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Biomedical subjects

R Edelson

Publications and source records attributed to R Edelson.

At least 19 recordsLinked to original sources
PubMed2001

Reversible resistance to apoptosis in cutaneous T cell lymphoma.

Mycosis fungoides and its leukemic variant, Sézary syndrome, represent the most common forms of cutaneous T cell lymphomas (CTCL). These disorders are clonal neoplasms characterized by the progressive accumulation of cells that resemble activated/memory CD4+ T cells. Unlike their normal counterparts, these malignant lymphocytes have prolonged life spans and are resistant to dying following treatment with most chemotherapeutic agents. This suggests that CTCL undergo abnormal programmed cell death; however, data regarding apoptotic defects in CTCL are limited. Regulation of apoptosis in lymphocytes that regularly undergo clonal expansion is necessarily complex and will be reviewed here. Clonally expanded lymphocytes rely primarily on Fas-mediated pathways to initiate apoptosis. Factors leading to the resistance of apoptosis in CTCL and new therapeutic approaches for reversing this resistance will be discussed, including the important role that the Fas death pathway may play in the pathogenesis and treatment of CTCL.

Antineoplastic Agents↗
PubMed2001

The clonotypic T cell receptor is a source of tumor-associated antigens in cutaneous T cell lymphoma.

To develop cancer vaccines for the treatment of cutaneous T cell lymphoma (CTCL), immunogenic peptides were identified by two approaches. First, through the use of "reverse immunology" the peptide sequence of the idiotypic region of the beta chain of the T cell receptor (TCR) was determined and a series of overlapping peptides synthesized and tested for CD8 T cell recognition. In two patients, the idiotypic CDR3 region provided immunogenic epitopes that were recognized in a class I-restricted fashion by autologous CD8 T cell lines. In a second strategy, peptides were isolated directly from class I MHC molecules on the CTCL surface and sequenced. A peptide with partial homology to sequences contained in the conserved variable portion of the clonotypic TCR beta chain was recognized as immunogenic by autologous CD8 T cells. Therefore, both approaches demonstrated that the clonotypic TCR in CTCL is a source of immunogenic tumor epitopes. To confirm that recognition of TCR-derived sequences provides immunoprotection against tumor growth, a murine model of T cell lymphoma was studied. The immunogenicity of a thymoma, which lacks cell surface TCR expression, was enhanced by transfection of the beta chain of the TCR. The studies reviewed in this paper demonstrate that the TCR can serve as one source for immunogenic tumor peptides in T cell lymphoma in vitro and in vivo. Presentation of TCR epitopes on dendritic cells that express high levels of MHC, costimulatory, and adhesion molecules may provide an effective means for immunization against T cell malignancy.

Amino Acid Sequence↗
PubMed1995

Regulation of transgenic class II major histocompatibility genes in murine Langerhans cells.

I-E is a class II major histocompatibility complex molecule normally expressed by Langerhans cells. A series of transgenic mice were developed previously that carry E alpha d gene constructs with promoter-region deletions that cause expression of I-E by different cell types when maintained on a B6 (I-E[-]) genetic background. To study cis-acting gene sequences that regulate expression of class II proteins by Langerhans cells, we identified transgenic I-E expression by tissue immunoperoxidase staining and by epidermal cell suspension immunofluorescence cytometry. Mice with a transgene containing 1.4 kilobase pairs (kb) of flanking sequence 5' to the E alpha initiation site expressed barely detectable levels of I-E on a tiny percentage of Langerhans cells, indicating that sequences promoting Langerhans cell expression of E alpha exist between 2.0 and 1.4 kb 5' of the E alpha initiation site. Removal of an additional 170 bp of 5' flanking sequence caused near-normal levels of expression by approximately one third of epidermal Langerhans cells, which contrasts with studies that showed minimal transgene expression by splenic dendritic cells in these animals. Thus, sequences between 1.4 and 1.23 kb 5' of the E alpha initiation site decrease expression of I-E by epidermal Langerhans cells, but enable I-E expression by splenic dendritic cells. These studies identify Langerhans cell-specific regulatory sequences and genetic regions controlling major histocompatibility complex class II gene expression in Langerhans cells and splenic dendritic cells. The genetic regions identified may be particularly important because differential regulation of class II major histocompatibility complex protein synthesis by Langerhans cells and dendritic cells may be crucial to immune functions of intact animals.

