PubMed Health⌕ Search

Biomedical subjects

A H Rook

Publications and source records attributed to A H Rook.

At least 73 records · Page 4Linked to original sources
PubMed1994

Retroviruses and cutaneous T-cell lymphoma.

Since the discovery of the first human retrovirus, HTLV-I, and its etiologic role in ATL, the search for a retrovirus and its role in the development and progression of CTCL has been vigorously pursued and debated. Current studies in CTCL have evaluated serum antibodies to retroviral proteins, electron microscopy to identify viruslike particles, and Southern blot analysis and PCR amplification to detect proviral DNA sequences. There have been inconsistent findings within and between a variety of studies, emphasizing the need for critical evaluation of experimental methods and their potential shortcomings. Several interesting observations have included (1) serologic evidence of HTLV-I infection in a small subset of CTCL patients, (2) cloning of a deleted HTLV-I proviral genome from a B-cell line established from the peripheral blood of a CTCL patient, (3) detection of retrovirus in Langerhans cells and B cells, and (4) molecular evidence for the presence of an HTLV-I-like retrovirus. By viewing CTCL as a model of tumor progression, mechanisms by which retroviruses play a role in the development and progression of CTCL are facilitated. Future studies will need to correlate the detection of proviral sequences and the nature of a retroviral infection with specific cell types and stage of disease and determine if these findings demonstrate a causal role in CTCL or a secondary phenomenon due to CTCL-associated immunosuppression. It is likely that new data will be reported between the writing of this article and the time of publication; however, the currently available data reviewed in this article do not provide conclusive evidence that retroviruses play a primary etiologic role in CTCL.

DNA, Viral↗
PubMed1993

T-cell receptor gene rearrangement studies as a diagnostic tool in lymphoproliferative skin diseases.

The growth of our knowledge in T-cell biology, in particular the molecular biology of the T-cell receptor (TCR), has provided a means to molecularly characterize lymphoproliferative diseases of the skin based on the presence or absence of a clonal population of T lymphocytes. TCR gene rearrangement studies, by Southern blot analysis, have aided the investigative dermatologist in gaining insights into the pathogenesis and clonal evolution of lymphoproliferative skin diseases. In addition, the application of TCR gene rearrangement studies as a diagnostic aid in the evaluation of lymphoproliferative skin diseases has been introduced into clinical dermatology. Despite its enormous research value, TCR gene rearrangement studies presently have limited applications as an independent diagnostic tool. However, as our knowledge and experience grows and as the application of new techniques provides us with greater detection sensitivity and specificity, the diagnostic utility of TCR gene rearrangement studies will be enhanced.

Blotting, Southern↗
PubMed1993

Molecular diagnosis of lymphocytic infiltrates of the skin.

BACKGROUND: Advances in our understanding of the molecular genetics of lymphocyte antigen receptors (B-cell immunoglobulin and T-cell antigen receptor), have led to the application of molecular biologic techniques to molecularly characterize lymphocytic infiltrates of the skin. Molecular diagnosis refers to the application of these techniques as a diagnostic aid in the clinicopathologic evaluation of cutaneous lymphocytic infiltrates. OBSERVATION: Molecular studies have clinical application in the determination of lineage and detection of retroviruses in cutaneous lymphoid neoplasms, distinguishing between lymphoproliferative and reactive infiltrates, and staging and monitoring response to therapy in cutaneous T-cell lymphoma. Southern blot analysis of immunoglobulin and T-cell antigen receptor gene rearrangements may fail to aid the clinician in establishing a diagnosis of a cutaneous malignancy due to the limits of detection sensitivity in minimally infiltrated lesions (eg, parapsoriasis and patch-stage mycosis fungoides) or the still uncertain prognostic significance of clonality in benign cutaneous diseases (eg, follicular mucinosis, pityriasis lichenoides et varioliformis acuta, lymphomatoid papulosis, and cutaneous lymphoid hyperplasia). CONCLUSIONS: Molecular studies have enormous research value, providing new means to explore the pathogenesis and clonal evolution of lymphoproliferative skin diseases. Presently, however, they have limited applications as an independent diagnostic tool. As our understanding of the clinical and biologic significance of the molecular detection of clonal lymphocyte populations in the skin expands and as the application of polymerase chain reaction amplification provides us with greater detection sensitivity and specificity, the clinical utility of molecular diagnosis of lymphocytic infiltrates of the skin will be enhanced.

Antibodies, Monoclonal↗
PubMed1993

Therapeutic applications of photopheresis.

Photopheresis is a useful therapy for advanced cutaneous T-cell lymphoma, particularly for Sezary syndrome. Additional conditions in which clinical studies have suggested a therapeutic role for photopheresis include certain autoimmune diseases and reversal of rejection of solid organ allografts. Because photopheresis is extremely well tolerated and evidence is lacking for a direct immunosuppressive effect produced by this therapy, randomized trials should be pursued to determine the full spectrum of clinical benefit of this novel therapeutic modality.

