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Biomedical subjects

Carole L Berger

Publications and source records attributed to Carole L Berger.

10 recordsLinked to original sources
PubMed2006

Langerhans cells: mediators of immunity and tolerance.

Langerhans cells provide the epidermis with a surveillance network that samples the external environment influencing the decision between immunity and tolerance. Langerhans cells are immature dendritic cells acquiring antigens from foreign invaders as well as damaged native tissue for display to the immune response. The current paradigm suggests that the state of maturity of Langerhans cells, defined by the display of molecules that provoke immune responses (histocompatibility, co-stimulators, adhesion and homing receptors), determines whether emigration of the Langerhans cell to lymph nodes signals immunity or tolerance. Other factors such as type of immunogen ingested, environmental danger signals and the level of cell death may also play a role in tipping the balance towards immunity or immunosuppression. As modulators of the immune response, Langerhans cells play a role in cutaneous autoimmunity in lupus and in cancers that have an affinity for the epidermis such as cutaneous T cell lymphoma.

Animals↗
PubMed2006

Increased expression of CTLA-4 in malignant T-cells from patients with mycosis fungoides -- cutaneous T cell lymphoma.

Mycosis fungoides (MF) is a low-grade lymphoma of cluster of differentiation (CD)4+, CD45RO+, cutaneous leukocyte antigen (CLA)+ T cells that homes to the skin. To understand the functional abnormalities in this disease, we study the regulation of cytotoxic T-lymphocyte antigen (CTLA)-4 in peripheral blood mononuclear cells (PBMCs) from patients with MF. CTLA-4 is a costimulatory molecule for T cells that functions in immunoregulation. Unlike the expression of CD28, which is expressed constitutively on T cells, CTLA-4 expression is highly regulated. In the analysis of PBMCs in MF, we found that CTLA-4 is stimulated by phorbol myristate acetate/A23187 to a greater level when compared to normals. This defect was seen in the dominant clones of T cells. The increased CTLA-4 expression was significant between normal and MF, with a correlation between higher expression of CTLA-4 and a higher grade of MF. In a patient whose disease progressed, the CTLA-4 level increased. The abnormal level of CTLA-4 was confirmed at both the transcription and translation levels. Although MF is associated with a Th2 bias, Th1 cytokines IL-2 and IFN-gamma enhanced CTLA-4 expression, while IL-4 did not. These findings reveal an abnormal regulation of CTLA-4 expression in MF and show that PBMCs from patients with MF have properties that are divergent from those of normal T cells.

Aged↗
PubMed2006

Transimmunization for cutaneous T cell lymphoma: a Phase I study.

Extracorporeal photochemotherapy (ECP) is a widely used immunotherapy for cutaneous T cell lymphoma (CTCL). It involves four sequential steps: conversion of blood monocytes into dendritic antigen presenting cells (DC) by repetitive adherence and disadherence to plastic surface; reinfusion of the new DC; presumed in vivo loading of the new DC with apoptotic malignant leukocytes; and expansion of the anti-tumor CD8 T cell pool. To assess the safety of a methodology designed to increase ex vivo contact between the apoptotic malignant cells and new DC prior to reinfusion, a single-center, open-label Phase I clinical study of a revised procedure--referred to as "Transimmunization"--was conducted in CTCL patients. Twenty-seven subjects were treated monthly for 3 to 5 months, alone or in combination with electron beam therapy. For those receiving Transimmunization alone, there was an overall diminution in infiltrative lesions in eleven (55%) of twenty patients. In the twelve leukemic CTCL patients, there was a significant mean reduction of 50.1% in the circulating malignant cells, as determined with family-specific anti-T cell receptor Vbeta monoclonal antibodies (P <or= 0.021). Because this therapy permits the synchronous induction and tumor loading of DC, with minimal toxicity, Transimmunization may merit further investigation in CTCL and other malignancies.

Adult↗
PubMed2005

Rapid construction of a dendritic cell vaccine through physical perturbation and apoptotic malignant T cell loading.