Animals↗
PubMed1994

Meralgia paresthetica in children.

We reviewed the findings in twenty children and adolescents who had meralgia paresthetica, a common entity in adults that has only rarely been reported in children. Ten patients had bilateral involvement; thus, the study included thirty lesions. Twenty-four lesions were eventually treated with open decompression of the lateral femoral cutaneous nerve; the results of twenty-one of these operations were followed for at least two years. The presenting symptom was severe pain resulting in marked restriction of activities. The pain could be reproduced with palpation of the nerve, and a trial injection of Xylocaine (lidocaine) always produced transient relief of symptoms. The average age at the onset of the symptoms was ten years (range, one to seventeen years); the diagnosis was missed initially in ten patients, which resulted in multiple, unnecessary diagnostic tests being done. The average duration of the symptoms before the patient was first seen was twenty-four months (range, two to eighty-four months), and the average duration of follow-up after the twenty-one operations was thirty-eight months (range, twenty-five to sixty months). Fourteen of the twenty-one operations led to an excellent result, with complete relief of pain and no restriction of activities; five led to a good result, with occasional pain but no limitation of sports or other activities; and two led to a fair result, with pain that interfered with sports activities but not with walking. We believe that meralgia paresthetica is much more common in children than has been previously recognized.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Profound deficiency in normal circulating T cells in erythrodermic cutaneous T-cell lymphoma.

BACKGROUND AND DESIGN: To accurately assess tumor burden in cutaneous T-cell lymphoma as well as to determine the number of residual normal circulating T cells, it is necessary to accurately distinguish malignant cells. Because cutaneous T-cell lymphoma cells regularly display many normal phenotypic markers of T cells (CD2+, CD3+, CD4+) these surface proteins have been of limited value. We have used a set of monoclonal antibodies with specificity for those T-cell receptor proteins containing variable regions on the beta chain to distinguish normal from malignant T cells in patients with cutaneous T-cell lymphoma. RESULTS: The results revealed an unanticipated and profound expansion of the malignant cell populations (59% to 87% of blood T cells) in six patients with total T-cell counts in the normal or near normal range. By subtracting the percentages of malignant T cells, identified in this manner, from the total T-cell counts, we found that the residual normal T-cell compartments were small (0 to 0.155 x 10(9)/L) in four of the six patients. Sézary cell counts by peripheral blood smear analysis by routine light microscopy underestimated the number of malignant T cells. Markedly elevated CD4/CD8 ratios (10 to 90) occurred in all cases, reflecting expansion of the CD4+ malignant population and parallel reduction of the normal residual CD8+ subset. CONCLUSIONS: Patients with erythrodermic cutaneous T-cell lymphoma often have markedly depressed levels of normal blood T cells, to the range seen in advanced acquired immunodeficiency syndrome, and absolute numbers of malignant cells substantially exceed those recognized with less sensitive techniques.

CD4-CD8 Ratio↗
PubMed1992

Correlations of unique clinical, immunotypic, and histologic findings in cutaneous gamma/delta T-cell lymphoma.

Cutaneous T-cell lymphoma is a malignancy of T cells that express a clone-specific heterodimer T-cell receptor for antigen. The second recognized case of an epidermotropic malignancy of T-cells expressing gamma/delta T-cell receptor-expressing cells is reported. The immunophenotype of the malignant T-cells was CD3+, CD2+, CD7+, gamma/delta T-cell receptor+, CD4-, CD8-, and alpha/beta T-cell receptor-. The clinical features were remarkable for extreme epidermotropism with a scant dermal lymphomatous infiltrate. Profound keratinocyte necrosis occurred in areas of malignant skin infiltrates. Despite cutaneous lesions covering more than 50% of the skin surface of the patient, no adenopathy or splenomegaly was detected. The intense epidermotropism of this patient's gamma/delta T-cell receptor-expressing cells and the putative cytolytic properties of CD4- CD8- gamma/delta contributed to the destruction of epidermis. Remission was induced with a combination of electron beam and extracorporeal photochemotherapy.

Antigens, CD↗
PubMed1992

Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy.

