ABSTRACT
BACKGROUND: Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma (CD4+ PCSM-TCL) is a rare lymphoproliferative disorder with a favorable prognosis. Distinguishing it from other cutaneous lymphomas is often a challenge. METHODS: We retrospectively collected CD4+PCSM-TCL cases from two centers (MD Anderson Cancer Center, USA and University of Milan, Italy) and evaluated their clinicopathological features. Array-comparative genomic hybridization (aCGH) analysis was performed on 11 cases. RESULTS: A total of 62 patients were identified. Single lesions were the most common clinical presentations (79%). Five patients (8%) showed multiple MF-like plaques. All patients' disease had an indolent course. The infiltrate was nodular and diffuse, multinodular or superficial but in all cases, it was characterized by small/medium pleomorphic CD4+/CD279(PD1+) lymphocytes grouped in clusters and 'pseudorosettes' around B-cells. aCGH analysis showed no significant genomic abnormalities. Single lesions were mainly treated with surgical excision (91%) and/or radiotherapy (95%) with low rate of relapse (12%). For multiple lesions, topical steroids, nitrogen mustard and phototherapy were mainly used but the rate of relapse was high (69%). CONCLUSIONS: CD4+PCSM-TCL is characterized by heterogeneous clinical presentations. The arrangement of atypical cells in clusters or pseudorosettes is a useful criterion for diagnosis. The absence of significant genomic alterations is in agreement with its indolent behavior.
Subject(s)
CD4-Positive T-Lymphocytes/pathology , Lymphoma, T-Cell, Cutaneous/pathology , Skin Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , CD4-Positive T-Lymphocytes/immunology , Comparative Genomic Hybridization , Dermatologic Surgical Procedures , Female , Humans , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/therapy , Male , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Polymerase Chain Reaction , Radiotherapy , Retrospective Studies , Skin Neoplasms/immunology , Skin Neoplasms/therapy , Young AdultSubject(s)
Dermatologic Agents/therapeutic use , Lymphoma, T-Cell, Cutaneous , PUVA Therapy/methods , Radiotherapy/methods , Skin Neoplasms , Skin/pathology , Aged , Antigens, Differentiation, T-Lymphocyte/analysis , Atrophy , Diagnosis, Differential , Disease Management , Humans , Lymphoma, T-Cell, Cutaneous/diagnosis , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Cutaneous/therapy , Male , Skin Neoplasms/diagnosis , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Skin Neoplasms/therapyABSTRACT
A 72-year-man presented with a 7-month history of progressive patches and plaques over the trunk and limbs. A skin biopsy confirmed mycosis fungoides (MF). After staging investigations, he was considered to have T2N0M0B0 (stage Ib) disease and began ultraviolet (UV) B phototherapy. Despite initial response, his disease progressed after 4 months, with enlarging patches and plaques but without nodal involvement. As second-line therapy, he received interferon alfa-2b (IFN--2b) 2.7 MU daily, which he tolerated well. He again experienced initial partial response (PR), but by 18 months, he had experienced tumor progression, with patches, plaques, and multiple tumors over the body (up to 3 cm; Fig 1). Biopsy of a neck tumor demonstrated tumor-stage MF,with no evidence of large-cell transformation. Approximately 30% of lymphocytes strongly expressed CD30. CD25 was negative. He began treatment with oral methotrexate 20mg per week, which he tolerated well, and achieved a PR lasting 7 months before multiple plaque and tumor lesions recurred, along with the development of inguinal lymphadenopthy. Biopsy of the skin lesions confirmed the same disease, and [18F]fluorodeoxyglucosepositron emission tomography demonstrated avidity in inguinal and internal iliac nodes, with lymphadenopathy measuring up to 3.5 cm. He has been referred for consideration of further systemic therapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Immunoconjugates/therapeutic use , Ki-1 Antigen/analysis , Ki-1 Antigen/metabolism , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/immunology , Mycosis Fungoides/drug therapy , Sezary Syndrome/drug therapy , Skin Neoplasms/drug therapy , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Female , Humans , MaleABSTRACT
