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PubMed1995

E-cadherin is functionally involved in the maturation of the erythroid lineage.

Differentiation and proliferation of hematopoietic progenitors take place in the bone marrow and is a tightly controlled process. Cell adhesion molecules of the integrin and immunoglobulin families have been shown to be involved in these processes, but almost nothing was known about the involvement of the cadherin family in the hematopoietic system. A PCR screening of RNA of human bone marrow mononuclear cells with specific primers for classical cadherins revealed that E-cadherin, which is mainly expressed by cells of epithelial origin, is also expressed by bone marrow cells. Western blot analysis and immunofluorescence staining of bone marrow sections confirmed this unexpected finding. A more detailed analysis using immunoaffinity columns and dual color flow cytometry showed that the expression of E-cadherin is restricted to defined maturation stages of the erythropoietic lineage. Erythroblasts and normoblasts express E-cadherin, mature erythrocytes do not. A functional role of E-cadherin in the differentiation process of the erythroid lineage was indicated by antibody-inhibition studies. The addition of anti-E-cadherin antibody to bone marrow mononuclear cultures containing exogeneous erythropoietin drastically diminished the formation of erythropoietic cells. These data suggest a non-anticipated expression and function of E-cadherin in one defined hematopoietic cell lineage.

Base Sequence↗

PubMed1993

Trait anxiety and anticipatory immune reactions in women receiving adjuvant chemotherapy for breast cancer.

We compared peripheral blood cell counts as well as mitogen activity and natural killer-cell activity in women undergoing adjuvant chemotherapy for breast cancer in the hospital prior to chemotherapy with assessment at home 2 days earlier. Patients compared to controls had an increased number of white blood cell counts in the hospital as compared to those at home, mediated by an increased total number of granulocytes. Among patients, those with high compared to low trait anxiety evidenced immune system changes. Total number of monocytes were reduced in patients with high compared to low trait anxiety and natural killer-cell activity tended to be compromised in the high anxiety group. Helper/inducer T-cells isolated from hospital blood samples were lower in patients with high as compared to low trait anxiety, while no difference was observed in samples taken at home. Conditioned nausea was associated with trait anxiety and patients with as compared to without conditioned nausea displayed immune changes similar to changes observed as a function of trait anxiety. State anxiety measured at the hospital did not relate to immune measures. The observed increase in granulocytes is consistent with an interpretation both in terms of conditioning and anticipatory stress. The anticipatory immunosuppression in patients with high compared to low trait anxiety is consistent with the hypothesis that chemotherapy patients may develop conditioned immunosuppression after repeated pairings of treatment-related stimuli with the unconditioned immunosuppressive effect of chemotherapy.

Adult↗

PubMed1985

Monokines and the metabolic pathophysiology of septic shock.

The role of the macrophage system in shock pathogenesis now embraces both classic endocytic functions as well as the more recently discovered function of the macrophages as a multifaceted secretory apparatus. Among the major macrophage secretory products are the monokines, regulatory proteins that mediate via both local or paracrine and systemic or endocrine mechanisms, the nonspecific host defense and metabolic responses to inflammation and sepsis. Evidence is reviewed for a monokine involvement in the alterations of protein, fat, and carbohydrate metabolism in sepsis and/or endotoxicosis, viz., enhanced muscle proteolysis, enhanced hepatic acute phase protein synthesis, depressed lipogenesis and lipoprotein lipase function, enhanced peripheral glucose oxidation, and depression of hepatic gluconeogenesis. Monokines are also related to the disturbed endocrine mechanisms of sepsis, viz., enhanced insulin secretion and depressed adrenal steroidogenesis. It is suggested that the macrophage system mediates via secretion of monokines an integrated fuel substrate and hormonal adjustment to sepsis, which on the one hand may provide optimal metabolic homeostasis for systemic host defense, but on the other hand, if allowed to act unchecked, may contribute to the metabolic dyshomeostasis of septic shock.

Animals↗

PubMed1996

Molecular characterization of immune derived proenkephalin mRNA and the involvement of the adrenergic system in its expression in rat lymphoid cells.

