Presence of circulating abnormal CD34+ progenitors in adult Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is related to the proliferation of cells, which are similar to Langerhans cells (LC) but possess many abnormal characteristics. Lesions are widespread and this fact suggests that LCH cells or their precursors are present in the blood of patients. In five adult patients, we have isolated and cultured CD34+ blood progenitors of dendritic cells. We studied their phenotype by flow cytometry and their functional properties in mixed culture with heterologous lymphocytes and with autologous lymphocytes in the presence of tri-nitro-phenyl antigen (TNP). The amount of CD34+ precursors was dramatically higher than controls but a high mortality occurred during the in vitro differentiation. The phenotype of surviving cells was similar to LC phenotype (CD1a+, CD83+, Lag+) but some of them expressed CD2. These cells were able to induce T cell proliferation in mixed culture. They could not initiate primary response to TNP, except in a patient treated with thalidomide. In our hands, these CD34+ cells may be precursors of LCH cells.     

Binding of live conidia of Aspergillus fumigatus activates in vitro-generated human Langerhans cells via a lectin of galactomannan specificity

Aspergillus fumigatus is the most common aetiological fungus responsible for human pulmonary aspergilloses. This study investigated the primary contact between Langerhans cells (LC), corresponding to dendritic cells present in pulmonary mucosa and live conidia of A. fumigatus. LC play a key role in antigen presentation for initiation of the primary T cell response. In vitro-generated LC (iLC) were differentiated from cultured human cord blood CD34+ cells and incubated at 4 degrees C or 37 degrees C with fluorescein-isothiocyanate (FITC)-stained conidia or control latex beads. In vitro, conidia were shown by microscopy and cytometry to adhere to iLC in a dose- and time-dependent manner. This adhesion was not limited to iLC because interstitial dendritic and other cells also fluoresced in the presence of conidia-FITC. A lectin other than mannose receptor-type lectin was demonstrated to be responsible of conidial binding. Inhibition of binding was observed with heterologous galactomannan and EDTA, indicating a C-lectin-like receptor with galactomannan structure specificity. After binding only a few conidia were internalized in acidic vesicles, as indicated by the cessation of conidial fluorescence. Conidial binding was followed by activation and maturation of iLC, suggesting that LC present in the lung may play a role in cellular host defence against aspergilloses.     

Lesions resembling Langerhans cell histiocytosis in association with other lymphoproliferative disorders: a reactive or neoplastic phenomenon?

Langerhans cell histiocytosis (LCH) has been described in association with a variety of neoplasms preceding, after, or synchronous with the other tumor. In some cases, a neoplasm may arise as a complication of therapy for LCH, and in others, the association may be coincidental. Synchronous occurrence has been reported most commonly in association with malignant lymphoma in which discrete proliferations of Langerhans cells (LCs) histologically indistinguishable from LCH are seen. In most cases, these LCs are closely related to or intermingling with the primary pathology. The nature of LCs in this context remains elusive with debate as to whether they represent a true clonal neoplasm or an exaggerated reactive phenomenon. The lack of evidence for LCH progression or disease elsewhere strongly supports the latter. We have encountered 5 examples of LCH-like proliferations occurring in the context of other lymphoproliferative disorders. These include 2 cases of mycosis fungoides and 1 of cutaneous B-cell pseudolymphoma, associations that to our knowledge have not been described before. Two patients were female, and the clonality of the LC proliferation was assessed using laser capture microdissection and the human androgen receptor. The results showed that the LCs forming discrete nodules in a case of cutaneous B-cell pseudolymphoma and a case of Hodgkin's lymphoma were polyclonal. This suggests that, at least in a proportion of cases, the aggregates of LCs occasionally identified within other lymphoproliferative lesions represent a reactive proliferation rather than a potentially aggressive second neoplasm.     