Autoimmune Diseases↗
PubMed1992

Extracorporeal photochemotherapy induces the production of tumor necrosis factor-alpha by monocytes: implications for the treatment of cutaneous T-cell lymphoma and systemic sclerosis.

Extracorporeal photopheresis (ExP) has been shown to be an efficacious and well-tolerated therapy in the treatment of cutaneous T-cell lymphoma (CTCL) and systemic sclerosis. However, the precise mechanisms of its action have not been defined. Because of a correlation between the development of fever in the early phase of treatment of CTCL and subsequent anti-tumor responses, we examined the production of the proinflammatory, pyrogenic cytokines tumor necrosis factor-alpha (TNF), IL-6, IL-1 alpha, and IL-1 beta before and after ExP. Monocytes were purified from peripheral blood specimens of normal volunteers (n = 4) or from peripheral blood specimens of CTCL (n = 6) or systemic sclerosis (n = 3) patients that were obtained immediately prior to ExP and also directly from the photopheresis unit after ExP, just prior to reinfusion into the patient. Monocytes were then cultured under various conditions for 16 h, after which the culture supernatants were collected and assayed for specific cytokine production. ExP induced a significant increase in the production of TNF (p less than 0.008) and IL-6 (p less than 0.05) as compared to non-ExP-treated cells, whereas no significant differences were observed in IL-1 alpha (p less than 0.5) and IL-1 beta (p less than 0.2) production following ExP. Exposure of monocyte cultures to IFN-gamma (100 U/mL) either before or after ExP further enhanced TNF production by 4 to 28 times. In contrast, incubation with IFN-alpha (100 U/mL) had no significant effect on TNF production. Addition of TNF (500 U/ml) to monocyte cultures obtained prior to ExP resulted in a slight but insignificant increase in TNF production in 2 of 10 cases. However, when monocytes obtained prior to ExP were incubated with 8-methoxypsoralen (8-MOP, 100 ng/ml), exposed to ultraviolet light A (UVA, 2J/cm2), washed, and then incubated with TNF, a significant increase (p less than 0.01) in TNF production was observed in 8 of 10 cases, suggesting that the combination of 8-MOP and UVA may sensitize cells to TNF. Based on studies of endotoxin (LPS)-stimulated production of TNF by monocytes, levels of endotoxin in culture reagents or photopheresis equipment could not account for the increased production of TNF following treatment by ExP. Increased TNF production as a result of ExP may have important implications for treating both CTCL and systemic sclerosis because, in the case of CTCL, it could mediate numerous anti-tumor effects, whereas, in the case of systemic sclerosis, it could suppress collagen synthesis and induce collagenase production.

Endotoxins↗
PubMed1992

Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells.

Sezary syndrome (SzS), the leukemic stage of cutaneous T-cell lymphoma (CTCL), is typically a CD4+ T-cell lympho-proliferative disease characterized by numerous immunologic abnormalities, including decreased T-cell responses to antigens and mitogens, decreased natural killer and lymphocyte-activated killer cell activities, eosinophilia, and increased levels of immunoglobulins, particularly IgE and IgA. Because this constellation of abnormalities is reminiscent of the pleiotropic in vitro activities of IL-4 and IL-5, we examined the possibility that malignant T cells in SzS may be producing increased amounts of IL-4 with a concomitant decrease in IL-2 and IFN-gamma production. Such a cytokine secretion pattern would be similar to that produced by murine Th2 cells. Serum IL-4 enzyme-linked immunosorbent assay measurements revealed that 33% of SzS patients (n = 21) had levels of IL-4 significantly higher (mean, 7.2 pg/ml; range, 0-48, p less than 0.05) than normal controls (mean, 1.59; range, 0-3.1). Although the majority of tested patients had elevated serum IgE, no direct correlation between serum IL-4 levels and serum IgE levels was observed. Peripheral blood mononuclear cells (PBMC) isolated from SzS patients and stimulated with phytohemagglutinin (PHA) produced significantly higher levels of interleukin (IL)-4 and significantly lower levels of IL-2 and interferon (IFN)-gamma than did PBMC from normal controls (p less than 0.02, p less than 0.05, and p less than 0.02, respectively). PBMC from SzS patients in remission produced IL-4 and IL-2 levels similar to that of the normal controls. To determine if IFN-gamma could inhibit the increased IL-4 production by PHA-stimulated PBMC from SzS patients, IFN-gamma was added to culture at 0, 24, or 48 h prior to the addition of PHA. Significant decreases in IL-4 production were seen only in cultures incubated with IFN-gamma for 24 and 48 h prior to the addition of PHA. IL-2 levels were not affected by IFN-gamma incubation. The increased IL-4 and decreased IL-2 and IFN-gamma production by PBMC from SzS patients suggests that Sezary cells have a cytokine profile similar to murine Th2 cells. Moreover, this cytokine secretion pattern may play an integral role in the immunopathogenesis of advanced CTCL. The results also suggest that IFN-gamma be a useful component in the spectrum of therapeutic approaches to SzS.

