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PubMed1999

Antibody therapy for treatment of multiple myeloma.

Monoclonal antibody therapy has emerged as a viable treatment option for patients with lymphoma and some leukemias. It is now beginning to be investigated for treatment of multiple myeloma. There are relatively few surface antigens on the plasma cells that are suitable for antibody-directed treatment. Possible molecules include HM1.24, CD38, ICAM-1 (CD54), CD40, CD45, CD20, and syndecan 1. There is now some clinical experience with anti-CD38 antibody in lymphoma and myeloma. However, to date, there has been minimal clinical activity observed. Additional antibodies are entering clinical trials. A new approach involves the generation of an anti-CD38 single-chain variable fragment (scFv) construct that acts as the carrier of a toxin gene instead of being conjugated directly to the toxin itself. It is hoped that expression of the toxin by CD38+ plasma cells will promote suicide of the malignant cells without affecting normal cells or generating an immunologic response to the toxin. Ongoing clinical trials are also attempting to target B-cell antigens such as CD20. Although CD20 is present only on 20% of myeloma cells, it may be present on myeloma precursor cells. This treatment has met with success in follicular lymphoma and is now being evaluated in clinical trials in both Europe and the United States for myeloma. Although these clinical trials are in very early stages, researchers are beginning to understand that antibody therapy can be used not only as a carrier molecule of radioisotopes and toxins, but also as molecules that can trigger tumor cells and promote growth arrest or apoptosis.

Antibodies, Monoclonal↗
PubMed2006

Human nasal polyp microenvironment maintained in viable and functional states as xenografts in SCID mice.

OBJECTIVES: We undertook to maintain human nasal polyp tissue in a viable and functional state in SCID (severe combined immunodeficiency) mice. METHODS: Small, nondisrupted pieces of human nasal polyp tissues were subcutaneously implanted into SCID mice depleted of natural killer cells. The resulting xenografts were examined histologically, and the sera were evaluated for the presence of human protein. RESULTS: The original histologic architecture of the polyp was maintained in the xenografts. The tissues, including pseudostratified columnar epithelial-lined polyps and subepithelial stroma, remained viable, and goblet cells continued to produce mucin for up to 26 weeks after engraftment. Human inflammatory leukocytes, including CD3+ T cells, CD20+ B cells, CD138+ plasma cells, and CD68+ monocytes and/or macrophages, were present. Identification of human immunoglobulin and human interferon-gamma in the sera of xenograft-bearing mice indicated that the B cells or plasma cells and T cells within the xenografts remained functional for 2 weeks after engraftment. CONCLUSIONS: The ability to engraft and maintain nasal polyps provides an in vivo human/mouse chimeric model with which to investigate the role of inflammatory leukocytes and stromal cells in the maintenance and progression of polyposis and to determine how exogenous cytokines may alter the interaction of inflammatory cells, stromal cells, and epithelial cells in the polyp.

Animals↗
PubMed1999

Efficacy of an anti-CD138 immunotoxin and doxorubicin on drug-resistant and drug-sensitive myeloma cells.

Multidrug resistance is an increasing problem in the treatment of cancer. We evaluated in vitro the effect of an anti-CD138 plasma-cell-specific immunotoxin (IT, B-B4-SO6) in combination with the chemotherapeutic drug doxorubicin on drug-sensitive and drug-resistant variants of the multiple-myeloma (MM)-derived cell line RPMI8226 and freshly isolated malignant-myeloma cells. Drug-resistant RPMI8226 cells were still sensitive to the IT, although to a lesser extent than drug-sensitive cells. In the clonogenic assay, using 10 nM B-B4-SO6, at least 5 logs kill was found for drug-sensitive RPMI8226 cells, vs. 2.5 logs kill for the drug-resistant RPMI8226 cells. When a sub-optimal dose of 1 nM IT was combined with 3 ng/ml doxorubicin, which was toxic for drug-sensitive but not for drug-resistant cells, an additive effect was found for drug-sensitive RPMI8226 cells. The IT did not influence the sensitivity of resistant cells for doxorubicin. We therefore speculate that this type of IT, may be of more value in combination with primary chemotherapy. The effect of B-B4-SO6 on malignant-myeloma cells of patients was investigated in a viability assay. Both drug-sensitive and drug-resistant cells from MM patients were sensitive to B-B4-SO6. After 2 days, a 50% kill of malignant cells was found when 10 nM IT were used. Doxorubicin was effective only on sensitive cells, and there was a tendency for an additive effect in the combination of these cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Ultraviolet-induced detection of halogenated pyrimidines: simultaneous analysis of DNA replication and cellular markers.

