recognition of polymorphic MHCs (major histocompatibility molecules). The CD4 and CD8 co-receptors, together with a compatible TCR-alpha beta, bind class II and class I MHC, respectively, delivering a signal that allows T cell maturation to proceed along the appropriate co-receptor lineage. During development, thymocytes first co-express CD4 and CD8 and subsequently commit to a single co-receptor phenotype. Debate exists over the stage at which positive selection occurs. Positive selection may precede or accompany co-receptor lineage commitment or occur subsequent to the acquisition of a single co-receptor phenotype. We developed transgenic (TG) mice expressing human CD4 (huCD4) on T cells. To study differentiation of CD8+ cells, huCD4 TG mice were bred with mice lacking class I MHC (class I-). This enabled us to assess maturation of mCD8+mCD4+huCD4+ thymocytes to mCD8+mCD4-huCD4+ cells after interaction between huCD4 and mclass II MHC. In the absence of huCD4, class I- mice failed to produce mCD8+ cells. However, expression of huCD4 allowed development of mCD8+mCD4-huCD4+ T cells, suggesting that selection of cells precommitted to the mCD8+mCD4- lineage occurred. Importantly, CD8+ T cells were increased in both the thymus and the periphery of huCD4 TG x class I- animals, indicating their intrathymic origin. V beta 14+ CD8+ T cells were also increased, as predicted for positive selection of CD8+ cells bearing class II-reactive TCRs. These data provide evidence that positive selection occurs at a late stage of thymocyte differentiation, after commitment to the CD8 lineage.

Animals↗
PubMed1994

Developmental regulation of the TCR zeta-chain. Differential expression and tyrosine phosphorylation of the TCR zeta-chain in resting immature and mature T lymphocytes.

The zeta subunit of the TCR complex targets receptor surface expression, is phosphorylated on tyrosine residues upon T cell activation, and is implicated in signal transduction after TCR ligation. Here we show that, although intrathymic expression of the murine TCR-associated zeta-chain relative to the other chains of the Ag receptor complex remains unchanged during early thymocyte development, there is a doubling of TCR-associated zeta-chain surface expression upon thymocyte maturation. The ratio of tyrosine-phosphorylated relative to nonphosphorylated TCR-associated zeta-chain also changes with thymocyte development. This ratio was quantified after the purification and detergent extraction of receptor complexes from freshly isolated immature or mature thymocytes. Immunoprecipitation of the zeta-chain released from the complex allowed for the isolation of the tyrosine-phosphorylated and nonphosphorylated forms of TCR-associated zeta-chain. Intracellular free zeta-chain was characterized by immunoprecipitation after clearing the cell lysate of intact TCR complexes. Densitometric analysis of immunoblots indicated that surface phosphorylated zeta-chain is more abundant in immature relative to mature T cell populations, whereas the inverse is true of intracellular phosphorylated zeta-chain. Surface phosphorylated zeta-chain also migrated at a higher m.w. than its cytoplasmic counterpart, suggesting that it is more highly modified on some or all of its available tyrosines. These findings demonstrate that the stoichiometry and post-translational modification of the TCR complex are regulated, in vivo, and may determine the functional maturation of T cell signaling, selection, and activation.

Animals↗
PubMed1994

Chronic parvovirus B19 infection and systemic necrotising vasculitis: opportunistic infection or aetiological agent?

We describe three patients who had infection with human parvovirus B19 in association with new-onset systemic necrotising vasculitis syndromes, two with features of polyarteritis nodosa and one with features of Wegener's granulomatosis. Chronic B19 infection, lasting 5 months to more than 3 years, was shown by enzyme immunoassay for IgG and IgM antibodies to B19 and polymerase chain reaction for B19 DNA in serum and tissue samples. The patients had atypical serological responses to the B19 infection, although none had a recognisable immunodeficiency disorder. Treatment with corticosteroids and cyclophosphamide did not control vasculitis. Intravenous immunoglobulin (IVIG) therapy led to rapid improvement of the systemic vascultis manifestations, clearing of the chronic parvovirus infection, and long-term remission. These observations suggest an aetiological relation between parvovirus B19 infection and systemic necrotising vasculitis in these patients and indicate a potentially curative role for IVIG in such disorders.

