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Biomedical subjects

R L Edelson

Publications and source records attributed to R L Edelson.

At least 55 records · Page 3Linked to original sources
PubMed1992

Application of a multiprobe RNase protection assay and junctional sequences to define V beta gene diversity in Sezary syndrome.

Nineteen patients with mycosis fungoides/Sezary syndrome (MF/SZ), a malignancy of the mature helper T-cell phenotype (CD4+TCR alpha beta+), were screened for clonotypic V beta expansions in peripheral blood with a multiprobe RNase protection assay. A different predominant V beta gene was identified in 9 of 14 patients with high peripheral blood CD4/CD8 ratios, whereas 4 of these patients showed T-cell expansions expressing V beta genes other than those included in the assay. In contrast, five patients with few, if any, malignant cells in the circulation had V beta expression levels similar to that in normal peripheral blood. A unique V-D-J sequence was found for each highly expressed V beta gene, thereby documenting monoclonality of the expanded T-cell populations. Polymerase chain reaction (PCR) primers specific for the D-J beta junction accurately identified the corresponding malignant clonotype in peripheral blood. The diverse TCR V beta gene usage found in these MF/SZ patients suggests that T-cell receptor (TCR) specificity has no bearing on this disease.

Adult↗
PubMed1991

Inhibition of antiskin allograft immunity induced by infusions with photoinactivated effector T lymphocytes (PET cells). Is in vivo cell transferrable?

We previously reported producing donor-specific tolerance to alloantigens by intravenous exposure to pretreated antidonor T cells. The current study extends that work by adoptively transferring the donor-specific tolerance into naive syngeneic recipients. Eight days after BALB/c mice received histoincompatible CBA/j skin grafts, their splenocytes which included an expanded population of cells mediating rejection were treated with 100 ng/ml 8-methoxypsoralen (8-MOP) photoactivated by 1 Joule/cm2 of ultraviolet A (UVA) light prior to infusion into naive BALB/c recipients. Whereas 8-MOP itself is biologically inert, photoactivated 8-MOP crosslinks DNA by covalently binding to pyrimidine bases. Recipient BALB/c mice which had been previously demonstrated to be hyporesponsive to CBA/j alloantigens in mixed leukocyte culture (MLC), cytotoxicity (CTL) and in vivo delayed type hypersensitivity (DTH) assays were the donors of spleen cells for the adoptive transfer experiments. Fifty to one hundred million viable spleen cells from these pretreated BALB/c mice were transferred into naive syngeneic recipients which then were tested for DTH response and allograft survival to the relevant and irrelevant antigens. The radiosensitivity of this transferrable suppression was evaluated by exposing the adoptively transferred cell population to 3200 rads of C-irradiation prior to cell transfer. The phenotype of the cells transferring this suppressive response was performed by depleting specific populations of cells with monoclonal antibodies prior to cell transfer. In vivo the DTH response of the pretreated BALB/c mice was specifically suppressed to the relevant alloantigen, correlating with retention of CBA/j skin grafts for up to 42 days post engraftment without visual evidence of rejection, in comparison to control mice complete rejection of the skin graft in less than 8 days. In vitro, splenocytes from BALB/c recipients of pretreated syngeneic splenocytes containing large numbers of BALB/c anti-CBA/j T cells proliferated less in MLC and generated lower cytotoxic T cell responses to CBA/j alloantigens than did controls and suppressed the naive and sensitized BALB/c MLC and CTL responses to CBA/j alloantigen. This specific suppressive response to alloantigen was optimally transferred into syngeneic naive recipients when the adoptive transfer was performed on the sixth day after the last infusion received by the spleen cell donor mice. The adoptive transfer of this suppressive response was abrogated by the prior X-irradiation of the donor spleen cells and significantly abolished by the depletion of Thy-1+, Lyt-2+, L3T4- T lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Antigen-specific tolerance induced by autoimmunization with photoinactivated syngeneic effector cells.