We have demonstrated that adherence and release of monocytes from a plastic surface drives their differentiation into immature dendritic cells (DC,) that can mature further during overnight incubation in the presence of apoptotic malignant T cells. Based on these results, we sought to develop a clinically, practical, rapid means for producing DC loaded with malignant cells. A leukapheresis harvest containing the clonal, leukemic expansion of malignant CD4+ T cells was obtained from the blood of patients with cutaneous T cell lymphoma (CTCL). CTCL cells were purified with a CD3-magnetic bead column where CD3 engagement rendered the malignant T cells apoptotic. The monocyte fraction was simultaneously activated by column passage, re-added to the apoptotic CTCL cells and co-cultured overnight. CTCL cell apoptosis, DC differentiation and apoptotic malignant T cell ingestion were measured by immunostaining. The results demonstrate that as monocytes passed through the column matrix, they became activated and differentiated into semi-mature DC expressing significantly increased levels of class II, CD83 and CD86 (markers associated with maturing DC) and reduced expression of the monocyte markers CD14 and CD36. Apoptotic malignant T cells were avidly engulfed by the phagocytic transitioning DC. The addition of supportive cytokines further enhanced the number of DC that contained apoptotic malignant T cells. Functional studies confirmed that column passaged DC increased class II expression as shown by significantly enhanced stimulation in mixed leukocyte culture compared to control monocytes. In addition, DC loaded with apoptotic CTCL cells stimulated an increase in the percentage and absolute number of CD8 T cells compared to co-cultivation with non-loaded DC. After CD8 T cells were stimulated by DC loaded with malignant cells, they mediated increased apoptosis of residual CTCL cells and TNF-alpha secretion indicating development of enhanced cytolytic function. We report a simple one-step procedure where maturing DC containing apoptotic malignant T cells can be prepared rapidly for potential use in vaccine immunotherapy. Ready access to both the DC and apoptotic cells provided by this system will allow extension to other malignancies through the addition of a variety of apoptotic tumor cells and maturation stimuli.

Journal Article↗
PubMed2004

Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells.

Studies in an in vitro model of cutaneous T-cell lymphoma (CTCL) demonstrated that CTCL cell proliferation is stimulated by direct contact with autologous, immature dendritic cells (DCs), suggesting that CD4(+) CTCL cell division is driven by antigens presented by DC major histocompatibility complex (MHC) class 2. We now report that the T-cell receptor (TCR) of the CD4(+) CTCL cells is triggered after interaction with DCs loaded with apoptotic CTCL cells, as shown by reduced membrane expression of CD3 and the TCR, up-regulation of cytotoxic T lymphocyte antigen-4 (CTLA-4), and calcium mobilization. CTCL cells adopt a T-regulatory (Treg) phenotype expressing CD25/CTLA-4 and FoxP3 and secreting interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta). Treg CTCL cells suppress normal T-cell antigen-driven secretion of IL-2 and interferon-gamma (IFN-gamma). Blocking DC MHC class 2 expression or transport inhibited CTCL cell adoption of a Treg phenotype. Allogeneic CTCL cells or normal CD4 T cells served as sources of apoptotic material for CTCL cell conversion to a Treg phenotype. Conversion of CTCL cells to Treg cells may explain the anergic, immunosuppressive nature of the malignancy.

Antibodies, Blocking↗
PubMed2004

The life cycle of cutaneous T cell lymphoma reveals opportunities for targeted drug therapy.

The diverse clinical presentations of cutaneous T cell lymphoma (CTCL) have been unified by immunologic characterization of the malignant T cells as an expansion of clonal, CD4+ inducer T cells with affinity for epidermal association with Langerhans cells (LC), an immature member of the dendritic cell (DC) family. Features of the life cycle of CTCL have recently been elucidated through development of an in vitro cell culture system. In this system, the proliferation and survival of the CTCL cells is tied to an association with immature monocyte-derived DC. Growth of the CTCL cells requires direct contact with the DC and both cell types survive in the presence of supportive cytokines for 3 months. Separation of the CTCL cells and the DC, or DC maturation truncates the synergy between the two cell populations and results in rapid death of both cell types. The CTCL cells perpetuate DC immaturity and survival through secretion of interleukin 10 (IL10) and transforming growth factor-beta (TGF-beta). The immature DC are aggressively phagocytic and can engulf apoptotic CTCL cells that have exhausted their proliferative potential and present peptides derived from the apoptotic material in class II MHC molecules to the T cell receptor (TCR) of the CD4+ CTCL cell. CTCL cells are induced to become T-regulatory (Treg) cells when their TCR is triggered by DC class II presentation of peptides derived from apoptotic material. Treg CTCL cells suppress immune responses and secrete IL10 and TGF-beta, cytokines that perpetuate DC immaturity, providing continued opportunity for DC stimulation of CTCL cell growth. Understanding the CTCL cell life cycle unveils a variety of potential targets that can be exploited for therapeutic intervention.