Primary cutaneous T cell lymphomas (CTCLs) are characterized by hyperproliferation of malignant CD4+ T cells with primary localization on the skin. The common characteristics are the migration of the malignant mature T-lymphocytes into the epidermis, with hyperproliferation of malignant CD4+ T cells and epidermotropism. Sézary syndrome (SS) is the leukemic variant. It was established that CTCLs arise from a clonal expansion of CD4+ T cells with an identical rearrangement of the T cell receptor. The purpose of this study was to evaluate the immunomodulation effect of photochemotherapy-A (psoralen plus ultraviolet A (PUVA)). Pre- and post-PUVA punch skin biopsies of nine patients were stained immunohistochemically for CD34+, CD8+, CD7+, CD16+, CD56+, CD1a+, Bcl2+, p53+, CD45RA+, and CD45RO+ cells. The results showed a pre-PUVA cells/mm(2) without significant difference among expansive or reactive cells. Post-PUVA analysis showed a significant decrease in the mean of expansive-reactive cells. PUVA immunomodulated decreasing cellular infiltrate. These findings could contribute to the comprehension of how PUVA acts. We achieved ectoscopic clearance of the lesions, although post-PUVA, there still was a mononuclear pathological infiltrate. This result demonstrates that the PUVA treatment should only be withheld when the histological analysis is normal.
Subject(s)
Ficusin/therapeutic use , Lymphoma, T-Cell, Cutaneous/drug therapy , PUVA Therapy , Photosensitizing Agents/therapeutic use , Skin Neoplasms/drug therapy , T-Lymphocytes/drug effects , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Biopsy , Female , Humans , Immunophenotyping , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Male , Middle Aged , Skin Neoplasms/immunology , Skin Neoplasms/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Treatment OutcomeABSTRACT
BACKGROUND: Follicular helper T cells are a subset of helper T cells that facilitate B-cell recruitment and maturation. Rare cases of cutaneous T-cell lymphoma manifesting as de novo tumor lesions in intertriginous skin contain an infiltrate rich in B cells. These cases may represent malignant counterparts of skin-homing follicular helper T cells. OBSERVATIONS: Two men and 1 woman (age range, 35-58 years) were seen with predominantly intertriginous tumor-stage cutaneous T-cell lymphoma lesions characterized by the absence of epidermotropism and the presence of a mixed infiltrate rich in B cells. Two of the patients died of the disease less than 3 years from the initial diagnosis. The surviving patient has aggressive disease and underwent hematopoietic stem cell transplantation. Two of the patients had a prominent CXCL13+, Bcl6/CD3+, and programmed death protein 1-positive follicular helper T-cell population. CONCLUSIONS: The intertriginous tumor variant of cutaneous T-cell lymphoma is heterogeneous but may be associated in some cases with a follicular helper T-cell immunophenotype. These patients may follow an aggressive clinical course. Tumor progression in sanctuary sites on patients receiving phototherapy may manifest as a similar clinical phenotype. Further characterization of the disease process is needed to confirm this observation.
Subject(s)
Mycosis Fungoides/immunology , Mycosis Fungoides/pathology , Skin Neoplasms/immunology , Skin Neoplasms/pathology , T-Lymphocytes, Helper-Inducer/immunology , Adult , Female , Humans , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Male , Middle Aged , T-Lymphocytes, Helper-Inducer/pathologyABSTRACT
One central challenge of allogeneic stem cell transplantation is the positive correlation between graft versus lymphoma effect (GvL) and graft-versus-host disease (GvHD). To date, specific targeting of GvL antigens with effector T cells and of GvHD antigens with specific regulatory T cells remains the subject of experimental research. In clinical reality, negative modulation of GvHD, e.g. by immunosuppression, reduces GvL and positive modulation of GvL, e.g. by donor lymphocyte infusions, often amplifies GvHD. Clinically feasible strategies to induce GvL while simultaneously reducing GvHD are urgently needed. Here, we report the case of an early relapsed primary cutaneous T cell lymphoma in tumor stage after allogeneic stem cell transplantation which was successfully treated with a parallel administration of donor lymphocyte infusions (DLI) and systemic PUVA and bexarotene which led to sustained complete remission without onset of acute GvHD. After termination of the treatment with PUVA/bexarotene subacute chronic GvHD occurred but was subsequently brought under control by extracorporeal photopheresis. We suggest that the combination of DLI and PUVA/bexarotene might be an interesting immunologic bimodal treatment option which warrants further investigation.