Proenkephalin (PENK), a classically defined opioid gene, was originally thought to be expressed almost exclusively in the mature nervous and neuroendocrine systems. In the last few years, it was demonstrated, however, that significant levels of PENK mRNA and PENK-derived peptides are transiently expressed in cells of the immune system. Very little is known about the molecular mechanisms regulating this transient expression. In order to investigate those mechanisms, we examined the in vivo expression of PENK mRNA in mesenteric lymph nodes after exposing rats to lipopolysaccharide. In the present study we demonstrate that: (i) promoter usage and splicing of PENK mRNA function similarly in mesenteric lymph nodes as in neural cells; (2) PENK expression in mesenteric lymph nodes is modulated by adrenaline via adrenergic receptors; and (3) the adrenergic system participates in the modulation of the LPS induced PENK mRNA expression. These results provide more evidence for the involvement of opioids in neuro-immune interactions.

Adrenergic Agonists↗

PubMed1987

Adenosine deaminase and purine nucleoside phosphorylase deficiencies: evaluation of therapeutic interventions in eight patients.

The courses of six patients with adenosine deaminase (ADA) and two with purine nucleoside phosphorylase (PNP) deficiencies were evaluated before and after therapy. The heterogeneity of immunologic and clinical parameters was striking in each enzyme deficiency. In both PNP and ADA deficiency, some patients had very low immunoglobulin levels, while others had normal levels. T-cell function was always low in patients with ADA deficiency. In the two patients with PNP deficiency, contrary to the classical descriptions of this disorder, T-cell function fluctuated with time. Five ADA-deficient patients were treated with irradiated normal red-cell transfusions as a form of enzyme replacement and showed no lasting benefit. Three of the ADA-deficient patients and one of the PNP-deficient patients were given transplants of haploidentical parental bone marrow stem cells without pretransplant immunosuppression. In the PNP-deficient patient, chimerism has not been documented on enzymatic testing. One ADA-deficient patient has demonstrated long-term engraftment with good B- and T-cell function. Haploidentical bone marrow transplantation is currently the preferred therapy for enzyme-deficient patients with absent T-cell function who do not have an HLA-identical donor, as it may result in a lasting reconstitution of immune function. In those patients with unsatisfactory responses to transplantation, however, specific enzyme replacement or gene therapy may be considered in the future.

Adenosine Deaminase↗

PubMed1992

Myeloid cell kinetics in response to haemopoietic growth factors.

The morphologically recognizable cells of haemopoietic tissue comprise some 95% of the total and their kinetic performance is both flexible and adaptable to stress conditions. The effects of the common myeloid growth factors on these cells have been examined. Using the classically developed analyses of cell kinetics with tritiated thymidine labelling autoradiography, it is shown that continuously infused or repeated injections of G-CSF increases the proliferative activity of marrow haemopoietic tissue in both mouse and man, shortening the average cell cycle times by 35 and 65% respectively, amplifying neutrophil production so that levels in the peripheral blood rise 10-15-fold. This amplified production, amounting to 3-4 extra proliferation divisions, is mostly confined to the proliferatively active maturing neutrophil cell compartments. In addition, the neutrophil maturation time is also reduced, leading to a rapid and sustained release of postmitotic cells within 1-2 days, compared with the normal time of 4-6 days. Neither GM-CSF nor IL-3 generates any significant amplification of neutrophil production in mice but, in humans, GM-CSF stimulates cell proliferation in the bone marrow to a similar degree as doses G-CSF. Studies on the granulocyte-macrophage progenitor population show that the proliferation stimulus in response to GM-CSF is not confined to the maturing populations. In the maturing neutrophil precursor population, average cell cycle times are shortened by 60%, but in this case the overall maturation times are unaffected and their time of release into the circulation is normal. The response to GM-CSF, however, is not so straightforward as that to G-CSF. The peripheral half-life of the mature cells is considerably prolonged and this is consistent with some suggestion of functional impairment. In addition, a significant release of immature cells and eosinophils (also expanded in the bone marrow in response to GM-CSF) dilutes the neutrophilic response. Monocyte production is also stimulated by G- and GM-CSF and, though no direct measurement of proliferation has been made, stimulation at all stages of their proliferation, maturation and release are implied.