BACKGROUND: We describe a new nonenzymatic methodology that allows the simultaneous detection of DNA replication and other cellular markers such as immunophenotyping. DNA replicating cells are identified by their incorporation of halogenated thymidine analogs, e.g., 5-bromo-deoxyuridine (BrdUrd). METHODS: Irradiation with ultraviolet (UV)-B or UV-A light in the presence of Hoechst 33258 and subsequent treatment with a hypotonic buffer makes BrdUrd accessible to monoclonal antibodies (mAb), thus allowing its sensitive detection. RESULTS: The photolysis of BrdUrd in DNA with UV light is sequence dependent and results in DNA damage, allowing the detection of remaining BrdUrd using hypotonic conditions. However, treatment with other inducers of single or double- strand breaks of DNA such as gamma irradiation or hydrogen peroxide did not allow BrdUrd detection. The new methodology is compatible with both mild crosslinking fixation, i.e., aldehydes, or coagulative fixation, i.e., alcohols. The successful identification of CD34+, CD138+, or CD19+ cells out of heterogeneous cell suspensions and their cell-cycle analysis are described. Results correlated very well with acid denaturation (r = 0.972). The average coefficient of variation (CV) of G(1) in the DNA histogram was smaller than 5%, resulting in good preservation of DNA distribution. Also, the signal-to-noise ratio was almost twice as high as for 2N acid denaturation, facilitating convenient discrimination of BrdUrd-positive cells. CONCLUSIONS: In contrast to previous approaches, this methodology eliminates the need for any additional enzymatic treatment such as DNA digestion or strand-break labeling after UV irradiation. The method is fast, convenient, and inexpensive and should be able to promote the use of halogenated pyrimidines in basic and clinical research of cancer, immunology, and pharmacology.

Antigens, CD19↗
PubMed2004

B-lymphocyte and plasma cell clonal expansion in monosymptomatic optic neuritis cerebrospinal fluid.

The CD19+ B-lymphocyte and CD138+ plasma cell repertoires in cerebrospinal fluid from four patients with monosymptomatic optic neuritis (ON) were analyzed by single-cell reverse transcriptase polymerase chain reaction. Amplified heavy (H)- and light (L)-chain antibody segments were sequenced and used to identify the rearranged germline and J segment of closest homology. Both the B-cell and plasma cell repertoires from ON cerebrospinal fluid demonstrated significant clonal expansion. Up to 75% of the amplified H- and L-chain sequences were contained in overrepresented populations and were somatically mutated, consistent with an antigen-targeted response. The relationship between clonal populations within the CD19+ B lymphocyte and CD138+ plasma cell populations suggests ongoing mutational pressure to refine antigen binding. Our observations demonstrate that an antigen-driven clonal B-lymphocyte and plasma cell response is prominent in the initial stages of central nervous system demyelination and suggest that detection of the disease-relevant antigens in ON may bear on the inciting antigens in chronic inflammatory disorders such as multiple sclerosis.

Amino Acid Sequence↗
PubMed2006

Morphologic and quantitative assessment of CD20+ B cell infiltrates in rheumatoid arthritis-associated nonspecific interstitial pneumonia and usual interstitial pneumonia.