Subject(s)
Graft vs Host Disease/therapy , Immunotherapy, Adoptive , Lymphocyte Transfusion , Lymphoma, T-Cell, Cutaneous/therapy , PUVA Therapy , Skin Neoplasms/therapy , Tetrahydronaphthalenes/pharmacology , Adult , Bexarotene , Graft vs Host Disease/immunology , Graft vs Leukemia Effect/immunology , Hematopoietic Stem Cell Transplantation , Humans , Lymphoma, T-Cell, Cutaneous/immunology , Male , Photopheresis/methods , Recurrence , Skin Neoplasms/immunologySubject(s)
Lymphoma, T-Cell, Cutaneous/therapy , Skin Neoplasms/therapy , Antineoplastic Agents/therapeutic use , Humans , Ki-1 Antigen/metabolism , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , PUVA Therapy , Photochemotherapy , Radiotherapy, Adjuvant , Skin Neoplasms/immunology , Skin Neoplasms/pathology , World Health OrganizationSubject(s)
Drug Therapy/methods , Graft vs Host Disease/therapy , Phototherapy/methods , Adult , Autoimmune Diseases/metabolism , Cell- and Tissue-Based Therapy/methods , Child , Clinical Trials as Topic , Female , Graft Rejection , HLA Antigens/chemistry , Humans , Immune System , Lymphoma, T-Cell, Cutaneous/immunology , Male , Sezary Syndrome/therapyABSTRACT
Cutaneous T cell lymphoma (CTCL) has always served as a proving ground where conceptual advances in immunology can be tested and the results translated into clinical practice. From the earliest studies that used sheep red blood cells to identify the malignant cell as a T lymphocyte to molecular demonstration of the clonalilty of the disease, basic science techniques have provided sign posts that allow us to understand the clinical features seen in the patients. We continue to apply this paradigm to develop new insights into the role of the immune system in CTCL with the goal of using this knowledge to enhance the therapeutic options available to the patient. This article will review the studies that have led to our current understanding of the immunobiology of CTCL and the new therapeutic approaches that are being tested in this disease.
Subject(s)
Lymphoma, T-Cell, Cutaneous/therapy , T-Lymphocyte Subsets/pathology , Adrenal Cortex Hormones/therapeutic use , Animals , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis , Bexarotene , Clone Cells/immunology , Clone Cells/pathology , Cytokines/therapeutic use , Dendritic Cells/immunology , Dendritic Cells/pathology , Diphtheria Toxin/therapeutic use , Gene Expression Regulation, Neoplastic , Humans , Immunophenotyping , Interleukin-2/therapeutic use , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Mice , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/pathology , PUVA Therapy , Photopheresis/instrumentation , Photopheresis/methods , Recombinant Fusion Proteins/therapeutic use , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , Tetrahydronaphthalenes/administration & dosageABSTRACT
Realizamos una revisión de la bibliografía sobre los linfomas cutáneos primarios tomando como base la nueva clasificación donde EORTC y OMS aunaron conceptos y criterios para ella. Destacamos que los linfomas cutáneos de células T tienen una mayor agresividad, tienen tendencia a lesiones más generalizadas y agresivas, y dentro de los más frecuentes del grupo se encuentran la micosis fungoide con todas sus variantes y el síndrome de Sézary. El linfoma T paniculítico con fenotipo alfa/beta debe ser considerado como tal, siendo la forma gamma/delta CD4- y CD8- con coexpresión CD56 incluido en la categoría de linfoma T gamma/delta. Los linfomas cutáneos de células B son menos agresivos y sus lesiones tienen preferencia por la zona de cabeza y cuello. En ellos