Agranulocytosis↗

PubMed2005

Aging affects the retinoic acid and the triiodothyronine nuclear receptor mRNA expression in human peripheral blood mononuclear cells.

BACKGROUND: Inadequate retinoid status has often been described as occurring with aging. Moreover, subclinical hypothyroid status has also been evoked in the elderly. Several studies performed in animals have described the crucial incidence of age-related hypo-functioning of retinoid and thyroid signalling pathways, particularly in the brain. OBJECTIVE: The aim of the present study was to clarify whether aging modifies retinoid and thyroid signalling in humans. METHODS: Using real-time RT-PCR the relative amount of mRNA of the retinoid (RARalpha, RARgamma and RXRalpha) and thyroid (TRalpha and TRbeta) nuclear receptors in peripheral blood mononuclear cells (PBMC) of young (24-57 years old, n = 22) compared with elderly (69-90 years old, n = 24) healthy subjects was quantitated. Classical plasma parameters used to characterize the retinoid and thyroid status - retinol (ROH), retinol-binding protein (RBP), free triiodothyronine (FT3) and thyroxine (FT4), thyroid-stimulating hormone (TSH) and transthyretin (TTR) - were also assessed. RESULTS: RARgamma expression was significantly decreased in elderly versus young subjects while no modification of the retinoid-related plasma parameters ROH and RBP were emphasized by aging. Concerning thyroid criteria, the elderly exhibited an increase in TSH concentration (+39%) without significant modifications of FT3 and FT4, which indicated an age-related sub-clinical hypothyroidism. Concurrently, the amount of TR mRNA (alpha as well as beta subtypes) was significantly decreased in the elderly. CONCLUSION: These data constitute the first evidence of an age-related hypo-activation of the retinoid and thyroid nuclear pathways in PBMC. Further study of the possible association between the expression of the retinoid and thyroid nuclear receptors and age-related cognitive alterations in humans would be interesting.

Adult↗

PubMed2003

Osteoclast apoptosis: the role of Fas in vivo and in vitro.

Both the number and the activity of osteoclasts are critical for maintaining normal bone turnover. The number is determined by rates of cell differentiation and death. Fas-mediated apoptosis is a dominant mechanism for apoptosis. Here, we show the presence of the Fas receptor on mouse, human, avian, and cultured RAW264.7 (murine) derived osteoclasts and the up-regulation of its expression during mouse osteoclast differentiation. Additionally, Fas is a fully functional death receptor in osteoclasts, and its signaling pathway is consistent with classical Fas signaling in other cell systems, involving mitochondrial release of cytochrome c and activation of caspases 3 and 9. This demonstration of Fas-mediated apoptosis in mature osteoclasts provides a new and potent mechanism for the regulation of osteoclast life span. The in vivo significance of Fas-mediated apoptosis in bone (osteoclasts) was demonstrated in aged Lpr and Gld mice, which have a dysfunctional immune system. Lpr mice, which have a defect in the Fas gene, have decreased bone mineral density, bone volume, trabecular thickness, and increased osteoclast number. Gld mice, which have a Fas ligand mutation, have a slight yet insignificant decrease in bone mineral density, but a highly significant increase in osteoclast number. Taken together, these data demonstrate that the Fas/Fas ligand system is important in the regulation of bone turnover and may represent a critical link between the immune system and bone remodeling in development and in various diseases.

Animals↗

PubMed2005

Leishmania donovani: differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays.