OBJECTIVE: B lymphocytes are emerging as important elements in the events leading to joint destruction in rheumatoid arthritis (RA). However, B lymphocytes have not been studied in rheumatoid arthritis (RA)-associated lung disease. We performed a morphologic and quantitative analysis of B lymphocytes and plasma cells in RA-associated interstitial pneumonia (IP) in comparison with idiopathic IP and normal lungs. METHODS: Open-lung biopsy specimens from patients with RA-associated IP (n = 18), patients with idiopathic IP (n = 21), and control subjects (n = 11) were stained with antibodies to CD20 and CD138. Morphologic patterns of stained specimens were characterized and staining was quantified using computer-assisted image analysis. RESULTS: In RA-associated IP, marked follicular B cell hyperplasia was detected, which was limited almost entirely to peribronchiolar lymphoid aggregates. Plasma cells were also present in large numbers, but showed a more diffuse tissue infiltration. Quantification of B cells demonstrated higher cellularity in RA-associated IP (median 2.0%, interquartile range [IQR] 1.0-5.7) as compared with idiopathic IP (0.9%, IQR 0.5-2.1). Control specimens showed a significantly smaller number of B cells compared with both diseases (0.4%, IQR 0.1-1.3). In RA patients who were smokers and in those who were male, the proportion of CD20+ tissue areas further increased to 4.3% (IQR 1.0-5.8) and 3.9% (IQR 0.7-6.9), respectively. CONCLUSION: We demonstrated a significant follicular B cell hyperplasia in RA-associated IP. The differences between RA-associated IP and idiopathic IP imply a differential emphasis of B cell-mediated mechanisms in the 2 diseases despite radiologic and histologic similarities and provide a rationale for studying functional aspects of B cell involvement in the pathogenesis of RA-associated IP.

Adult↗
PubMed2006

CNS viral infection diverts homing of antibody-secreting cells from lymphoid organs to the CNS.

Neurotropic coronavirus infection of mice results in acute encephalomyelitis followed by viral persistence. Whereas cellular immunity controls acute infection, humoral immunity regulates central nervous system (CNS) persistence. Maintenance of serum Ab was correlated with tissue distribution of virus-specific Ab-secreting cells (ASC). Although virus-specific ASC declined in cervical lymph node and spleen after infectious virus clearance, virus-specific serum Ab was sustained at steady levels, with a delay in neutralizing Ab. Virus-specific ASC within the CNS peaked rapidly 1 wk after control of infectious virus and were retained throughout chronic infection, consistent with intrathecal Ab synthesis. Surprisingly, frequencies of ASC in the BM remained low and only increased gradually. Nevertheless, virus-specific ASC induced by peripheral infection localized to both spleen and BM. The data suggest that CNS infection provides strong stimuli to recruit ASC into the inflamed tissue through sustained up-regulation of the CXCR3 ligands CXCL9 and CXCL10. Irrespective of Ag deprivation, CNS retention of ASC coincided with elevated BAFF expression and ongoing differentiation of class II+ to class II-CD138+CD19+ plasmablasts. These results confirm the CNS as a major ASC-supporting environment, even after resolution of viral infection and in the absence of chronic ongoing inflammation.

Acute Disease↗
PubMedDate not supplied

Evidence of abortive plasma cell differentiation in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma.

Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) show genotypic features of germinal centre-derived B-cells in most cases. Nevertheless, these cells typically lack expression of B-cell antigens. Previous studies have suggested that plasma cell differentiation may occur in HRS cells and that this may account for the down-regulation of B-cell antigens. However, these results are controversial. We have addressed this question using immunohistochemistry and a panel of antibodies directed against antigens which are differentially expressed during terminal B-cell differentiation. Pax-5, a transcription factor required for B-lineage commitment, and IRF4/Mum1, which is physiologically expressed in germinal centre cells and plasma cells, were consistently detectable in HRS cells. Bcl-6, a transcription factor expressed in germinal centre B-cells, was present in HRS cells of approximately 25% of cHL cases. Expression of the B-lymphocyte-induced maturation protein-1 (Blimp-1), a key regulator of plasma cell differentiation, was observed in HRS cells of 23% of cHL cases. In these cases, Blimp-1 expression was restricted to a small proportion of HRS cells. HRS cells were consistently negative for the plasma cell marker CD138. These results suggest that plasma cell differentiation may be initiated in a small subset of HRS cells but remains abortive. Thus, terminal differentiation is unlikely to explain the lack of B-cell antigen expression in HRS cells.