se debe investigar por serología, infecciones previas, en especial por Borrelia burgdorferi. Las nuevas aclaraciones sobre los diferentes linfomas B, principalmente en los primarios difusos y en los perifoliculares, facilita la elección de una terapéutica más o menos agresiva. Se avanza cada día más en el estudio de estas patologías, debiéndose realizar un estudio exhaustivo clínico y laboratorial donde se incluya el estudio inmunohistoquímico e inmunogenético, sin los cuales no se llega a realizar un acertado diagnóstico. Cada entidad definida como linfoma tiene como característica el hecho de presentar un inmunofenotipo, un inmunogenotipo y un conjunto de anormalidades moleculares que la hacen diferenciable de otro tipo de linfoma, lo que permite diagnosticarlo, estadificarlo y predecir su comportamiento biológico. Múltiples terapéuticas en uso y/o en fase de investigación cambiarán en un futuro cercano la evolución de los linfomas cutáneos primarios. Podemos mencionar los anticuerpos monoclonales. Los anti CD20 (rituximab) son los más efectivos y los más estudiados. Dentro de otros se encuentran ya en estudios avanzados alemtuzumab (anti CD52), epratuzumab (anti CD22), apolizumab (anti HLA-DR) y galiximab...(AU)
We have a bibliographic revision of primary cutaneous limphomas using the EORTC and WHO new classification in order to unify concepts. Cutaneous T cell like lymphomas (C+CL) have a higher aggressiveness with a generalized and aggressive tendency; being the most frecuents all varieties of micosys fungoide (MF) and Sézary sindrome. Those lymphomas with a/ß phenotype must be estrictly considered as a subcutaneous panniculiticlike + cell lymphoma; and those with ?/d phenotype as +/NK cell lymphoma; wich has a very agressive clinical course. Cutaneous B cell lymphomas are less aggressive and its lesions are preferably situated in head and neck, in this cases previous infections must be investigated, specially Borrelia burgdoferi infections. The new classifications of diferents B lymphomas, principally betwen primary cutaneous and folliculars, facilitates the selection of a correct therapy. The study of these pathologies advances every day. It is very important to include immunihistochemical, immunogenetic and immunophenotype studies so as rech bo the correct diagnosis and classification of the lymphomas. New therapies and new combination of therapies will offer a promising future.(AU)
Subject(s)
Lymphoma, T-Cell, Cutaneous/epidemiology , Lymphoma, T-Cell, Cutaneous/immunology , Mycosis Fungoides/immunology , Immunophenotyping , Lymphoma/classification , Mycosis Fungoides/diagnosis , Mycosis Fungoides/drug therapy , Mycosis Fungoides/etiology , Mycosis Fungoides/mortality , Mycosis Fungoides/radiotherapy , Photochemotherapy , Phototherapy/methods , Carmustine/adverse effects , Antineoplastic Agents/therapeutic use , Combined Modality Therapy , Interferon-alpha/administration & dosage , Interferon-alpha/therapeutic use , PrognosisABSTRACT
Realizamos una revisión de la bibliografía sobre los linfomas cutáneos primarios tomando como base la nueva clasificación donde EORTC y OMS aunaron conceptos y criterios para ella. Destacamos que los linfomas cutáneos de células T tienen una mayor agresividad, tienen tendencia a lesiones más generalizadas y agresivas, y dentro de los más frecuentes del grupo se encuentran la micosis fungoide con todas sus variantes y el síndrome de Sézary. El linfoma T paniculítico con fenotipo alfa/beta debe ser considerado como tal, siendo la forma gamma/delta CD4- y CD8- con coexpresión CD56 incluido en la categoría de