Different classes of topoisomerase (TOP) inhibitors and antitrypanosomatid agents exhibited variable efficacies against Leishmania donovani parasites and human mononuclear cells both at the level of DNA topoisomerase I (TOPI) catalytic activity and in cytotoxicity assays. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high efficacies against parasite and host enzymes as well as against parasite and mononuclear cells, but pentamidine showed around 2 orders of magnitude greater specificity for Leishmania TOPI and amastigote cells (P<0.05). The protoberberine coralyne and the flavonoid quercetin were highly potent, but non-selective, inhibitors in vitro, although the latter showed slight selectivity for parasite TOPI. Camptothecin was selective for mononuclear cells at both levels (P<0.05) and sodium stibogluconate was selective only at the enzyme level displaying 30-fold greater potency against parasite TOPI (P<0.05). These data suggest that at least part of pentamidines' leishmanicidal activity may be mediated through TOPI inhibition, and support the feasibility of exploiting differences between Leishmania and human TOPs to develop modified compounds with improved selectivity.

Acid Phosphatase↗

PubMed1998

Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs.

CD8+ cytotoxic T lymphocytes (CTLs) mediate resistance to infectious agents and tumours. Classically, CTLs recognize antigens that are localized in the cytoplasm of target cells, processed and presented as peptide complexes with class I molecules of the major histocompatibility complex (MHC). However, there is evidence for an exogenous pathway whereby antigens that are not expected to gain access to the cytoplasm are presented on MHC class I molecules. The most dramatic example is the in vivo phenomenon of cross-priming: antigens from donor cells are acquired by bone-marrow-derived host antigen-presenting cells (APCs) and presented on MHC class I molecules. Two unanswered questions concern the identity of this bone-marrow-derived cell and how such antigens are acquired. Here we show that human dendritic cells, but not macrophages, efficiently present antigen derived from apoptotic cells, stimulating class I-restricted CD8+ CTLs. Our findings suggest a mechanism by which potent APCs acquire antigens from tumours, transplants, infected cells, or even self-tissue, for stimulation or tolerization of CTLs.

Antigen Presentation↗

PubMed1991

Differential dose-related haematological effects of GM-CSF in pancytopenia: evidence supporting the advantage of low- over high-dose administration in selected patients.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional haematopoietin which can promote production of several blood cell lineages, though the predominant target cells are neutrophils, monocytes, and their precursors. Occasional undesirable clinical effects include eosinophilia, an increase in blasts, or thrombocytopenia. Here, we describe four patients who were treated with GM-CSF, at subcutaneous doses significantly lower than are conventional, and experienced an unusual response pattern. Three patients had severe pancytopenia associated with chronic lymphocytic leukaemia (CLL) or myelodysplastic syndrome (MDS) and exhibited an unexpected switch in the responsive lineage on high- versus very low-dose therapy. The two CLL patients developed marked eosinophilia (up to 10.0 x 10(9) cells/l) without an increase in neutrophils on 125-300 micrograms/m2/d of GM-CSF. In contrast, when the dose was lowered to 10 micrograms/m2/d, the neutrophils rose to physiological levels, without significant eosinophilia. The MDS patient showed a rapid rise in peripheral blasts (baseline level = 0; post-therapy level = 5.0 x 10(9)/l), without a change in other cell types, when receiving 60 micrograms/m2/d of GM-CSF. After GM-CSF was held, blasts returned to baseline levels; reinstituting therapy at the very low dose of 6 micrograms/m2/d was followed by an increase in platelet counts from 50 to 185 x 10(9)/l with only a minor increase in blasts. The fourth patient, who suffered from severe aplastic anaemia complicated by recurrent gastrointestinal haemorrhage, was only treated with the low-dose regimen. He showed a predominant platelet effect with counts rising from 9 to 169 x 10(9)/l. Very low-dose GM-CSF therapy was devoid of constitutional side effects. The biological implications of these GM-CSF responses are discussed. Our results indicate that, in some patients, GM-CSF may stimulate different target cells depending on the dose. Therefore, in contrast to the results of administration of many classical drugs, there may not always be a direct relationship between the amount of GM-CSF given and the optimal effect.

Adult↗

PubMed1996

Cloning of mouse ptx3, a new member of the pentraxin gene family expressed at extrahepatic sites.