Animals↗
PubMed1992

Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial.

BACKGROUND AND DESIGN: In a pilot study of extracorporeal photochemotherapy, two patients with systemic sclerosis who received this therapy experienced significant clinical improvement. These results prompted the development of a multicenter trial to examine the benefit of extracorporeal photochemotherapy in the treatment of systemic sclerosis. Seventy-nine patients with systemic sclerosis of recent onset (mean symptom duration, 1.83 years) and progressive skin involvement during the preceding 6 months entered a randomized, parallel-group, single-blinded clinical trial comparing extracorporeal photochemotherapy treatments given on 2 consecutive days monthly with treatment with D-penicillamine at a maximum dose of 750 mg/d. Blinded clinical examiners evaluated skin severity score (thickness), percent surface area involvement, oral aperture, and hand closure. Serial skin biopsies and pulmonary function studies were also performed. RESULTS: Following 6 months of treatment, significant improvement in skin severity score occurred in 21 (68%) of 31 patients receiving photochemotherapy and in eight (32%) of 25 receiving D-penicillamine treatment, while significant worsening occurred in three (10%) of 31 receiving photochemotherapy and in eight (32%) of 25 receiving penicillamine treatment, thus indicating a significantly higher response rate for individuals who received photochemotherapy (P = .02). At both the 6- and 10-month evaluation points, the mean skin severity score, mean percent skin involvement, and mean oral aperture measurements were significantly improved from baseline among those who received photochemotherapy. Mean right and left hand closure measurements had also improved significantly by 10 months of therapy. By comparison, among the patients treated with D-penicillamine, none of the parameters of cutaneous disease had improved significantly after 6 months of therapy, although for those individuals in whom treatment was continued, the mean skin severity score and mean percent skin involvement had improved by 10 months. Skin biopsy studies revealed a correlation between clinical improvement and decreased thickness of the dermal layer. Adverse effects of extracorporeal photochemotherapy were minimal and did not require discontinuation of treatment in any of the patients receiving this therapy; six patients permanently discontinued the use of D-penicillamine treatment due to adverse effects. CONCLUSIONS: For patients with systemic sclerosis of recent onset, extracorporeal photochemotherapy is a well-tolerated treatment that may partially reverse the process that results in cutaneous sclerosis.

Adult↗
PubMed1991

Malignant and nonmalignant T cell lines from human T cell lymphotropic virus type I-negative patients with Sézary syndrome.

The establishment of an in vitro model for cutaneous T cell lymphomas and Sézary syndrome has been difficult since T cells from individuals with these diseases do not proliferate in response to T cell mitogens. We found that conditioned media, collected from mitogen-activated PBMC from Sézary patients, contain an IL-2 receptor inducing factor. Despite their ostensible proliferative disorder, using a combination Sézary cell-conditioned media and rIL-2, we established IL-2 responsive, human T cell lymphotropic virus type I negative T cell lines from 23 patients, nine of which contain cells with the structural and/or genetic characteristics of neoplastic Sézary T cells.

Cell Division↗
PubMed1991

Molecular diagnosis of cutaneous T-cell lymphoma: polymerase chain reaction amplification of T-cell antigen receptor beta-chain gene rearrangements.

The goal of our study was to molecularly diagnose CTCL, by cloning the T-cell antigen receptor beta chain (TCR-beta) gene rearrangement from the malignant T cells of a patient with Sézary syndrome, in order to generate a specific oligonucleotide probe capable of detecting CTCL cells through polymerase chain reaction (PCR) amplification. Total RNA isolated from peripheral blood lymphocytes was reverse transcribed and resultant first strand cDNA was PCR amplified utilizing a concensus primer to the TCR-beta variable region (V beta) and a 3' primer to the TCR-beta constant region (C beta). PCR reaction products were subcloned into a plasmid vector and sequenced. Sequence analysis revealed that the patient's in-frame TCR-beta gene rearrangement utilized V beta 6.4, D beta 1.1, J beta 2.2, and C beta 2.1 gene segments. Oligo-primers to V beta 6.4 and J beta 2.2 were utilized to PCR amplify genomic DNA taken from the patient's blood and involved skin. Screening the amplified DNA with an oligo-probe specific for the patient's V-D-J junctional sequences resulted in the detection of the patient-specific sequences. No sequences were detected from DNA from other malignant or benign infiltrates. Thus, we have defined a "molecular fingerprint" specific for a patient's malignant T-cells and can molecularly diagnose CTCL through PCR amplification.