linfoma T gamma/delta. Los linfomas cutáneos de células B son menos agresivos y sus lesiones tienen preferencia por la zona de cabeza y cuello. En ellos se debe investigar por serología, infecciones previas, en especial por Borrelia burgdorferi. Las nuevas aclaraciones sobre los diferentes linfomas B, principalmente en los primarios difusos y en los perifoliculares, facilita la elección de una terapéutica más o menos agresiva. Se avanza cada día más en el estudio de estas patologías, debiéndose realizar un estudio exhaustivo clínico y laboratorial donde se incluya el estudio inmunohistoquímico e inmunogenético, sin los cuales no se llega a realizar un acertado diagnóstico. Cada entidad definida como linfoma tiene como característica el hecho de presentar un inmunofenotipo, un inmunogenotipo y un conjunto de anormalidades moleculares que la hacen diferenciable de otro tipo de linfoma, lo que permite diagnosticarlo, estadificarlo y predecir su comportamiento biológico. Múltiples terapéuticas en uso y/o en fase de investigación cambiarán en un futuro cercano la evolución de los linfomas cutáneos primarios. Podemos mencionar los anticuerpos monoclonales. Los anti CD20 (rituximab) son los más efectivos y los más estudiados. Dentro de otros se encuentran ya en estudios avanzados alemtuzumab (anti CD52), epratuzumab (anti CD22), apolizumab (anti HLA-DR) y galiximab...
We have a bibliographic revision of primary cutaneous limphomas using the EORTC and WHO new classification in order to unify concepts. Cutaneous T cell like lymphomas (C+CL) have a higher aggressiveness with a generalized and aggressive tendency; being the most frecuents all varieties of micosys fungoide (MF) and Sézary sindrome. Those lymphomas with a/ß phenotype must be estrictly considered as a subcutaneous panniculiticlike + cell lymphoma; and those with ?/d phenotype as +/NK cell lymphoma; wich has a very agressive clinical course. Cutaneous B cell lymphomas are less aggressive and its lesions are preferably situated in head and neck, in this cases previous infections must be investigated, specially Borrelia burgdoferi infections. The new classifications of diferents B lymphomas, principally betwen primary cutaneous and folliculars, facilitates the selection of a correct therapy. The study of these pathologies advances every day. It is very important to include immunihistochemical, immunogenetic and immunophenotype studies so as rech bo the correct diagnosis and classification of the lymphomas. New therapies and new combination of therapies will offer a promising future.
Subject(s)
Lymphoma, T-Cell, Cutaneous/epidemiology , Lymphoma, T-Cell, Cutaneous/immunology , Mycosis Fungoides/immunology , Antineoplastic Agents/therapeutic use , Carmustine/adverse effects , Photochemotherapy , Phototherapy/methods , Immunophenotyping , Interferon-alpha/administration & dosage , Interferon-alpha/therapeutic use , Lymphoma/classification , Mycosis Fungoides/diagnosis , Mycosis Fungoides/etiology , Mycosis Fungoides/mortality , Mycosis Fungoides/drug therapy , Mycosis Fungoides/radiotherapy , Prognosis , Combined Modality TherapyABSTRACT
Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVA-induced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Downstream of PAF, interleukin-10 was involved in PUVA-induced immune suppression but not inflammation. Better understanding of PUVA's mechanisms may offer the opportunity to dissect the therapeutic from the detrimental (ie, carcinogenic) effects and/or to develop new drugs (eg, using the PAF pathway) that act like PUVA but have fewer side effects.