BACKGROUND: This original cohort of patients with erythrodermic cutaneous T-cell lymphoma (CTCL) was reported to have clinical improvement with photopheresis during the 12 months of the original study. No long-term follow-up data have been available to examine the impact of this therapy on the disease. OBJECTIVE: Our purpose was to provide long-term follow-up on the original 29 erythrodermic CTCL patients treated with photopheresis and to compare these results with historical controls. METHODS: Files of patients from the original photopheresis study centers were reviewed and their current status was documented. RESULTS: The median survival of the treated patients was 60.33 months from the date of diagnosis and 47.9 months from the date of the start of photopheresis therapy. A complete remission has been maintained in four of the six patients who achieved complete responses in the original study. The best responses were seen in patients with a lower CD4/CD8 ratio in the peripheral blood at the start of therapy. CONCLUSION: Photopheresis can influence the natural history of erythrodermic CTCL by inducing remissions and prolonging survival with minimal toxicity.

CD4-CD8 Ratio↗
PubMed1991

Endocytosis of the TCR/CD3 complex and the class-I major histocompatibility complex in a human T cell line.

We investigated the expression of the T cell receptor (TCR)/CD3 complex on a CD4-positive human T cell lymphoma cell line treated with phorbol myristate acetate (PMA) and/or CA2+ ionophore using fluorescence flow cytometry and fluorescence microscopic analysis. PMA induced a significant decrease in the expression of the CD3 complex on the cell membranes. Fluorescence microscopy confirmed that the down regulation is due to internalization of the antigens. Ca2+ ionophore treatment had no effect on the internalization of the CD3 complex. Double staining revealed that the vesicles containing the internalized CD3 complex and those containing intra-cytoplasmic class I major histocompatibility complex antigen had similar distribution in the PMA-stimulated cells, implying coexistence of these two antigens in a cytoplasmic perinuclear distribution.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1990

Phototoxic liposomes coupled to an antibody that alone cannot modulate its cell-surface antigen kill selected target cells.

Molecules such as antibodies that bind to cell surfaces can be used to deliver cytotoxic drugs to selected cells. To be effective the drug must usually be taken into the cells by endocytosis. In this study a T-cell line (CCRF-CEM) was effectively killed by liposomes carrying a photosensitizer and bearing the antibody OKT4 (anti-CD4). The unconjugated antibody does not induce antigenic modulation in the target cells, an indication of the absence of endocytosis, and would therefore not normally have been selected as an agent for drug delivery. It cannot, however, be concluded with certainty that the conjugates act at the cell surface and several alternative explanations of their efficacy are offered.

Animals↗
PubMed1990

Inhibition of autoimmune disease in a murine model of systemic lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes.

MRL/l mice develop progressive, virulent autoimmune disease that has many of the features of systemic lupus erythematosus. Prophylactic treatment of MRL/l mice with syngeneic photoinactivated autoimmune splenocytes improves survival and inhibits the fulminant hyperproliferation of abnormal T cells and the production of high titer anti-DNA antibody invariably found in untreated mice. The proliferation of Thy 1+ splenic T cells was significantly decreased, and prolonged retention of the response to T-cell mitogen was found in treated mice. Treatment with unmodified cells induced a partial inhibition of disease features which did not prolong survival rates. These results suggest that phototherapy potentiates a normal immunoregulatory process which enables suppression of the development of abnormal cell populations in young MRL/l mice with relatively intact immune systems.

Animals↗
PubMed1989

Inhibition of antiskin allograft immunity by infusions with syngeneic photoinactivated effector lymphocytes.

Induction of tolerance for skin allotransplantation requires selective suppression of the host response to foreign histocompatibility antigens. This report describes a new approach that employs pretreatment of effector cells with 8-methoxy-psoralen (8-MOP) and ultraviolet A light (UVA) to render the effector cells of graft rejection immunogenic for the syngeneic recipient. Reinfusion of photodamaged cells resulted in an immunosuppressive host response that permitted prolonged retention of histoincompatible skin grafts and specifically inhibited in vitro and in vivo responses that correlate with allograft rejection. Eight days after BALB/c mice received CBA/j skin grafts, their splenocytes served as a source of alloreactive effector cells. The splenocytes were treated with 100 ng/ml 8-MOP and 1 J/cm2 UVA before reinfusion into naive BALB/c recipients. Recipient mice were tested for tolerance to alloantigens in mixed leukocyte culture (MLC), cytotoxicity (CTL), delayed type hypersensitivity assays (DTH), and challenge with a fresh CBA/j graft. Splenocytes from BALB/c recipients of photoinactivated splenocytes containing the effector cells of CBA/j alloantigen rejection proliferated poorly in MLC and generated lower cytotoxic T cell responses to CBA/j alloantigens in comparison with sensitized and naive controls. Splenocytes from these hyporesponsive mice suppressed the MLC and CTL response to alloantigen from sensitized and naive BALB/c mice. In vivo the DTH response was specifically suppressed to the relevant alloantigen in comparison with controls. Moreover, BALB/c mice treated in this fashion retained a CBA/j skin graft for up to 42 d posttransplantation without visual evidence of rejection. These results indicate that the in vivo and in vitro response to alloantigen can be attenuated by pretreating the host with photoinactivated splenocytes containing the effector cells of alloantigen rejection.