Expression of apoptosis-regulatory proteins in lesions of pulmonary Langerhans cell histiocytosis

AIMS: Pulmonary Langerhans cell histiocytosis (PLCH) is characterized by the presence of lesions containing numerous activated Langerhans cells (LCs). An uncontrolled immune response sustained by activated LCs seems to be involved in the pathogenesis of the disease. The aim of this study was to establish whether disruption of LC apoptosis related to the expression of the Bcl-2 family proteins is implicated in the maintenance of PLCH lesions. METHODS: Six patients with PLCH were evaluated by morphological and immunohistochemical techniques to explore the incidence of apoptosis in pathological LCs and to characterize the expression of Bcl-2-related proteins by these cells. RESULTS: Very few LCs present in PLCH lesions exhibited nuclear apoptotic changes or expressed cleaved caspase-3, whereas they all strongly expressed the anti-apoptotic molecule Bcl-x(L). Interestingly, pulmonary LCs present in intervening lung tissue not involved by the pathological process and known to be immature dendritic cells did not express Bcl-2 family proteins. CONCLUSIONS: These findings suggest that activated LCs present within PLCH lesions are poorly susceptible to apoptosis and, thus, are able to sustain the pathological process by causing continuous local stimulation of T cells. Functional studies are needed, however, to demonstrate that they are actually resistant to programmed cell death.     

Neoplasms associated with pulmonary eosinophilic granuloma

We found a high prevalence of pulmonary and extrapulmonary neoplasms in patients with pulmonary eosinophilic granuloma (PEG) who were studied at our institution. Among 21 patients with PEG, 10 (48%) had associated benign (one patient) or malignant (nine patients) tumors. Patients with tumors were older at the time of diagnosis of PEG (48.9 vs 34.5 years). Tumors included three lung carcinomas, one pulmonary carcinoid tumor, two lymphomas, five extrapulmonary carcinomas, and one mediastinal ganglioneuroma. Two malignant neoplasms developed in each of two patients. Six tumors preceded, three followed, and three occurred concomitantly with the diagnosis of PEG. Slides from eight PEG-associated tumors and 18 control neoplasms from patients without PEG were also stained immunohistochemically for S100 protein. Four PEG-associated (50%) and 11 control (61%) tumors contained S100 protein-positive interstitial cells. Our study suggests, but does not prove, that there may be more than a random association between PEG and neoplasms. Cigarette smoking, moreover, is an important risk factor for both PEG and lung carcinomas. Our immunohistochemical findings indicate that S100 protein-positive cells in tumors usually bear little or no relationship to PEG. In patients with an underlying malignant neoplasm, PEG simulates pulmonary metastases clinically and, occasionally, histopathologically.     

Do epidermal Langerhans cells,migrating from skin lesions,induce the paracortical hyperplasia of dermatopathic lymphadenopathy?

In the present study, immunohlstochemical and Immuno-electron microscopic techniques were used to differentiate Langerhans cells (LC) from interdigitating cells (IDC) in the lymph nodes (LN) of dermatopathic lymphadenopathy. The majority of the dendritic cells that existed In the LN of dermatopathic lymphadenopathy were positive for OKT-6 (CD la) antibody. It was concluded that these dendritic cells were not IDC, but LC. Electron microscopically, LC In these LN contained a few Blrbeck granules (BG). In order to prove the fact that these dendritic cells were LC, the existence of BG was investigated ultrastructurally by examining serial sections, and Immunoelectron microscopically for CD 1a positive cells. Most of the LC in the lymph nodes we examined were negative for the anti-prollferating nuclear antigen (PCNA) antibody. This finding may mean that LC in the LN are fully developed cells and do not divide In the LN. Langer-hana cells may migrate from the skin lesions to the paracortical areas in the LN, which then may become enlarged.     

CpG motifs induce Langerhans cell migration in vivo

Cytosine-guanosine (CpG) oligonucleotide (CpG-oligo) sequences are immunostimulatory motifs that are present in bacterial DNA and their presence in plasmids might contribute to the immune response generated by DNA vaccination. The cell targets of CpG motifs in vivo have not been characterized yet. In this report we assessed the in vivo effects of CpG motifs on Langerhans cells (LC) migration. We showed that intradermal injection of 10 microg of CpG-containing oligonucleotides in mouse ear induced the local depletion of LC within 2 h of exposure as shown by CD11c and Ia immunohistological staining. To demonstrate that LC depletion was due to LC migration, CpG oligonucleotides were injected into the explants ex vivo, and the CD11c(+) cells emigrating from the cultured isolated skin within medium were evaluated by immunostaining and FACS analysis. Our findings demonstrate that CpG motifs induce LC/dendritic cell (DC) migration out of the skin. To assess whether CpG motifs may act directly on LC/DC to induce their emigration we next analyzed the effects of CpG motifs in vitro on the expression of adhesion molecules involved in LC/DC migration. The results of these experiments show that alpha(6) integrins, E-Cadherin, ICAM-1, CD11b and CD11c were differentially regulated upon CpG-oligo treatment of immortalized DC. CpG treatment (10 microg/ml for 8 h) resulted in a 100% increase in ICAM-1 staining intensity, a 50% decrease in E-Cadherin staining and a 25% decrease in alpha(6) integrins staining, while no changes in the levels of CD11b and CD11c expression were recorded. Changes in adhesion molecule expression were mirrored by concomitant changes in the cell morphology that included cell depolarization, the appearance of filopods and loss of adherence. This study provides the first in vivo evidence that CpG motifs signal the migration of LC from the epidermis.     