Subject(s)
Apoptosis/drug effects , Apoptosis/radiation effects , Immune Tolerance/drug effects , Immune Tolerance/radiation effects , PUVA Therapy , Platelet Activating Factor/immunology , Animals , Candida albicans/immunology , Candidiasis/drug therapy , Candidiasis/immunology , Candidiasis/pathology , Combined Modality Therapy/methods , Female , Ficusin/pharmacology , Humans , Hypersensitivity, Delayed/drug therapy , Hypersensitivity, Delayed/immunology , Hypersensitivity, Delayed/pathology , Immune Tolerance/immunology , Immunosuppression Therapy/methods , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Interleukin-10/immunology , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Male , Mice , Mice, Knockout , PUVA Therapy/adverse effects , PUVA Therapy/methods , Platelet Membrane Glycoproteins/deficiency , Platelet Membrane Glycoproteins/immunology , Psoriasis/drug therapy , Psoriasis/immunology , Psoriasis/pathology , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/immunology , Signal Transduction/drug effects , Signal Transduction/immunology , Signal Transduction/radiation effectsSubject(s)
Lymphoma, T-Cell, Cutaneous , Skin Neoplasms , Adolescent , Adult , Aged , Aged, 80 and over , Diagnosis, Differential , Female , Germany/epidemiology , Humans , Lymphoma, T-Cell, Cutaneous/diagnosis , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/epidemiology , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/mortality , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Cutaneous/therapy , Male , Middle Aged , Multicenter Studies as Topic , Mycosis Fungoides/diagnosis , Mycosis Fungoides/pathology , Mycosis Fungoides/therapy , Neoplasm Staging , PUVA Therapy , Photopheresis , Randomized Controlled Trials as Topic , Registries , Sezary Syndrome/diagnosis , Sezary Syndrome/therapy , Skin/pathology , Skin Neoplasms/diagnosis , Skin Neoplasms/drug therapy , Skin Neoplasms/epidemiology , Skin Neoplasms/genetics , Skin Neoplasms/immunology , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Skin Neoplasms/therapyABSTRACT
Treatment with 8-methoxypsoralen (8-MOP) and ultraviolet A light (UVA) has been reported to modulate cytokine production in various cells. Our study was conducted to see the effects of 8-MOP/UVA on the expression/production of cytokines in peripheral blood lymphocytes and monocytes in relation to the therapeutic mechanisms of extracorporeal photochemotherapy. 8-MOP/UVA augmented the expression of mRNAs for interferon-gamma (IFN-gamma) and interleukin (IL)-2 and reduced those for IL-4 and IL-10 in peripheral blood mononuclear cells (PBMCs) from normal subjects and Sézary syndrome patients. This enhancement of Th1 cytokines was caused by increment of cytokine production by Th1 cells but not by conversion of Th2 cells to produce Th1 cytokines. The number of IFN-gamma-secreting lymphocytes was markedly increased in 8-MOP/UVA-treated PBMCs 20 h after treatment, and its amount was elevated in culture supernatants. However, this enhanced production of IFN-gamma was found only until three days after 8-MOP phototreatment, and its level was rapidly declined by five days after treatment. In addition to this Th1-polarized action, 8-MOP/UVA-treated PBMCs produced enhanced amounts of IL-8 upon stimulation with anti-CD3/CD28 antibodies. Phototreated CD4+ but not CD8+ cells provided excellent T cell help for monocytes to produce IL-8 via a direct cell-to-cell contact mechanism. These findings suggest that 8-MOP/UVA has a transient but biologically active Th1-skewing action in T cells, and the phototreated T cells simultaneously stimulate monocytes to produce IL-8. It is suggested that 8-MOP/UVA exerts a beneficial therapeutic effect on malignant Th2 neoplasms as a Th1-skewing cytokine modifier and that 8-MOP-phototreated CD4+ T cells allow monocytes to become effective tumor antigen-presenting cells for tumor-specific cytotoxic T cells.