Amino Acid Sequence↗
PubMed1991

Combined therapy for Sézary syndrome with extracorporeal photochemotherapy and low-dose interferon alfa therapy. Clinical, molecular, and immunologic observations.

Extracorporeal photochemotherapy is a well-tolerated treatment of palliative benefit for patients with the Sézary syndrome, but up to 25% of patients do not respond to this form of therapy. Interferon alfa is a glycoprotein with immunomodulatory properties that is also an active agent in the treatment of Sézary syndrome; however, dose-related toxic effects often limit its long-term use. A patient with rapidly advancing Sézary syndrome was treated with a combination of extracorporeal photochemotherapy and low doses of subcutaneous interferon alfa-2b. In addition to the almost complete clearing of his skin lesions and the marked diminution of his extensive lymphadenopathy after 16 weeks of combined therapy, disappearance of the malignant T-cell clone from the peripheral blood was documented by Southern blot analysis. Normalization of the peripheral blood lymphocyte phenotypic profile and an increase in natural killer cell activity were also observed. The excellent clinical response to combined therapy has been sustained, without adverse effects, during 18 months of treatment and 22 months of continued follow-up. The long-term disappearance of the malignant clone from the blood of a patient with Sézary syndrome in response to therapy has not been previously described and thus represents a novel observation. Extracorporeal photochemotherapy and low-dose interferon alfa are well-tolerated therapies that, when combined, may have additive efficacy in the treatment of Sézary syndrome. These results suggest that further exploration of this therapeutic combination is warranted.

Combined Modality Therapy↗
PubMed1990

L-tryptophan ingestion associated with eosinophilic fasciitis but not progressive systemic sclerosis.

OBJECTIVE: To assess the use of L-tryptophan by patients with eosinophilic fasciitis and compare this with its use by patients with progressive systemic sclerosis (scleroderma). DESIGN: Retrospective and prospective analysis. Six patients with eosinophilic fasciitis were identified retrospectively and two prospectively. Retrospective identification of patients was done by questioning hospital-affiliated rheumatologists and dermatologists and by searching the hospital dermatopathology database. The patients with scleroderma or morphea were prospectively identified by questioning consecutive office patients with these established diagnoses. SETTING: University of Pennsylvania rheumatology and dermatology practices. PATIENTS: Eight patients with eosinophilic fasciitis; 40 consecutive patients with scleroderma (27 with diffuse cutaneous and 13, limited cutaneous disease); 3 patients with morphea. RESULTS OF DATA ANALYSIS: All eight patients with eosinophilic fasciitis had taken L-tryptophan before the onset of their disease. All had myalgias and high peripheral eosinophil counts (most greater than 5000 cells/mm3). Only 1 of 40 patients with scleroderma (no patients with morphea) had used L-tryptophan preceding illness (P less than 0.001 compared with eosinophilic fasciitis). Six patients with eosinophilic fasciitis had taken L-tryptophan for less than 8 months. One patient had taken it for 9 years before developing skin induration. Two patients were newly identified as having hypothyroidism; two developed neuropathy; and two had severe flexion contractures (several occurring in areas without skin induration). Five patients had low-titer antinuclear antibodies, indicating a possible autoimmune process. Most patients had only a partial response to systemic corticosteroid therapy. One patient has had important disease regression in response to isotretenoin therapy that was evident even while she continued to take L-tryptophan. CONCLUSIONS: L-Tryptophan use can lead to eosinophilic fasciitis whereas it does not appear to cause classic scleroderma. The disease process does not automatically remit after discontinuation of L-tryptophan-containing products.

Adult↗
PubMed1989

Extracorporeal photochemotherapy in the treatment of cutaneous T cell lymphoma and autoimmune disorders affecting the skin.

Extracorporeal photochemotherapy (ECPCT) is a new form of chemoimmunotherapy which involves the ex vivo exposure of malignant peripheral blood cells to 8-methoxypsoralen (8-MOP) and ultraviolet A (UVA) radiation followed by reinfusion of the treated cells. This treatment has resulted in an unprecedented number of prolonged remissions in patients with therapeutically resistant forms of cutaneous T cell lymphoma (CTCL) characterized by the systemic dissemination of a clonal population of malignant helper T lymphocytes. Although the mechanism of the beneficial effect is uncertain, an immune reaction to the reinfused modified T cells probably results in tumour regression. Because the T cell antigen receptor (TCR) is an immunogenic structure and because an identical TCR is present on the entire clonal population of malignant T cells in each individual with CTCL, modification of this structure represents the most likely target for the effects of 8-MOP and UVA. Understanding of the precise events leading to tumour regression in CTCL during treatment with ECPCT may lead to the expanded use of this therapy for other lethal haemopoietic malignancies.

Autoimmune Diseases↗