Expression of gp40, the murine homologue of human epithelial cell adhesion molecule (Ep-CAM), by murine dendritic cells

Dendritic cells (DC) can be distinguished from other antigen-presenting cells (APC) by their morphology, motility and ability to initiate primary responses in naive T cells. Certain cell surface proteins (e.g. major histocompatibility complex antigens, co-stimulatory/adhesion molecules and DEC205) are selectively expressed by DC, and may contribute to the potent APC activity of these leukocytes. As an outgrowth of studies of adhesion molecules expressed by epithelia and Langerhans cells (LC), we examined DC from murine epidermis and various lymphoid tissues for evidence of expression of gp40, a glycoprotein recently identified as the murine homologue of human epithelial cell adhesion molecule (Ep-CAM). gp40 was detected on freshly-obtained LC, cultured LC and LC that migrated from skin explants, as well as on keratinocytes. In skin-associated lymph nodes, gp40 was selectively expressed by some DC in T cell-dependent areas. DC-enriched preparations from skin-associated lymph nodes and spleen contained many cells that co-expressed DC markers (CD11c and DEC205) and high levels of gp40. Lower levels of gp40 were present on DC from gut-associated lymph nodes. These results demonstrate that the putative homophilic adhesion molecule gp40 is expressed by subpopulations of DC in selected tissues; we propose that gp40 expression may have functional consequences for DC.     

Dissection of human Langerhans cells' allostimulatory function: The need for an activation step for full development of accessory function

In the present study, we analyzed the mechanism by which human Langerhans cells (LC), the dendritic cells (DC) from epidermis, support the induction of a primary allogeneic T cell response. We reported that paraformaldehyde (PF) fixation completely abrogated the stimulatory property of freshly isolated LC, although the level of major histocompatibility complex (MHC) class II antigen (Ag) expression was unaltered by the fixative. Addition of either interleukin (IL)-ip and/or IL-6, during the mixed epidermal cell lymphocyte reaction, failed to restore the proliferative response. By contrast, when human LC were incubated for 3 days in culture medium before fixation, they retained a low but significant allostimulatory capacity. Trypsin treatment of incubated LC before fixation did not impair their function, suggesting that stimulatory activity by fixed incubated LC did not merely reflect a repair of LC membrane after trypsin trauma suffered during epidermal cell (EC) isolation. More interestingly, we found that addition of interferon-y during LC incubation mediated an enhanced allostimulatory activity by the PF-fixed LC. Acquisition of allostimulatory property by in vitro activated and fixed LC did not correlate with increased MHC class II Ag expression at the cell surface. By contrast, we showed that ICAM-1 Ag expression by human LC is involved in this maturation process. Finally, we found that once human LC have been activated, IL-1β but not IL-6, could serve as a costimulatory factor in the primary allogeneic T cell response. In conclusion, the data suggest that human LC accessory function is not constitutive but requires an activation step which can be provided by interferon-y during LC-T cell interaction.     