Subject(s)
Cytokines/biosynthesis , Lymphoma, T-Cell, Cutaneous/drug therapy , PUVA Therapy , Skin Neoplasms/drug therapy , Cytokines/genetics , Humans , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Interleukin-8/biosynthesis , Interleukin-8/genetics , Lymphoma, T-Cell, Cutaneous/immunology , Models, Immunological , Monocytes/drug effects , Monocytes/immunology , RNA, Messenger/biosynthesis , Skin Neoplasms/immunology , T-Lymphocytes, Cytotoxic/immunology , Th1 Cells/drug effects , Th1 Cells/immunology , Th2 Cells/drug effects , Th2 Cells/immunologyABSTRACT
We previously identified a protein that was stimulatory for malignant Sézary T cells, termed Sézary T-cell activating factor (SAF). However, the identity of this protein has not been fully elucidated, nor has it's role been determined in the pathogenesis of cutaneous T-cell lymphoma (CTCL). The basis for epidermotropism and proliferation of malignant cells in the skin of patients with CTCL is unknown. Using a monoclonal antibody inhibitory for SAF activity, we demonstrated that SAF is present in the skin of 16 of 27 samples from patients with mycosis fungoides, the predominant form of CTCL. In this report, the SAF determinant is demonstrated to be associated with Chlamydia pneumoniae bacteria by immunohistochemistry, immunoelectron microscopy, and culture analysis. Reactivity of antibodies against an outer membrane protein of C. pneumoniae or against the lipopolysaccharide of Chlamydiae spp. demonstrated that these determinants are coexpressed in 90% of the SAF-positive samples. We confirmed the presence of C. pneumoniae DNA and RNA in the skin by PCR and reverse transcription-PCR and by sequence analysis of the PCR products. The expression of the C. pneumoniae antigens and SAF appears to be associated with active disease in that C. pneumoniae antigens were absent or greatly diminished in the skin of three patients examined after Psoralen and long-wave UVA radiation treatment. Our results suggest that SAF is a Chlamydia-associated protein and that further investigation is warranted to determine whether SAF and C. pneumoniae play a role in the pathogenesis of CTCL.
Subject(s)
Bacterial Outer Membrane Proteins/immunology , Chlamydia Infections/immunology , Chlamydophila pneumoniae/immunology , Receptors, Interferon/immunology , Sezary Syndrome/immunology , T-Lymphocytes/immunology , Antibodies, Monoclonal/pharmacology , Antigens, Bacterial/genetics , Antigens, Bacterial/immunology , Antigens, Bacterial/pharmacology , Bacterial Outer Membrane Proteins/genetics , Bacterial Outer Membrane Proteins/pharmacology , Biopsy , Cells, Cultured , Chlamydophila pneumoniae/genetics , Chlamydophila pneumoniae/ultrastructure , Epidermis/immunology , Epidermis/microbiology , Epidermis/pathology , Gene Expression Regulation, Bacterial/immunology , Gene Expression Regulation, Bacterial/radiation effects , Humans , Keratinocytes/cytology , Lipopolysaccharides/immunology , Lipopolysaccharides/pharmacology , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/microbiology , Microscopy, Immunoelectron , Monocytes/immunology , Monocytes/microbiology , PUVA Therapy , Skin Neoplasms/drug therapy , Skin Neoplasms/immunology , Skin Neoplasms/microbiology , Transcription, Genetic/immunologyABSTRACT
Esta comunicación tiene por objeto informar a la comunidad médica sobre un caso sumamente infrecuente de linfoma cutáneo primario de céluas T (CTCL). Se trata de un CTCL pleomórfico de células pequeñas que, dentro de la clasificación de la EORTC corresponde al grupo considerado provisional. En este grupo se ubican todos los CTCL de los que se desconocen su evolución y pronóstico dado el número insuficiente de casos estudiados. Asimisno se realiza una revisión del tema de la que surgen las siguientes consideraciones: 1) los linfomas cutáneos primarios y los linfomas ganglionares no Hodgkin, son idénticos desde el punto de vista morfológico pero constituyen entidades diferentes tanto desde el punto de vista clínico cuanto biológico, 2) las clasificaciones de Kiel y REAL resultan insuficientes para tratar esta problemática, 3) la clasificación de la EORTC parece ser la más apropiada aunque aún no existe suficiente experiencia sobre algunos tipos de CTCL.