Adolescent↗
PubMed1994

Indirect mechanisms of HIV pathogenesis: how does HIV kill T cells?

Although twelve years have passed since the identification of HIV as the cause of AIDS, we do not yet know how HIV kills its target, the CD4+ T cell, nor how this killing cripples the immune system. Prominent theories include direct killing of infected CD4+ T cells by the action or accumulation of cytopathic viral DNA, transcripts or proteins, or by virus-specific cytotoxic T lymphocytes, and indirect killing of uninfected CD4+ T cells (and other immune cells) by autoimmune mechanisms, cytokines, superantigens, or apoptosis. In the past year, studies have provided tantalizing clues as to why infected cells may not die and how these infected cells kill innocent bystander cells.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis.

During human immunodeficiency virus (HIV) infection there is a profound and selective decrease in the CD4+ population of T lymphocytes. The mechanism of this depletion is not understood, as only a small fraction of all CD4+ cells appear to be productively infected with HIV-1 in seropositive individuals. In the present study, crosslinking of bound gp120 on human CD4+ T cells followed by signaling through the T cell receptor for antigen was found to result in activation-dependent cell death by a form of cell suicide termed apoptosis, or programmed cell death. The data indicate that even picomolar concentrations of gp120 prime T cells for activation-induced cell death, suggesting a mechanism for CD4+ T cell depletion in acquired immune deficiency syndrome (AIDS), particularly in the face of concurrent infection and antigenic challenge with other organisms. These results also provide an explanation for the enhancement of infection by certain antibodies against HIV, and for the paradox that HIV appears to cause AIDS after the onset of antiviral immunity.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Immature thymocytes are protected from deletion early in ontogeny.

Self/non-self discrimination occurs within the thymus, where T cells undergo positive selection to produce a repertoire that recognizes foreign antigen in the context of self major histocompatibility complex proteins and negative selection to eliminate from the repertoire those T cells with self-reactive specificities. We have previously shown that two subpopulations of immature antigen receptor-bearing thymocytes exist, one that is susceptible to negative selection induced by ligation of the T-cell receptor for antigen and a second that is resistant to T-cell receptor-mediated negative selection. In the current work, we show that all antigen receptor-bearing thymocytes in early fetal thymuses are resistant to negative selection and that thymocytes susceptible to deletion do not develop until later gestational ages. Thus, deletion is a relatively late event in T-cell ontogeny. In addition, these data suggest that a thymocyte population can be isolated early in ontogeny that is capable of transducing selective signals through the antigen receptor, which do not lead to deletion but may result in positive selection.

Animals↗
PubMed1991

Surface expression of a T cell receptor beta (TCR-beta) chain in the absence of TCR-alpha, -delta, and -gamma proteins.

The antigen receptor expressed by mature T cells has been described as a disulfide-linked alpha/beta or gamma/delta heterodimer noncovalently associated with CD3, a complex of transmembrane proteins that communicates signals from the T cell receptor (TCR) to the cell interior. Studies suggest that all component chains must assemble intracellularly before surface expression can be achieved. We described, however, a CD4+/CD8+ transformed murine thymocyte, KKF, that expresses surface TCR-beta chains in the absence of gamma, delta, and alpha proteins; these beta chains are only weakly associated with CD3-epsilon and CD3-zeta. Furthermore, KKF responds differently to stimulation through TCR-beta and CD3-epsilon, a functional dissociation that has been ascribed to a CD4+/CD8+ subpopulation of normal thymocytes. KKF's unique TCR structure may offer an explanation for the functional anomalies observed.

Animals↗
PubMed1991

Altered antigen receptor signaling in anergic T cells from self-tolerant T-cell receptor beta-chain transgenic mice.

T-cell tolerance to the minor lymphocyte-stimulating antigen Mls-1a in a T-cell receptor (TcR) V beta 8.1 transgenic line of mice is maintained by both clonal deletion and clonal anergy. Approximately 20-50% of peripheral CD4+ (but not CD8+) T cells isolated from these mice are anergic and fail to proliferate following TcR ligation. We have examined key events in T-cell signaling in peripheral T cells isolated from these mice. In this report, we show that the anergic CD4+ T cells did not mobilize calcium or express receptors for interleukin 2 (IL-2) following TcR ligation. However, the cells retained viability and functional potential because stimulation with phorbol 12-myristate 13-acetate and ionomycin bypassed the block in receptor-mediated signaling and induced IL-2 receptor expression and proliferation of the anergic cells.