Cell Transformation, Neoplastic↗
PubMed2002

Extranodal marginal zone B cell lymphomas of the uvea: an analysis of 13 cases.

The majority of primary lymphoproliferative lesions of the uvea represent low-grade B cell lymphomas and often display a prominent plasmacellular differentiation. The purpose of the current study was to classify the uveal lymphoproliferations according to the REAL classification; examine the immune profile of the plasmacellular differentiated tumour cells using the plasma cell-related antigens multiple myeloma oncogene-1-protein (MUM1), Vs38c, CD38 and CD138; and to compare this profile with that of mature reactive plasma cells. Following fixation, 13 lymphoproliferative lesions of the uvea were categorized on the basis of their morphology and immunophenotype according to the REAL classification. Included in the immunohistochemistry were B cell-specific activator protein (BSAP), MUM1, Vs38c, CD38 and CD138. Nested polymerase chain reaction (PCR) was also performed on DNA extracted from paraffin sections for the detection of gene rearrangements of the heavy immunoglobulin chain (IgH). All of the 13 uveal tract lymphoproliferative lesions represented malignant lymphoma of B cell non-Hodgkin type and could be diagnosed as 'extranodal marginal zone B cell lymphomas' (EMZL). The degree of plasmacellular differentiation varied between the tumours. In contrast to their non-plasmacytoid counterparts, the 'plasmacytoid' EMZL tumour cells were negative for the B cell markers CD20 and BSAP, and demonstrated heterogeneous positivity for the markers MUM1, Vs38c, CD38 and CD138. The most consistent marker was MUM1, being observed in all tumours. Co-expression of all plasma cell markers was observed in four (31%) uveal EMZL. Loss of CD138 expression was observed in six (46%) tumours, of Vs38c expression in five (38%) and of CD38 in one (7%) tumour. Although the diagnosis of malignant lymphoma was unequivocally based on morphological and immunophenotypical features, the molecular analysis was able to demonstrate clonal B cell populations in only one uveal EMZL. All uveal lymphoid proliferations investigated represented EMZL, with the corresponding morphology and immunophenotype as seen in EMZL in other extranodal locations. MUM1, followed by CD38 expression, were the most constant plasma cell antigens in the plasmacytoid EMZL tumour cells, with both Vs38c and CD138 positivity being lost in many tumours. Aberrant immune profiles of plasma cell-related antigens may be of help in the establishment of malignancy in uveal lymphoproliferative lesions, particularly where interpretation of light chain expression and/or PCR results is difficult.

ADP-ribosyl Cyclase↗
PubMed2005

PRDM1/Blimp-1 is expressed in human B-lymphocytes committed to the plasma cell lineage.

PRDM1/Blimp-1 (in human and mouse, respectively) has a central role in determining and shaping the secretory arm of mature B-cell differentiation. In this study, a mouse monoclonal antibody that recognizes PRDM1 was used to detail its distribution in normal human lymphoid tissue and in lymphoid neoplasms that correspond to different stages of B-cell differentiation. PRDM1 was expressed in germinal centre blasts that co-express Pax5, CD19, CD20, and CD10, but not BCL6 or MTA-3. Pax5 was downregulated and full plasma cell morphology and phenotype were acquired by PRDM1+, nuclear cREL-, pre-plasma cells upon exit from the germinal centre. Activated extrafollicular B-cells (CD30+, Pax5+) were largely PRDM1-. PRDM1 was also absent in tissue histiocytes and the majority of resting T-cells and S-100+ antigen-presenting cells. PRDM1 and CD138 were expressed simultaneously in human lymphomas with plasma cell differentiation, but not in marginal zone lymphomas or chronic lymphocytic leukaemias. A minority of diffuse large B-cell lymphomas expressed PRDM1 and Hodgkin lymphomas were largely PRDM1-. Infiltrating T-cells in PRDM1- B-cell lymphomas expressed PRDM1. In conclusion, PRDM1 staining is a reliable and informative assay to define plasma cell commitment and differentiation in human normal and neoplastic B-cell lineages.