Subject(s)
Humans , Female , Adult , Clinical Evolution , Lymphoma, Non-Hodgkin , Lymphoma, T-Cell, Cutaneous/classification , Lymphoma, T-Cell, Cutaneous/diagnosis , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, T-Cell, Cutaneous/therapy , Lymphoma, T-Cell/diagnosis , Lymphoma, T-Cell/therapy , Neoplasm Staging , PrognosisABSTRACT
Esta comunicación tiene por objeto informar a la comunidad médica sobre un caso sumamente infrecuente de linfoma cutáneo primario de céluas T (CTCL). Se trata de un CTCL pleomórfico de células pequeñas que, dentro de la clasificación de la EORTC corresponde al grupo considerado provisional. En este grupo se ubican todos los CTCL de los que se desconocen su evolución y pronóstico dado el número insuficiente de casos estudiados. Asimisno se realiza una revisión del tema de la que surgen las siguientes consideraciones: 1) los linfomas cutáneos primarios y los linfomas ganglionares no Hodgkin, son idénticos desde el punto de vista morfológico pero constituyen entidades diferentes tanto desde el punto de vista clínico cuanto biológico, 2) las clasificaciones de Kiel y REAL resultan insuficientes para tratar esta problemática, 3) la clasificación de la EORTC parece ser la más apropiada aunque aún no existe suficiente experiencia sobre algunos tipos de CTCL. (AU)
Subject(s)
Humans , Female , Adult , Lymphoma, T-Cell/diagnosis , Lymphoma, T-Cell/therapy , Clinical Evolution , Lymphoma, T-Cell, Cutaneous/classification , Lymphoma, T-Cell, Cutaneous/diagnosis , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/therapy , Lymphoma, T-Cell, Cutaneous/pathology , Lymphoma, Non-Hodgkin , Prognosis , Neoplasm StagingSubject(s)
Chromatin/drug effects , DNA Damage , DNA/chemistry , Furocoumarins/toxicity , Mutagens/toxicity , Animals , Base Composition , Base Sequence , Furocoumarins/therapeutic use , Humans , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/immunology , Lymphoma, T-Cell, Cutaneous/pathology , Methoxsalen/chemistry , Models, Molecular , Molecular Sequence Data , Nucleic Acid Conformation , PUVA Therapy , Transcription, Genetic/drug effectsABSTRACT
Interferon-alpha combined with retinoid or PUVA is used for the treatment of cutaneous T-cell lymphoma. Anti-IFN-alpha antibodies (IFN ab) occur regularly during IFN-alpha treatment. We investigated the incidence of neutralizing and binding IFN ab and analysed their relationship with clinical and immunological parameters. A group of 17 CTCL patients were treated with IFN alpha-2a three times weekly subcutaneously at a dose of 3 Mill. I.U. combined either with retinoid (acitretin, Neotigason; 0.5 mg/kg bodyweight) daily or with 5-methoxypsoralen (1.2 mg/kg bodyweight) plus UVA radiation three times weekly. Prior to and during treatment we monitored stage, skin involvement by a tumour burden index, serum levels of beta 2-microglobulin, neopterin, binding and neutralizing IFN ab, Interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2r) and the CD4/CD8 ratio of peripheral blood mononuclear cells. We observed two complete, two partial and six minor responses, four patients with stable disease and three patients with progressive disease. Of the 17 patients, 7 developed binding IFN ab, but only 2 had neutralizing IFN ab which were associated with high titres of binding IFN ab. IFN ab formation was more frequent in patients with normal CD4/CD8 ratios and a high tumour burden index and showed a trend to be more frequent in PUVA-cotreated patients than in retinoid-cotreated patients. Responses were more frequently seen in IFN ab-negative patients. IFN ab developed in patients treated with PUVA or retinoid combined with IFN. Binding as well as neutralizing IFN ab may have an impact on the treatment success in CTCL patients.