Animals↗
PubMed1991

T-cell development and transmembrane signaling: changing biological responses through an unchanging receptor.

The antigen receptor repertoire is conditioned by discriminating forces in the thymus. Cells that see antigen only in the context of self major histocompatibility gene products are positively selected and those that recognize self antigens are deleted. The molecular mechanisms by which this complex conditioning is achieved via a single antigen receptor is one of the most fascinating problems in immunology. Here Terri Helman Finkel and colleagues review the literature and present a unifying mechanistic model of this process.

Animals↗
PubMed1989

The thymus has two functionally distinct populations of immature alpha beta + T cells: one population is deleted by ligation of alpha beta TCR.

During T cell development, the processes of selection and tolerance act on the universe of expressed T cell receptors in the thymic cortex to form the repertoire of mature T cells that will respond to foreign antigen in the context of self-MHC in that animal. We have subdivided the cortical thymocytes into three functionally distinct populations: one population which is antigen-receptor negative, a second population which is antigen-receptor positive and is resistant to deletion by signaling through the antigen receptor, and a third population which is also antigen-receptor positive but is sensitive to deletion. These results have implications for the cellular compartments in which positive and negative selection occur and for the biochemical mechanisms that mediate selection and tolerance.

Animals↗
PubMed1989

Alpha beta T cell receptor and CD3 transduce different signals in immature T cells. Implications for selection and tolerance.

Ligand binding to alpha beta TCR has different consequences in thymocytes at different developmental stages, causing alternatively positive selection, clonal deletion, or activation. These various functional consequences may be due to changes in the signaling properties of the receptor complex during development. In this report we show that alpha beta TCR engagement on immature thymocytes has different effects on intracellular free calcium concentrations than alpha beta TCR engagement on mature T cells. In contrast, CD3 engagement on immature thymocytes and mature T cells has the same effect on intracellular free calcium, suggesting that altered signal transduction in immature thymocytes may be due to inefficient alpha beta TCR-CD3 coupling. These studies also suggest that in certain T cell populations, activation events resulting from ligation of CD3 may not accurately reflect the activation events resulting from ligation of the physiologic receptor, alpha beta TCR.

Animals↗
PubMed1987

Priming of neutrophils and macrophages for enhanced release of superoxide anion by the calcium ionophore ionomycin. Implications for regulation of the respiratory burst.

Phagocytic cells can be primed for enhanced stimulated release of superoxide anion (O2-) by exposure to a variety of biologic agents, including gamma-interferon and lipopolysaccharide. We examined the role of calcium ion in this priming, using the calcium ionophore ionomycin. Preincubation with ionomycin, 1 to 10 nM, primed human neutrophils to release up to 7-fold more O2- during stimulation with 1 microM formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). With 160 nM phorbol myristate acetate as stimulus, ionomycin caused a doubling of O2- production in mouse peritoneal macrophages. Incubation of phagocytes with ionomycin at priming concentrations did not directly stimulate O2- release. Priming of neutrophils occurred in 1-2 min and was associated with a marked reduction in the lag time for O2- release after f-Met-Leu-Phe stimulation and with an increase in the rate of O2- production. Kinetic analysis of NADPH-dependent O2(-)-producing activity in sonicates of resting human neutrophils incubated with sodium dodecyl sulfate suggested that modification of the enzyme responsible for the respiratory burst was not responsible for priming. Priming of neutrophils with ionomycin had no apparent effect on either the activity or subcellular distribution of protein kinase C. The effect of ionomycin on the cytosolic free calcium concentration ([Ca2+]c) was assessed in neutrophils using the calcium-sensitive fluorescent dye fura-2. Ionomycin at priming concentrations caused an approximate doubling of the base-line [Ca2+]c. When neutrophils were exposed to various concentrations of ionomycin, a parallel rise in [Ca2+]c and priming was observed. A rise in [Ca2+]c of approximately 0.8 microM caused half-maximal priming. These results suggest that an increase in [Ca2+]c is not sufficient to initiate release of O2-, but they support the concept that Ca2+ can serve as a second messenger in this event.

Animals↗