Genotypic analysis of pulmonary Langerhans cell histiocytosis

Reported studies show that the systemic form of Langerhans cell histiocytosis (LCH) is a clonal expansion of Langerhans cells (LC) associated with aberrant expression of several oncogenes or tumor-suppressor genes. LCH of the lung is a heterogenous group of lesions thought to be a reactive rather than neoplastic process. The histogenesis of the LCH of the lung is uncertain, and to date there are no studies investigating its underlying molecular abnormalities. We performed comparative genotypic analysis by using allelic loss (LOH) of polymorphic microsatellite markers associated with tumor suppressor genes. Fourteen cases of formalin-fixed, paraffin-embedded LCH of the lung were studied. Microdissection of a total of 26 nodules from 14 patients and paired reference lung tissue was performed under stereomicroscopic visualization. To evaluate allelic loss, we used a panel of 11 polymorphic microsatellite markers that were situated at or near tumor suppressor genes on chromosomes 1p, 1q, 3p, 5p, 9p, 17p, and 22q. The PCR products were analyzed by using capillary electrophoresis to identify germline heterozygous alleles and LOH. Allelic loss at 1 or more tumor suppressor gene loci was identified in 19 of 24 nodules. The total fractional allelic loss (FAL) ranged from 6% (1q) to 41% (22q), with a mean of 22%. The FAL in individual cases ranged from 0 (7 nodules) to 57% (1 nodule). Fifteen discordant allelic losses at 1 to 3 chromosomal loci were identified in 8 patients with multiple synchronous nodules. Our results show that LOH of tumor suppressor genes is present in the LCH of the lung, and they indicate that the putative tumor suppressor genes situated on chromosomes 9p and 22q may play a role in the development of a subset of the LCH of the lung.     

Coated Langerhans cell granules in histiocytosis X cells

Histiocytosis X cells (HXC) and epidermal Langerhans cells (LC) are thought to be closely related because they share morphologic features and immunologic markers. One of these common markers, the LC granule, is an acknowledged morphologic criterion for the identification of these cell types, but its function and, thus, significance are as yet unknown. In this study, we report the presence of a fuzzy coat radiating from the cytoplasmic face of the LC granule membrane in HXC. This bristly coat is indistinguishable from that of coated vesicles and pits and, thus, represents a strong morphologic clue to the function of LC granules because coated structures have been shown to be involved in the selective transport of molecules in eukaryotic cells.     

Gene expression analysis of dendritic/Langerhans cells and Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a neoplastic disorder that results in clonal proliferation of cells with a Langerhans cell (LC) phenotype. The pathogenesis of LCH is still poorly understood. In the present study, serial analysis of gene expression (SAGE) was applied to LCs generated from umbilical cord blood CD34+ progenitor cells to identify LC-specific genes and the expression of these genes in LCH was investigated. Besides the expression of several genes known to be highly expressed in LCs and LCH such as CD1a, LYZ, and CD207, high expression of genes not previously reported to be expressed in LCs, such as GSN, MMP12, CCL17, and CCL22, was also identified. Further analysis of these genes by quantitative RT-PCR revealed high expression of FSCN1 and GSN in all 12 LCH cases analysed; of CD207, MMP12, CCL22, and CD1a in the majority of these cases; and CCL17 in three of the 12 cases. Immunohistochemistry confirmed protein expression in the majority of cases. The expression of MMP12 was most abundant in multi-system LCH, which is the LCH type with the worst prognosis. This suggests that expression of MMP12 may play a role in the progression of LCH. These data reveal new insight into the pathology of LCH and provide new starting points for further investigation of this clonal proliferative disorder.     

Epithelial plasma cell granuloma-like tumors of the lungs. A hitherto unrecognized tumor

We present two cases of benign pulmonary epithelial tumors located in the middle lobes of the lungs. The patients were women of 56 and 36 years of age. The tumors were morphologically similar to plasma cell granuloma. At the tumor periphery, the lesion cells formed thin organoid rows of cells and vague trabeculae, disclosing morphologically their epithelial nature. In addition, the tumors strongly stained immunohistochemically with antibodies to cytokeratins, TTF-1 and EMA, and they were negative for immunoglobulin kappa and lambda light chains. We are not aware of similar tumors described in the literature, and we suggest the name "epithelial plasma cell granuloma-like tumors" for these lesions.     

Pulmonary neuroendocrine carcinomas. A review of 234 cases and a statistical analysis of 50 cases treated at one institution using a simple clinicopathologic classification

