Summary CD1A is a cell surface protein expressed on Langerhans cells and cortical thymocytes that could potentially be used as an immunotherapeutic target in Langerhans Cell Histiocytosis (LCH), the cortical subtype of T‐cell acute lymphocytic leukaemia (T‐ALL) and other CD1A‐positive tumours. The monoclonal antibody (mAb) CR2113 was selected from a panel of six fully human mAbs isolated from a semi‐synthetic phage display library, based on specificity and avidity against cells expressing CD1 antigen variants. CR2113 recognized CD1A in T‐ALL cell lines and patient samples. Confocal microscopy revealed that the CR2113‐CD1A complex was internalized at 37°C. Furthermore, while CR2113 induced moderate complement‐dependent cytotoxicity (CDC), potent antibody‐dependent cell cytotoxicity (ADCC) activity was observed against CD1A expressing cell lines as well as T‐ALL cell lines and T‐ALL patient samples. In vivo experiments showed that CR2113 as a naked antibody has modest but specific anti‐tumour activity against CD1A‐expressing tumours. CR2113 is a high‐affinity human anti‐CD1A mAb with significant ADCC activity. These properties make CR2113 a candidate for clinical diagnostic imaging and therapeutic targeting of LCH as well as potential use in other clinical applications.
SummaryLangerhans cell histiocytosis (LCH) is a clonal, proliferative disorder of phenotypically immature CD1a + Langerhans cells (LC). The aetiology of LCH is unknown and data supporting an immune dysregulatory disorder as well as a clonal neoplasm have been reported. Telomere shortening has been associated with cancers and premalignant lesions as well as promoting chromosomal instability. To determine whether LCH LC have altered telomere lengths, we used dual detection of CD1a expression by immunofluorescence and telomere length by fluorescence in situ hybridization of LCH LC and lymphocytes in local, multisystem and systemic LCH and compared these with telomere lengths of LC and lymphocytes in reactive lymph nodes. LCH LC showed significantly shorter telomere lengths than LC from reactive lymph nodes or unaffected skin. Lymphocyte telomere lengths showed similar profiles among the different samples. These data show a significant telomere shortening in LCH LC in all stages of disease involvement compared with LC from reactive lymph nodes, suggesting that LCH may share mechanisms of telomere shortening and survival with clonal preneoplastic disorders and cancer, although an initiating infectious or immune event is still possible.
Neoplastic diseases of macrophages (M phi) and dendritic cells (DC), collectively called histiocytoses, are relatively rare. The etiology of most forms of histiocytosis is poorly understood, and the development of animal models is crucial for further research in this field. Previously, an animal model for malignant histiocytosis (MH), involving transformed histiocytic cells, has been generated by infecting mice with malignant histiocytosis sarcoma virus (MHSV). However, increased insight into the heterogeneity of M phi and DC, and the associated reappraisal of human proliferative diseases involving these cells inspired us to re-evaluate the mouse model. We analyzed spleen, bone marrow, and lymph nodes of susceptible mice at various time points after infection. From day 11 onwards, a heterogeneous population of cells, consisting of CD8 alpha(+) Langerin(+) DC, ER-MP58(+) CD11b(+) myeloid precursor cells, CD169(+) metallophilic M phi, and CD71(hi) erythroblasts, was affected by viral transformation. In different mice, these subsets expanded at different rates in different organs, causing a variable disease profile in terminal stages. Cell lines, which were generated from MHSV-transformed tumors, showed a DC-like morphology and phenotype, and appeared to be arrested in different stages of maturation. Upon injection into healthy mice, different preferential homing patterns were observed for the various cell lines, and the cells acquired distinct phenotypes depending on the organ of homing. This indicates that these transformed cells adapt to their microenvironment by switching between precursor, DC/Langerhans cell, and M phi phenotypes. Our results demonstrate that the MHSV model represents a heterogeneous neoplastic disease with characteristics of M phi/DC sarcomas.
Langerhans Cell Histiocytosis (LCH) is characterized by the clonal proliferative of immature Langerhans cells resulting in a disorder with a wide variety of clinical manifestations and outcomes. Current therapies are based on the use of chemotherapeutic and immunosuppressive agents, usually in combination. Treatments are relatively non-specific, associated with significant adverse side effects and are ineffective in a significant number of patients. More effective and less toxic treatments are therefore needed. The selective expression of the nonclassical MHC protein, CD1a, on the lesional Langerhans cells in LCH makes this antigen an excellent immunotherapeutic target. To this end, we have generated a completely human monoclonal antibody (Mab) that specifically binds to a native, external epitope of CD1a using a human spleen phage display library. Epitope binding regions were selected for recognition of external domains of native CD1a and sequences showing specific binding were cloned into a human IgG1 backbone. The anti-CD1a Mab, termed 2113, shows high affinity and specificity for CD1a and is internalized after binding to the surface of CD1a expressing cells. The 2113 Mab also demonstrates significant complement dependent lysis (CDC) and antibody dependent cell cytotoxicity (ADCC) against CD1a expressing cells. No direct antibody mediated apoptosis was observed for 2113 binding to CD1a. A preclinical murine CD1a positive tumor model is being used to test the 2113 Mab for selective localization and tumor cytotoxicity. This Mab should provide an excellent reagent for therapeutic targeting of LCH and CD1a positive hematologic malignancies as well as possibly having application in the treatment of autoimmune disorders, prevention of graft-versus-host disease and augmenting cancer vaccines through direct antigen delivery to Langerhans cells.
The purpose of this study was to analyze telomere lengths in Langerhans Cell Histiocytosis (LCH). LCH is a clonally derived, proliferative disorder of phenotypically immature CD1a+ Langerhans cells (LCs). The etiology of LCH is unknown and data supporting an immune dysregulatory disorder as well as a clonal neoplasm have been reported. Telomere shortening has been associated with cancers and premalignant lesions as well as being important in promoting chromosomal instability. We therefore conducted a study to quantitatively determine the telomere lengths in LCH. Tissue arrays of reactive lymph nodes, local, multisystem, and systemic LCH containing 9, 7, 12, and 10 specimens respectively were used. These tissue arrays included 2 specimens that had unaffected skin represented, providing an opportunity to examine non-pathologic LCs. The tissue arrays were first hybridized with a N-terminal covalently linked Cy3-labeled, telomere specific peptide nucleic acid (PNA) probe to stain telomeres. The slides were then processed for indirect immunofluorescence to identify LCs using an anti-CD1a primary antibody followed by an anti-mouse IgG fraction Alexa Fluor 488. Finally, slides were counterstained with 4′-6-diamidino-2-phenylindole (DAPI). Digital fluorescent telomere signals were visualized using a Nikon Eclipse E400 epifluorescence microscope and telomere lengths were analyzed with ImageJ software. A total of 1039 measurements were made from 38 individuals. A significant shortening of telomeres was demonstrated in LCH LCs of local, multisystem and systemic LCH in comparison to telomere lengths of reactive lymph node LCs and normal skin, which were not significantly different. To investigate whether telomere length shortening of LCH LCs is selective, we analyzed the telomere length in lymphocytes in LCH specimens and in the reactive lymph node specimens. There was no significant evidence of telomere shortening of lymphocytes in LCH compared to lymphocytes in reactive lymph nodes (p=0.1862). These data show significant telomere shortening in the LCs in all stages of disease involvement with more variability among local cases. These observations suggest that in most cases LCH may share important mechanisms of telomere shortening and survival with clonal pre-neoplastic disorders and cancer.
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