Animals↗
PubMed2003

Tc-99m methoxyisobutylisonitrile bone marrow imaging for predicting the levels of myeloma cells in bone marrow in multiple myeloma: correlation with CD38/CD138 expressing myeloma cells.

The percentage of myeloma cells in bone marrow is subsequently an important index of disease in patients with multiple myeloma (MM). Bone marrow myeloma cells can be detected by strong CD38/CD138 positivity and light scatter characteristics using flow cytometry. The aim of the study was to evaluate the relationship between the degree of Tc-99m methoxyisobutylisonitrile (MIBI) uptake and the percentage of CD38/CD138 expressing myeloma cells in the bone marrow of patients with MM. A total of 15 patients with MM (mean age: 61.7+/-2.4 years; 7 F and 8 M) were included in the study. Tc-99m MIBI imaging was obtained 20 min after injection of 740 MBq Tc-99m MIBI. Planar spot images of the pelvis and thorax were acquired. The uptake of Tc-99m MIBI in the bone marrow was evaluated using a qualitative and also a semiquantitative scoring system for the bone marrow in areas that included the proximal femurs, anterior iliac crest, and sternum. In all patients, flow cytometry was performed for assessing the percentage of CD38/CD138 expressing myeloma cells in the bone marrow samples. There was a statistically significant positive correlation between the percentage of CD38/CD138 expressing plasma cells in bone marrow and both mean qualitative (r=0.689, p=0.005) and semiquantitative (r=0.669, p=0.006) results of Tc-99m MIBI uptake. In conclusion, our results indicate that increased Tc-99m MIBI uptake of bone marrow is related to the percentage of plasma cell infiltration of bone marrow. Tc-99m MIBI bone marrow imaging may be a useful tool for predicting the levels of myeloma cells in bone marrow of patients with MM.

ADP-ribosyl Cyclase↗
PubMed2001

Immunomagnetic enrichment of CD138 positive cells from weakly infiltrated myeloma patients samples enables the determination of the tumor clone specific IgH rearrangement.

In multiple myeloma, the polymerase chain reaction (PCR) of the Ig heavy chain with allele-specific oligonucleotide (ASO) primers is a common and well-described method of identifying the tumor clone in peripheral blood (PB), bone marrow (BM) or leukapheresis products (LA). A factor which is crucial to the detection of clonal Ig rearrangements lies in the 'purity' of the tumor tissue used for the consensus PCR. We describe the application of a method to enrich CD138 positive myeloma cells derived from weakly infiltrated PB-, BM- and LA-samples. These are subjected to immunomagnetic enrichment with the MACS system, using an CD138 antibody directly conjugated to magnetic beads to obtain an enriched tumor cell population and the subsequent amplification of tumor specific IgH rearrangements. We investigated 29 samples (ten PB, ten BM, nine LA) with a median myeloma cell content of 0.5%. The approach led to a median enrichment factor of 118. Tumor-specific rearrangements could be amplified reproducibly from samples containing less than 0.1% myeloma cells.

Consensus Sequence↗
PubMed2004

Expression of receptor activator of NF-kappaB ligand (RANKL) mRNA in human multiple myeloma cells.

PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and a result of excessive osteoclast activation. Recently, the receptor activator of NF-kappaB ligand (RANKL) was found to be the critical factor for osteoclastogenesis. Studies showed that myeloma cells induce RANKL expression in bone marrow stromal cells, but it remained a controversy whether myeloma cells directly express RANKL. METHODS: Therefore, we analyzed the expression of RANKL mRNA in freshly isolated CD138 positive plasma cells from patients with multiple myeloma and osteolytic bone lesions, using three different primer pairs against human RANKL. RESULTS: RANKL mRNA could be detected in bone marrow plasma cells from myeloma patients with osteolytic myeloma bone disease. CONCLUSIONS: These findings show that myeloma cells directly express RANKL and indicate that specific blockade of RANKL may be an effective treatment for myeloma bone disease.

Bone Marrow↗
PubMed2006

Plasmablastic lymphoma: a clinicopathologic correlation.

Plasmablastic lymphoma (PBL) is an uncommon, recently described B-cell-derived lymphoma that displays distinctive affinity for extranodal presentation in the oral cavity. Plasmablastic lymphoma is strongly associated with human immunodeficiency virus (HIV) infection, but has been reported in HIV-negative individuals. Plasmablastic lymphoma may be poorly recognized by pathologists, which is partly attributable to its relatively rare occurrence and unusual immunophenotype. Five cases of oral cavity lymphomas conforming to the current World Health Organization morphological criteria for PBL were retrieved from the consultation files at the Armed Forces Institute of Pathology. An immunohistochemical panel consisting of CD3, CD20, CD30, CD38, CD45RB, CD79a, CD138, Bcl-2, Bcl-6, Alk-1, Ki-67, EBV-LMP-1, and HHV8 was performed. All 5 cases were immunoreactive for CD38 and/or CD138, confirming plasma cell differentiation of the tumor cells. CD20 was immunoreactive in 1 case, and CD79a was positive in 2 cases. HHV8 and EBV-LMP-1 were nonreactive in all cases. Follow-up revealed only 1 patient alive with no evidence of disease. Our cases show that PBL is an aggressive type of B-cell lymphoma predominantly found in the oral cavity. Plasmablastic lymphoma is often associated with HIV infection.

ADP-ribosyl Cyclase 1↗
PubMed2006

Primary plasma cell leukemia: morphologic, immunophenotypic, and cytogenetic features of 4 cases treated with chemotherapy and stem cell transplantation.

Plasma cell leukemia (PCL) is a neoplastic disorder of plasma cells of which there are 2 forms, primary PCL and secondary PCL, the latter occurring in patients with a history of plasma cell myeloma. We describe 4 patients with primary PCL. In all cases, the bone marrow aspirate smears and biopsy specimens demonstrated a diffuse infiltrate of atypical plasma cells that were difficult to classify using morphologic criteria alone. Immunophenotypic studies showed that each case was positive for plasma cell-associated antigens (cytoplasmic immunoglobin, CD38, or CD138) and negative for CD20. Of 4 cases, 3 had complex karyotypes, including the t(11;14)(q13;q32) or del(11)(q13). Despite chemotherapy and the use of novel therapeutic agents and stem cell transplantation, all 4 patients had short survival.

ADP-ribosyl Cyclase 1↗
PubMed2006

Quantitative analysis of clonal bone marrow CD19+ B cells: use of B cell lineage trees to delineate their role in the pathogenesis of light chain amyloidosis.

Light chain amyloidosis (AL) is a bone marrow (BM) plasma cell neoplasia with systemic deposition of Ig light chain amyloid fibrils. Here, we report the identification of clonal CD19 B cells in the BM and the use of a novel mathematical algorithm to generate B cell lineage trees of the clonal CD19 B cells and CD138 plasma cells from the BM of AL patients to delineate the relationship between these two clonal populations. The CD19+ clonal B cells in the BM of AL patients related to the clonal plasma cells represent a pre-plasma cell precursor population. The B cell lineage trees from AL patients also show significant differences in clonal diversification and antigenic selection compared to clones from normal, healthy controls. These data provide a robust example of the use of graphical quantification methods in delineating the role of neoplastic precursors in the pathogenesis of hematopoietic malignancies.

Algorithms↗