Development of a protocol that could invoke specific suppression of an undesired immune response, while sparing normal immune competence, would be of great clinical value. This report demonstrates that multiple infusions of splenocytes sensitized in vivo to sheep red blood cells (SRBC) and photoinactivated in vitro with 8-methoxypsoralen and ultraviolet A light can render a syngeneic recipient selectively unresponsive to subsequent challenge with this antigen. Mice treated in this fashion did not develop a T cell-mediated delayed type hypersensitivity (DTH) reaction to SRBC. In contrast, control mice exposed to nonimmune splenocytes pretreated in an identical manner developed a normal DTH response to SRBC, thereby demonstrating that drug and light in the absence of effector T cells were not suppressive. Inhibition of the DTH response was antigen specific, since animals rendered unresponsive to SRBC developed a normal DTH response to chicken red blood cells. Cell transfer experiments demonstrated that unprimed recipients of splenocytes from mice rendered unresponsive to SRBC could not mount a DTH reaction when challenged. Moreover, this procedure can also suppress established immunity to that antigen. The use of photoinactivated syngeneic antigen-reactive effector cells as immunosuppression agents suggests that this method may be clinically useful in inhibiting pathogenic antigen-specific immunologic reactions.

Animals↗
PubMed1991

Photopheresis: a clinically relevant immunobiologic response modifier.

Photopheresis, the process by which peripheral blood is exposed in an extracorporeal flow system to photoactivated 8-methoxypsoralen (8-MOP), is an effective new treatment for certain disorders caused by aberrant T lymphocytes. It has become a standard therapy for advanced cutaneous T cell lymphoma and shows promise in the treatment of four autoimmune disorders (pemphigus vulgaris, the progressive systemic sclerosis form of scleroderma, rheumatoid arthritis, systemic lupus erythematosus) and in reversal of immunologic rejection of transplanted organs. Positive immunologic alterations observed in patients with AIDS-related complex merit further investigation, and preliminary trials in the management of patients with multiple sclerosis, myasthenia gravis and autoimmune insulin-dependent diabetes mellitus have recently been initiated. The inability of the treatment to meaningfully alter the course of the B cell malignancy, chronic lymphocytic leukemia, suggests that B cell proliferations, at least those involving malignant cells, may be more resistant to this treatment. The mechanism of action of photopheresis is likely to be multifaceted, but at least in experimental systems appears to involve an immunization against the pathogenic T cells, in a highly specific manner. Photoactivated 8-MOP initiates a cascade of cellular events by forming covalent photoadducts with nuclear DNA, with cell surface molecules and possibly with other cytoplasmic components of the ultraviolet exposed leukocytes. For reasons not yet clear, exposure of populations of T cells containing expanding a clone(s) of pathogenic T cells to photoactivated 8-MOP alters these cells so that their reinfusion induces a therapeutically significant immunologic reaction that targets unirradiated T cells of the same pathogenic clone(s). It is suggested that the specificity of the induced immunologic reaction may result, in sequence, from the exquisitely titratable damage that 8-MOP inflicts upon cells of the pathogenic clone(s), the return of these cells to an immunocompetent individual, the removal of the photo-damaged cells from the blood by the reticuloendothelial system and the preferential induction of an immune response against cells of the pathologically expanded clone(s).

Animals↗
PubMed1991

Photopheresis for rheumatoid arthritis.

For rheumatoid arthritis, an effective therapy with minimal toxicity would be welcome. In a six-month pilot study of seven patients with a variety of presentations and previous treatments, we tested a therapy involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links lymphocyte DNA; the injured cells are returned to the patient. Prior experimental studies had indicated that this regimen produces an immune reaction against antigens on treated T Cells, and a clinical trial in cutaneous T cell lymphoma had been successful. The current patients were treated on two successive days monthly (or, later on, biweekly). Between 12 and 16 weeks of therapy there appeared to be a breakpoint after which joint counts and joint scores of four patients began to improve. In three of them, these measures eventually diminished by mean values of 71% and 80%, respectively, of their baseline values, along with variable improvement in less direct indicators of clinical response. The joints of the fourth patient improved modestly (by 33% and 59%, respectively, of baselines) but he required alternative therapy, and those of the remaining three patients did not improve. Mean slopes for the joint counts were significantly different from zero after the apparent breakpoint (but not before), whether one examined the four apparent responders (p = 0.01) or the entire group of seven (p = 0.01). After completion of therapy, there was also a delay, of two to three months, in the clinical deterioration of those who had improved. There was only one mechanical adverse effect--a single episode of transient hypotension in 102 treatment sessions--and no toxic ones. This preliminary study suggests that extracorporeal photochemotherapy may be effective at least in the short term in certain patients with rheumatoid arthritis, with less apparent toxicity than that of any of the drugs currently used for this disorder. It deserves further evaluation.