CONTEXT: Primary pulmonary neuroendocrine tumors are traditionally classified into 3 major types: typical carcinoid (TC), atypical carcinoid (AC), and large cell neuroendocrine carcinoma (LC) or small cell neuroendocrine carcinoma (SC). Confusion arises frequently regarding the malignant nature of TC and the morphologic differentiation between AC and LC or SC. OBJECTIVE: To provide clinicopathologic evidence to streamline and clarify the histomorphologic criteria for this group of tumors, emphasizing the prognostic implications. PATIENTS: To minimize variability in diagnostic criteria and treatment plans, we analyzed a group of patients whose diagnosis and treatment occurred at a single institution. We reviewed 234 cases of primary pulmonary neuroendocrine tumors and thoroughly studied 50 cases of resected tumors from 1986 to 1995. RESULTS: On the basis of morphologic characteristics and biologic behaviors of the tumors, we agree with many previous investigators that these tumors are all malignant and potentially aggressive. Based on our accumulated data, we have modified Gould criteria and reclassified these tumors into 5 types: (1) well-differentiated neuroendocrine carcinoma (otherwise called TC) (14 cases, with less than 1 mitosis per 10 high-power fields [HPF] with or without minimal necrosis); (2) moderately differentiated neuroendocrine carcinoma (otherwise called low-grade AC) (6 cases, with less than 10 mitoses per 10 HPF and necrosis evident at high magnification); (3) poorly differentiated neuroendocrine carcinoma (otherwise called high-grade AC) (10 cases, with more than 10 mitoses per 10 HPF and necrosis evident at low-power magnification); (4) undifferentiated LC (5 cases, with more than 30 mitoses per 10 HPF and marked necrosis); and (5) undifferentiated SC (15 cases, with more than 30 mitoses per 10 HPF and marked necrosis). The 5-year survival rates were 93%, 83%, 70%, 60%, and 40% for well, moderately, and poorly differentiated, and undifferentiated large cell and small cell neuroendocrine carcinomas, respectively. We found nodal metastasis in 28% of TC in this retrospective review, a figure higher than previously recorded. CONCLUSION: Using a grading system and terms comparable to those used for many years and used for neuroendocrine tumors elsewhere in the body, we found that classification of pulmonary neuroendocrine carcinomas as well, moderately, poorly differentiated, or undifferentiated provides prognostic information and avoids misleading terms and concepts. This facilitates communication between pathologists and clinicians and thereby improves diagnosis and management of the patient.     

Low-dose UVB radiation perturbs the functional expression of B7.1 and B7.2 co-stimulatory molecules on human Langerhans cells

In previous studies, we have shown that ultraviolet (UV) B radiation perturbs the APC function of Langerhans cells (LC) by interfering with as-yet unidentified co-stimulatory signals. Recently, B7.1 and B7.2 on APC were shown to deliver important co-stimulatory signals through interaction with their counterreceptors CD28 and CTLA-4 on T cells. To determine whether UVB affects the functional expression of B7.1 or B7.2 on LC, B7.1 and B7.2 expression was studied on human LC by multiparameter flow cytometry. Little, if any, B7.1 or B7.2 was detected on LC freshly isolated from skin. However, following 48 h of tissue culture, expression of both B7.1 and B7.2 were markedly up-regulated. To test whether these molecules were functional, primary mixed epidermal cell leukocyte reactions (MECLR) were performed. Blocking monoclonal antibody (mAb) to B7.1 or B7.2 both inhibited the MECLR, with anti-B7.2 being much more effective than anti-B7.1. UVB radiation dose-dependently (100–200 J/m²) suppressed the culture-induced up-regulation of B7.1 and B7.2 on LC. Since LC exposed to the same UVB flux (UVB-LC) failed to stimulate alloreactive T cells in a MECLR, we questioned whether this was related to their inability to provide B7 co-stimulation. Indeed, when effective B7-CD28 signaling was ascertained by adding submitogenic doses of exogenous anti-CD28 mAb to UVB-LC, the proliferative response of alloreactive T cells was restored. We conclude that the suppressive effects of low-dose UVB radiation on the APC function of LC are, at least in part, due to an inhibition of functional B7.1 and B7.2 expression.     