Pentraxins, which include C reactive protein (CRP) and serum amyloid P component (SAP), are prototypic acute phase reactants that serve as indicators of inflammatory reactions. Here we report genomic and cDNA cloning of mouse ptx3 (mptx3), a member of the pentraxin gene family and characterize its extrahepatic expression in vitro and in vivo. mptx3 is organized into three exons on chromosome 3: the first (43 aa) and second exon (175 aa) code for the signal peptide and for a protein portion with no high similarity to known sequences the third (203 aa) for a domain related to classical pentraxins, which contains the "pentraxin family signature." Analysis of the N terminal portion predicts a predominantly alpha helical structure, while the pentraxin domain of ptx3 is accommodated comfortably in the tertiary structure fold of SAP. Normal and transformed fibroblasts, undifferentiated and differentiated myoblasts, normal endothelial cells, and mononuclear phagocytes express mptx3 mRNA and release the protein in vitro on exposure to interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF)alpha. mptx3 was induced by bacterial lipopolysaccharide in vivo in a variety of organs and, most strongly, in the vascular endothelium of skeletal muscle and heart. Thus, mptx3 shows a distinct pattern of in vivo expression indicative of a significant role in cardiovascular and inflammatory pathology.

3T3 Cells↗

PubMed2003

CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach.

We describe here a classical molecular modeling exercise that was carried out to provide a basis for the design of novel antagonist ligands of the CCR2 receptor. Using a theoretical model of the CCR2 receptor, docking studies were carried out to define plausible binding modes for the various known antagonist ligands, including our own series of indole piperidine compounds. On the basis of these results, a number of site-directed mutations (SDM) were designed that were intended to verify the proposed docking models. From these it was clear that further refinements would be necessary in the model. This was aided by the publication of a crystal structure of bovine rhodopsin, and a new receptor model was built by homology to this structure. This latest model enabled us to define ligand-docking hypotheses that were in complete agreement with the results of the SDM experiments.

Amino Acid Substitution↗

PubMed1998

Specific immune induction following DNA-based immunization through in vivo transfection and activation of macrophages/antigen-presenting cells.

The initiation of an adaptive immune response requires Ag presentation in combination with the appropriate activation signals. Classically, Ag presentation and immune activation occur in the lymph node and spleen, where a favorable organ architecture and rich cellular help can enhance the process. Recently, several investigators have reported the use of DNA expression cassettes to elicit cellular and humoral immunity against diverse pathogens. Although the immune mechanisms involved are still poorly understood, plasmid inoculation represents a model system for studying immune function in response to invading pathogens. In this report, we demonstrate the presence of activated macrophages or dendritic cells in the blood lymphocyte pool and peripheral tissues of animals inoculated with DNA expression cassettes. These cells are directly transfected in vivo, present Ag, and display the surface proteins CD80 and CD86. Our studies indicate that these cells function as APC and can activate naive T lymphocytes. They may represent an important first step APC in genetic immunization and natural infection.

Animals↗

PubMed2004

Role of microglia in central nervous system infections.

The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed.

Animals↗

PubMed2005

Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity.