Adult↗
PubMed1991

Autoregulation of the immune response in autoimmune disease and cardiac transplantation by photoinactivated autologous lymphocytes.

These studies demonstrate that photochemotherapy can be successfully evaluated in animal models. The therapy mediates specific suppression of immune responses and appears to operate at the level of the effector T cells. Future studies will focus on isolation and characterization of the host response to photochemotherapy. The extention of this form of therapy to conditions mediated by dysfunctional regulation of effector T cells is already in progress in clinical trials of cardiac allograft transplantation and autoimmune disease. The results of these trials will provide more evidence on the role of this form of therapy in autoregulation of the immune response.

Animals↗
PubMed1991

Treatment of rheumatoid arthritis by extracorporeal photochemotherapy. A pilot study.

In a 6-month pilot study of 7 patients with rheumatoid arthritis, 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 lymphocyte DNA; the injured cells are reinfused into the patient. Prior experimental studies had indicated that this regimen produces an immune reaction against antigens on treated T cells, and a clinical trial in patients with cutaneous T cell lymphoma had been successful. The current study patients were treated monthly, on 2 successive days (or biweekly, later on). Between 12 and 16 weeks of therapy, there appeared to be a breakpoint, after which the joint counts and joint scores of 4 of the patients began to improve. In 3 of the 4 patients, these measures eventually diminished by a mean of 71% and 80% of baseline values, respectively, and there was variable improvement in less direct indicators of clinical response. The joint counts and scores of the fourth patient improved modestly (by 33% and 59% of baselines, respectively) but he required alternative therapy, and those of the remaining 3 study patients did not improve. Mean slopes for the joint counts were significantly different from zero after the apparent breakpoint (but not before), whether one examined the 4 apparent responders (P = 0.01) or the entire group of 7 patients (P = 0.01). After completion of therapy, there was also a delay, of 2-3 months, in the clinical deterioration of those patients who had improved. There was only 1 mechanical adverse effect--a single episode of transient hypotension in 102 treatment sessions--and no toxic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Photoactivatable antisense DNA: suppression of ampicillin resistance in normally resistant Escherichia coli.

Antisense oligodeoxyribonucleotides complementary to a segment of the beta-lactamase gene and containing psoralen monoadducts at specific sites were examined for their ability to make normally resistant bacteria sensitive to ampicillin. Irradiation of oligonucleotides and psoralens with long-wavelength ultraviolet radiation (380-400 nm) produced monoadducted antisense molecules. High-performance liquid chromatography was used to purify microgram quantities of photoactivatable antisense DNA. Escherichia coli transformed with a plasmid containing the gene for beta-lactamase were used to test a series of oligonucleotides containing psoralen monoadducts after additional exposure to the photoactivating effects of long-wavelength ultraviolet radiation (320-400 nm). Normally resistant bacteria treated with this photoactivatable form of antisense DNA (0.4 microM) were specifically sensitized to ampicillin. The reduction in colony formation ranged from 31 to 79% in comparison to control oligonucleotides which did not contain photoactivatable monoadduct moieties. Bacteria treated in a similar manner but in the presence of tetracycline instead of ampicillin were not affected. The activity of beta-galactosidase, whose gene is located on the same plasmid as beta-lactamase, was not affected.

Ampicillin Resistance↗
PubMed1991

Inhibition of anti-skin allograft immunity induced by infusions with photoinactivated effector T lymphocytes--the congenic model.