Cytological features of basal cell adenocarcinoma of the salivary glands

The cytological features of basal cell adenocarcinoma (BAC) of the salivary gland, a rare carcinoma, have not been well described. This study included patients who were histopathologically diagnosed with BAC and who underwent preoperative fine‐needle aspiration cytological examination. Cytological characteristics, including background, arrangement and shape of the neoplastic cells, nuclear and cytoplasmic features, and presence of stromal spindle cells, were reviewed. Seven patients were enrolled in the study. The cytological specimens were cellular and composed of large or small clusters with occasional discohesive neoplastic cells at the periphery. The predominant cellular morphology was spindle‐shaped in four cases, and small round‐shaped in three cases. These neoplastic cells were tightly packed, showed high cellularity and overlapping nuclei, and had mildly to moderately enlarged round to oval nuclei with occasional small nucleoli and scant cytoplasm. Stromal spindle cells were observed around the basaloid cells in three cases (42.9%). All histology‐proven stromal spindle cell‐positive cases had stromal spindle cells in the cytological specimens. The study findings clearly demonstrate the relatively high frequency of stromal spindle cells in cytological specimens of BAC. This finding is characteristic of BAC, although basal cell adenoma of salivary gland frequently has stromal spindle cells in the cytological specimens. The characteristic that differentiates BAC from basal cell adenoma is the presence of tightly packed and high cellular clusters with discohesive neoplastic cells. An understanding of these cytological features can aid the cytodiagnosis of BAC.     

Immunocytochemical investigation of Langerin (CD207) is a valuable adjunct in the cytological diagnosis of Langerhans cell histiocytosis of the thyroid

Langerhans cell histiocytosis (LCH) is an uncommon disease encompassing three clinically different entities: eosinophilic granuloma, Hand-Schüller-Christian disease, and Abt-Letterer-Siewe disease. Despite usually being a multisystemic disease affecting numerous different organs, involvement of the thyroid gland is extremely rare, and only a few cases in adults have been described in the literature. Herein, we present the case of a 28-year-old male patient presenting with LCH involving the skin, the skeletal system, and the thyroid gland. Fine needle aspiration (FNA) of the thyroid was performed and showed the typical Langerhans cells (LC) with foamy cytoplasm and slender nuclei with longitudinal grooves against a background of inflammatory cells with only a few eosinophilic granulocytes. Immunocytochemically, the LC showed positive staining with antibodies against CD1a and Langerin, a recently detected glycoprotein exclusively expressed in LC. Langerin is the major protein that makes up the so-called Birbeck granules, the electronmicroscopical hallmark of LC. Since LCH involvement of the thyroid is occasionally mistaken for papillary thyroid carcinoma cells, we propose that application of Langerin in combination with CD1a is a helpful diagnostic adjunct for the correct assessment of LCH affecting the thyroid gland.     

Ⅲ期鼻咽癌免疫细胞反应与生物学行为及预后的关系

目的 探讨４３例Ⅲ期鼻咽癌Ｔ,Ｂ淋巴细胞,巨噬细胞及郎格汉斯细胞的浸润反应与其生物学行为及预后的关系。方法 应用免疫组化ＳＰ法对４３例Ⅲ期鼻咽癌免疫细胞反应与生物学行为及预后的关系进行分析,结果 ４３例Ⅲ期鼻咽癌郎格汉斯细胞及巨噬细胞浸润阳性表达率分别为６０％（２６例）,７２％（３１例,ＣＤ６８阳性）,５１％（２２例,溶菌酶阳性）,它们均与患者的５年生存率呈正相关（Ｐ〈０．００５和Ｐ〈０．０５）     

Transforming growth factor-beta produced by progressor tumors inhibits, while IL-10 produced by regressor tumors enhances, Langerhans cell migration from skin

The induction of epidermal immunity depends on activation of local dendritic cells (DC), Langerhans cells (LC), to migrate from the skin to local lymph nodes and mature into potent immunostimulatory cells. We have previously shown that progressor skin tumors, which evade immunological destruction, prevent contact sensitizer-induced LC migration from the skin to draining lymph nodes. In contrast, regressor tumors, which evoke protective immunity, did not inhibit DC mobilization. In this study we utilized the skin explant model to determine the factors produced by skin tumors which regulate LC migration from the skin. Supernatants from two progressor squamous cell carcinoma lines both inhibited LC migration, whereas supernatants from two regressor squamous cell carcinoma lines both enhanced LC mobilization. Transforming growth factor (TGF)-beta1 inhibited, while IL-10 enhanced, LC migration from cultured skin. Both reduced the ability of LC to mature into potent allostimulators. Antibody neutralization identified that TGF-beta1 produced by the progressor tumor was responsible for inhibition of LC migration, while IL-10 produced by the regressor tumor enhanced LC mobilization. Thus these studies show that skin tumors influence DC mobilization from tumors by production of cytokines, and that TGF-beta1 is one factor produced by tumors which can immobilize LC and keep them in an immature form. This is likely to be an important mechanism of tumor escape from the immune system as progressor tumors inhibited, while regressor tumors enhanced DC mobilization.