Animals↗
PubMed2003

Current concepts of the immunobiology and immunotherapy of cutaneous T cell lymphoma: insights gained through cross-talk between the clinic and the bench.

An understanding of the immunologic features of cutaneous T cell lymphoma (CTCL) has led to insights into the life cycle of the malignancy. The identification of the T cell lineage of the neoplastic CTCL cells has allowed unification of diverse clinical presentations under a single entity. The CD4 inducer T cell phenotype of the malignant cells has provided an understanding of the patient's ability to resist infection with certain bacteria. The clonality of the tumor cells, beyond its diagnostic implications, has made them a valuable resource for studying both normal and neoplastic T cell biology. The recently identified immunosuppressive features of the malignant T cells and their dependency for survival on an interaction with immature dendritic cells have explained previously cryptic clinical observations and identified new targets for immunotherapy. Future insights gained both from the bedside and the bench will provide not only an understanding of the immunobiology of the malignancy but also open new avenues for therapeutic intervention.

Cancer Vaccines↗
PubMed2002

The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells.

In the initial stage of cutaneous T-cell lymphoma (CTCL), proliferating CTCL cells are concentrated in the epidermis in close association with an immature dendritic cell (DC), the Langerhans cell. Because long-term in vitro culture of CTCL cells has proven difficult, the in vivo association with the major antigen-presenting cell (APC) of the epidermis has been postulated to play a role in directly stimulating the clonal T-cell proliferation. We report that CTCL cells can be reproducibly grown in culture for 3 months when cocultured with immature DCs. CTCL cells retain the phenotype and genotype of the initial malignant clone, whereas the APCs are a mixture of immature and mature DCs. CTCL cell and DC survival was dependent on direct membrane contact. Growth was inhibited by antibodies that bound to the T-cell receptor (TCR) or interfered with the interaction of CD40 with its ligand on the CTCL cell. Addition of antibody to CD3 or the clonotypic TCR caused rapid CTCL cell apoptosis followed by engulfment by avidly phagocytic immature DCs and subsequent DC maturation. The opportunity to study CTCL cells and immature DCs for prolonged periods will facilitate studies of tumor cell biology and will allow investigation of the intriguing hypothesis that CTCL cell growth is driven through TCR recognition of class II-presented self-peptides. In addition, the culture of CTCL cells will permit evaluation of therapies in vitro before clinical intervention, thereby improving safety and efficacy.

Antigen Presentation↗
PubMed2002

Transimmunization, a novel approach for tumor immunotherapy.

This review describes our experience with the development of a novel form of immunotherapy that may represent the first practical and effective means of performing tumor-loaded dendritic cell (DC) immunotherapy. We have modified the highly successful extracorporeal photopheresis (ECP) treatment that has been used in the therapy of cutaneous T cell lymphoma (CTCL). autoimmune disease, transplantation rejection episodes and graft-versus-host disease to enhance its efficacy by the addition of an overnight incubation period. This adaption of ECP is termed "transimmunization (TI)" since the new therapy permits transfer of tumor antigens that have been previously poorly recognized to potent antigen presenting cells where the tumor epitopes can be displayed in the full context of major histocompatibility, co-stimulatory and adhesion molecules. The TI modification of ECP is a practical and safe means of rapidly inducing DC differentiation from peripheral blood monocytes in the presence of apoptotic tumor cells. Uptake of the apoptotic CTCL cells by the immature DC, in the presence of inflammatory cytokines, further drives their maturation into potent antigen presenting cells. Reinfusion of these tumor-loaded DC, that have access to the full spectrum of tumor antigens, has the potential to invoke an anti-tumor immune response in the recipient. Standard ECP has been a very useful form of immunotherapy and a modification of this approach that can enhance its ellicacy and utility should broaden its application to a larger variety of disorders including potentially the treatment of solid tumors and the modulation of the immune response in graft-versus-leukemia and graft-versus-host transplantation regimens. An understanding of the mechanism of ECP and TI will provide the physician with the ability to more finely tune the desired immune response and thereby, provide an enhanced immunotherapy for malignancy and other disorders of immunocompetence.

Dendritic Cells↗