We have previously reported the capacity to produce donor-specific tolerance to alloantigens by intravenous exposure to pretreated antidonor T cells. The current study has refined this system by using congenic mice differing only at the H-2 major histocompatibility complex genetic loci. Twelve days after B10 mice received MHC-incompatible B10.D2 skin grafts, their splenocytes that included an expanded population of cells mediating rejection were treated with 100 ng/ml 8-methoxypsoralen (8-MOP) photoactivated by 1 J/cm2 of ultraviolet A prior to infusion into naive B10 recipients. Whereas 8-MOP itself is biologically inert, photoactivated 8-MOP crosslinks DNA by covalently binding to pyrimidine bases. Recipient B10 mice were tested for tolerance to B10.D2 alloantigens in mixed leukocyte culture (MLC), cytotoxicity (CTL), and to in vivo delayed type hypersensitivity assays and challenged with a fresh B10.D2 graft. In vivo, the DTH response of the pretreated B10 mice was specifically suppressed to the relevant alloantigen, correlating with retention of B10.D2 skin grafts for up to 22 days postengraftment without visual evidence of rejection, in comparison to control complete rejection of the skin graft in less than 12 days. In vitro, splenocytes from B10 recipients of pretreated syngeneic splenocytes containing large numbers of B10 anti-B10.D2 T cells proliferated less in MLC and generated lower cytotoxic T cell responses to B10.D2 alloantigens than did controls and suppressed the B10 MLC and CTL responses to B10.D2 alloantigen. These results reveal that, in a highly defined congenic transplantation system, infusions of photoinactivated effector cells resulted in selective inhibition of the in vivo responses that correlated with allograft rejection and permitted prolonged retention of histoincompatible skin grafts. This approach may have significant practical applicability for treatment of human disorders caused by aberrant T cells.

Animals↗
PubMed1991

Formation and removal of 8-MOP-DNA photoadducts in keratinocytes: effects of calcium concentration and retinoids.

8-methoxypsoralen (8-MOP)-DNA photoadducts were quantified in freshly isolated human and murine keratinocytes and cultured keratinocyte cell lines after in vitro treatment with 8-MOP (1-200 ng/ml) and ultraviolet A (UVA; 0.2-24.0 J/cm2). Greater doses of 8-MOP and UVA led to proportionately greater numbers of photoadducts, with a dose reciprocity relationship between the amounts of 8-MOP and UVA. No significant difference in photoadduct formation was observed between basal and differentiated cells. However, the transformed keratinocyte cell lines showed fewer photoadducts than did normal keratinocytes, which appeared to be correlated with the finding that the adduct formation was inhibited in normal keratinocytes cultured with phorbol 12-myristate 13-acetate, because this agent leads to epidermal hyperproliferation. In viable keratinocytes that were treated with a sublethal dose of 8-MOP and UVA (15 ng/ml and 1 J/cm2, respectively), 54% of photoadducts formed were removed over a 20-h period. Adduct removal depended on the calcium concentration in the media; cells cultured in standard high calcium levels showed a higher removal rate than those cultured in low-calcium media. The addition of retinoids (etretinate, acitretin, and 13-cis retinoic acid) to the culture induced 55 to 80% of suppression of the adduct removal. The calcium ionophore A23187 partially restored the suppression of photoadduct removal induced by retinoids. The present studies suggest that calcium performs an important role in the photoadduct removal and raise the possibility that the synergism of systemic retinoids and psoralen plus UVA photochemotherapy relates to the former's inhibition of repair of 8-MOP photoadducts in DNA.

Adrenal Cortex Hormones↗
PubMed1991

High-performance liquid chromotography analysis of 8-methoxypsoralen monoadducts and crosslinks in lymphocytes and keratinocytes.

Human lymphocytes and murine keratinocytes were treated with clinically relevant doses of 8-methoxypsoralen and long-wavelength ultraviolet radiation. The extent of 8-MOP photoadduct formation was determined by liquid scintillation analysis. The distribution of photoadducts was determined by HPLC analysis of enzymatically hydrolyzed DNA from these cells. Analysis of photoadduct formation in lymphocytes and keratinocytes showed that 4',5'-monoadducts were the predominant photoadducts (42% and 41%, respectively). Monoadduct and crosslink yields were dependent on cell type as well as irradiating wavelength. The photochemical conversion of 400 nm-induced 4',5'-monoadducts to crosslinks, as well as 3,4-monoadducts in poly(dA-dT), was measured.

Animals↗
PubMed1991

Inhibitory effect of 8-methoxypsoralen plus ultraviolet-A on interleukin-1 production by murine keratinocytes.