HLA-G is a non-classical major histocompatibility complex (MHC) class I antigen with highly limited tissue distribution under non-pathological conditions. Although capable of acting as a peptide-presenting molecule, its strong immune-inhibitory properties identify HLA-G as a mediator of immune tolerance with specific relevance at immune-privileged sites such as trophoblast or thymus. To assess the role of HLA-G in CNS immunity, we investigated its expression in brain specimens from patients with multiple sclerosis (n = 11), meningitis (n = 2) and Alzheimer's disease (n = 2) and non-pathological CNS controls (n = 6). Furthermore, cultured human microglial cells and CSF of patients with multiple sclerosis and controls were assessed. Furthermore, CSF from MS patients and controls, as well as cultured human microglial cells were assessed. Using several HLA-G specific mAb and immunohistochemistry, HLA-G protein was found strongly expressed in brain specimens from patients with multiple sclerosis while it was rarely detectable in the non-pathological control specimens. In multiple sclerosis brain specimens, HLA-G immunoreactivity was observed in acute plaques, in chronic active plaques, in perilesional areas as well as in normal appearing white matter. In all areas microglial cells, macrophages, and in part endothelial cells were identified as the primary cellular source of expression. HLA-G was also found in other disease entities (meningitis, Alzheimer's specimens) where expression correlated to activation and MHC class II expression on microglial cells. Importantly, ILT2, a receptor for HLA-G, was also found in multiple sclerosis brain specimens thus emphasizing the relevance of this inhibitory pathway in vivo. HLA-G mRNA and protein expression and regulation could also be corroborated on cultured human microglial cells in vitro. Further, expression of HLA-G in the CSF of multiple sclerosis patients and controls was analysed by flow cytometry and ELISA. Monocytes represented the main source of cellular HLA-G expression in the CSF. Corresponding to the observations with the tissue specimens, CSF mean levels of soluble HLA-G were significantly higher in multiple sclerosis than in non-inflammatory controls (171 +/- 31 versus 39 +/- 10 U/ml; P = 0.0001). The demonstration of HLA-G and its receptor ILT2 on CNS cells and in areas of microglia activation implicate HLA-G as a contributor to the fundamental mechanisms regulating immune reactivity in the CNS. This pathway may act as an inhibitory feedback aimed to downregulate the deleterious effects of T-cell infiltration in neuroinflammation.

Adult↗

PubMed2000

The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells.

Bispecific antibodies (bsAb) are considered as promising tools for the elimination of disseminated tumour cells in a minimal residual disease situation. The bsAb-mediated recruitment of an immune effector cell in close vicinity of a tumour cell is thought to induce an antitumoural immune response. However, classical bispecific molecules activate only a single class of immune effector cell that may not yield optimal immune responses. We therefore constructed an intact bispecific antibody, BiUII (anti-CD3 x anti-EpCAM), that not only recognizes tumour cells and T lymphocytes with its two binding arms, but also binds and activates Fcgamma-receptor positive accessory cells through its Fc-region. We have demonstrated recently that activated accessory cells contribute to the bsAb-induced antitumoural activity. We now analyse this stimulation in more detail and demonstrate here the BiUII-induced upregulation of activation markers like CD83 and CD95 on accessory cells and the induction of neopterin and biopterin synthesis. Experiments with pure cell subpopulations revealed binding of BiUII to CD64+ accessory cells and CD16+ NK cells, but not to CD32+ B lymphocytes. We provide further evidence for the importance of the Fc-region in that this bispecific molecule stimulates Fcgamma-R-positive accessory cells to eliminate tumour cells in vitro by direct phagocytosis.

Antibodies, Bispecific↗

PubMed1997

Sezary lineage cells can be induced to proliferate via CD28-mediated costimulation.

Sezary syndrome and mycosis fungoides are related chronic lymphoproliferative diseases caused by the malignant growth of CD4+ T lymphocytes that display hyperconvoluted nuclei and a predilection for skin homing. Despite the malignant nature of these cells, they paradoxically do not grow in vitro, either spontaneously or following exposure to mitogens. Partly because of this technical limitation, the cellular lineage and causes of abnormal growth resulting in a classical hyperconvoluted Sezary cell are poorly characterized. To better understand these aspects, we examined Sezary lineage cell growth in vitro. We found that, contrary to previous reports, Sezary lineage cells are capable of in vitro proliferation in response to either PHA or anti-CD3 mAb, if exogenous costimulation is provided. The CD28-B7 interaction provides at least one of the costimulatory signals capable of inducing Sezary lineage cell growth. Namely, Sezary lineage cells from three of six Sezary syndrome patients proliferated in response to PHA if an anti-CD28 mAb was also added to the in vitro culture. The remaining three patients' Sezary lineage cells were dependent upon CD28-B7-mediated costimulation, but in addition required other intercellular signals present on blood mononuclear cells. The relative lack of costimulation from the patients' own PBMC is not due to an intrinsic defect in the mycosis fungoides/Sezary syndrome patients' immune accessory cells. Rather, it appears primarily due to an inability of Sezary cells to significantly up-regulate CD40 ligand (gp39) following in vitro exposure to PHA.

Aged↗