Animals↗
PubMed1989

Molecular cloning of CD1a (T6), a human epidermal dendritic cell marker related to class I MHC molecules.

To investigate the structure, function, and control of CD1a, we have cloned a 1.6-kbp cDNA which encodes the expressed CD1a protein and includes untranslated 5' and 3' sequences and the poly-A tail. As the protein recognized by the monoclonal antibody OKT6, CD1a is a useful marker for Langerhans cells (LC). CD1a is found on these cells and on thymocytes, suggesting an important immunologic role for this molecule. We constructed a cDNA library in lambda gt10 using mRNA from MOLT-4, a cell line that expresses the CD1a surface antigen. We then screened the library with an oligonucleotide synthesized according to a known partial sequence for CD1a, and subcloned the cDNA and its restriction fragments into pGEM for sequencing and probe production. Based on this sequence the CD1a protein is predicted to consist of three extracellular domains (alpha 1-3), a hydrophobic transmembrane region, and a cytoplasmic tail. DNA 5' to the alpha 1 region may undergo alternative exon splicing. There is high sequence identity between the beta-2 microglobulin binding region of MHC I molecules and CD1a. The secondary structure predicted for CD1a is very similar to the actual structure of HLA-A2, a classical MHC I molecule. The similarity includes the beta pleated sheets and alpha helices which form the antigen binding groove of the alpha-1 and alpha-2 domains. The homology predicted between CD1a and HLA-A2 in these regions appears to exist on the level of secondary structure despite low primary nucleotide and amino acid sequence identity. The structural data and probes we have developed should facilitate studies of the function of CD1a as well as novel investigations of LC.

Amino Acid Sequence↗
PubMed1987

Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results.

Systemically disseminated cutaneous T-cell lymphoma is generally resistant to chemotherapy and radiotherapy. We tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links DNA. After oral administration of methoxsalen, a lymphocyte-enriched blood fraction was exposed to ultraviolet A (1 to 2 J per square centimeter) and then returned to the patient. The combination of ultraviolet A and methoxsalen caused an 88 +/- 5 percent loss of viability of target lymphocytes, whereas the drug alone was inactive. Twenty-seven of 37 patients with otherwise resistant cutaneous T-cell lymphoma responded to the treatment, with an average 64 percent decrease in cutaneous involvement after 22 +/- 10 weeks (mean +/- SD). The responding group included 8 of 10 patients with lymph-node involvement, 24 of 29 with exfoliative erythroderma, and 20 of 28 whose disease was resistant to standard chemotherapy. Side effects that often occur with standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. Although the mechanism of the beneficial effect is uncertain, an immune reaction to the infused damaged cells may have restricted the activity of the abnormal T cells. This preliminary study suggests that extracorporeal photochemotherapy is a promising treatment for widespread cutaneous T-cell lymphoma.

Administration, Oral↗
PubMed1987

Selective killing of T lymphocytes by phototoxic liposomes.

Two-fold specificity in drug delivery obtained through the localized activation of drugs by physical means and the attachment of drugs to proteins that bind to target cells might be used for highly selective cancer chemotherapy or for immunosuppression. Toward this end, a monoclonal antibody against an antigen on the surface of T lymphocytes was covalently attached to liposomes containing a phototoxic drug, pyrene, bound to the lipid bilayer. When unfractionated peripheral blood lymphocytes, or B- and T-cell lines, were irradiated after treatment with these liposomes, T cells were killed while B cells were spared, demonstrating the validity of the approach in a simple in vitro assay.

Antibodies, Monoclonal↗