We report the effects of 8-methoxypsoralen (8-MOP) plus ultraviolet-A (UV-A) irradiation on interleukin-1 (IL-1) production by murine epidermal keratinocytes, correlating its effect on IL-1 with cell viability, DNA synthesis, and 8-MOP-DNA photoadduct formation. Freshly isolated murine keratinocytes were treated with various doses of 8-MOP (5-100 ng/mL; incubation time, 30 min) plus 1 J/cm2 UV-A and cultured for 1-3 days. The IL-1/epidermal cell-derived thymocyte-activating factor (ETAF) activity in both supernatant and cell extract was reduced proportionately with increasing doses of 8-MOP/UV-A. Interleukin-1 inhibitors induced by 8-MOP plus UV-A were not detected in either supernatant or cell extract. A clear reduction of the IL-1 production was induced by the treatment as low as 15 ng/mL 8-MOP plus 1 J/cm2 UV-A, which led to the formation of 0.52 8-MOP photoadducts per million DNa bases and affected neither cell viability nor DNA synthesis of the treated cells. Cells treated with 100 ng/mL 8-MOP and 1 J/cm2 UV-A exhibited 57% suppression of IL-1 production in both 2- and 3-day culture samples. This treatment resulted in the formation of 3.8 photoadducts per million bases as well as significant abrogation of DNA synthesis although cell viability was unchanged. These observations provide some insights into the phototoxicity mechanisms of 8-MOP and the effect of PUVA therapy on the cytokine regulation in keratinocytes.

Animals↗
PubMed1991

[In situ transcription and determination of mRNA in human thymic antigen 1a positive cells within epidermis].

This paper introduces a method of study on the characteristics of cell surface protein. We used human thymic antigen 1a anti-sense oligonucleotide primer, radiolabeled deoxynucleotide and in situ transcription with cells. The results of in situ transcription and determination of mRNA in CD1a positive cells isolated from the epidermis of the prepuce of normal neonate showed that most of the positive cells contained specific CD1a mRNA, and the specificity and sensitivity of this method were higher and the procedure was relatively simple.

Antigens, CD1↗
PubMed1991

Ocular findings in cutaneous T-cell lymphoma.

Seventeen patients with cutaneous T-cell lymphoma undergoing an investigative treatment regimen using extracorporeal photochemotherapy underwent ophthalmologic examinations to investigate the ocular findings in this disease. The most frequent finding was seborrheic blepharoconjunctivitis, which was noted in 13 of 17 patients. Other common lid findings included cicatricial ectropion, meibomianitis, chalazia, and madarosis. Corneal and conjunctival disease was also increased in this group of patients. The syndrome of cutaneous T-cell lymphoma has recently been redefined, and a discussion of the revised concept of this disease is included. Previous studies used the old definition of this disease and were limited to the subgroups of mycosis fungoides and Sezary syndrome, which comprise only one third of the cutaneous T-cell lymphoma population.

Adult↗
PubMed1990

BE-2 antigen: appearance in activation and long-term growth of T cells.

The BE-2 lymphocyte surface protein is frequently expressed by the malignant cells of cutaneous T-cell lymphoma (CTCL) but is not detectable on the surface of normal resting peripheral blood lymphocytes. The expression of BE-2 by normal T cells can be induced by lectin stimulation. Membrane expression of BE-2 surpasses that of the membrane receptor for IL-2, another T-cell activation marker, at day 5. The peak expression of BE-2 appears at day 6-8. The appearance of BE-2 could also be demonstrated after anti-CD3 and allogeneic stimulation. Long-term T-cell clones derived from normal donors and maintained in culture with periodic stimulation were also found to express BE-2 continuously. Thus, BE-2 is a late activation marker not expressed on normal peripheral blood lymphocytes and pathologically expressed on circulating malignant cells in the disease CTCL.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1990

Cell membrane DNA: a new target for psoralen photoadduct formation.

The effects of 8-methoxypsoralen plus long wavelength ultraviolet radiation on cell membrane DNA were examined. Treatment of human lymphocytes with 100 ng/ml 8-methoxypsoralen and 5 J/cm2 UVA led to the formation of 7.1 +/- 3.8 photoadducts per million bases. A monoclonal antibody, specific for 8-methoxypsoralen 4',5'-monoadducts, was used to detect photoadducts in the cell membrane DNA of human lymphocytes and three lymphoblastoid cell lines. Treatment of lymphocytes with 8-MOP and UVA reduced the lymphocyte DNA binding capacity by 56%. Cell membranes of normal lymphocytes were shown to contain three high affinity DNA binding proteins of 28, 59, and 79 kDa, respectively.

Cell Line↗