Search PubMed⌕ Search

Biomedical subjects

G Moldenhauer

Publications and source records attributed to G Moldenhauer.

At least 91 records · Page 5Linked to original sources
PubMed1989

Expression of HLA-A, -B, -C, -DR, -DP, -DQ, and of HLA-D-associated invariant chain (Ii) in non-neoplastic mammary epithelium, fibroadenoma, adenoma, and carcinoma of the breast.

Non-neoplastic mammary gland, 20 benign tumors and 206 carcinomas of the breast were immunohistochemically examined for expression of HLA-A, -B, -C, HLA-DR, -DP, and -DQ molecules and the HLA-D associated invariant chain (Ii). In contrast to cells from benign lesions, tumor cells of 51.2% of carcinomas had an abnormally low content of HLA-A, -B, and -C determinants ranging from reduction of antigenic density per cell (28.8%) over an incomplete (15.6%) to complete loss of antigens (6.8%). Associated with lymphohistiocytic stromal infiltrates, HLA-D/Ii determinants were found to be induced in benign duct and acinar epithelium after the order Ii greater than or equal to HLA-DR greater than or equal to HLA-DP greater than or equal to HLA-DQ. These antigens were also expressed, mostly noncoordinately, in 55.5% of carcinomas, and in 98 cases according to the above order. In 28.6%, Ii expression clearly exceeded HLA-D antigen expression; conversely, 6.2% contained HLA-DR+/Ii- tumor cell subsets. In breast carcinoma, the association of reduced HLA-A, -B, and -C expression and a noninduction of HLA-DR was highly significant (P less than 0.0009), suggesting an abnormal signal acting down-regulating on the expression of both classes of antigens. Because the modality of HLA-A, -B, and -C and HLA-D/Ii expression correlated with neither tumor type nor grade, it might be an independent parameter.

Adenofibroma↗
PubMed1988

Role of the CD22 human B cell antigen in B cell triggering by anti-immunoglobulin.

As B cells mature during ontogeny the CD22 human differentiation Ag is exported from the cytoplasm onto the membrane. Surface expression is lost in terminal differentiation and after activation. In tonsils, CD22 is expressed on the surface of 60 to 80% of the dense B cells. Some IgM+ dense cells, however, and buoyant in vivo activated B cells are CD22-. This differential expression of CD22 and the finding that an anti-CD22 mAb augmented anti-Ig induced B cell proliferation suggested that CD22 may play a role in B cell activation. In this study we have found that CD22+ but not CD22- B cells could be triggered by anti-IgM or anti-IgD to have increased free intracellular calcium ([Ca2+]i). The presence of CD22 rather than of IgD seems to determine the ability of B cells to respond to anti-Ig with a [Ca2+]i flux. Also the proliferative response to anti-Ig or anti-Ig + B cell growth factor was restricted to the CD22+ population. Anti-CD22 mAb, although not inducing [Ca2+]i on their own after binding to B cells, did augment [Ca2+]i fluxes by anti-Ig when cross-linked. Together these results suggest that CD22 may regulate triggering of B cells through surface Ig perhaps by acting as a "bridge" to transmit an early signal into the cytoplasm.

Antibodies, Anti-Idiotypic↗
PubMed1988

The B cell-associated CD37 antigen (gp40-52). Structure and subcellular expression of an extensively glycosylated glycoprotein.

The human B lymphocyte-associated CD37 antigen (gp40-52) has been characterized by the monoclonal antibody HD28. The CD37 antigen is strongly expressed on surface immunoglobulin positive B lymphocytes and weakly on a subpopulation of T lymphocytes and myeloid cells. The total molecular mass of the antigen ranges from approximately 40 to 52 kDa in B cell-derived leukemias and malignant lymphomas as well as in normal and anti-mu/B cell growth factor-activated tonsillar B cells. The polydisperse nature of the electrophoretic pattern of the CD37 antigen was found to be due to a microheterogeneity in its carbohydrate moiety. Biochemical analysis showed that the CD37 antigen derived from B cell-lines BJAB and LICR-LON-HMy2 consists of a single chain protein core of approximately 25 kDa to which two N-linked, complex carbohydrate antennae of various length are bound. The glycosylation of the molecule comprises about 50% of the total molecular mass. The molecule does not contain O-linked carbohydrate chains. In contrast, the non-Hodgkin's lymphoma cell line, OCI.LY1, which is growth-dependent on human serum, carries a CD37 antigen with an additional carbohydrate chain resulting in a total molecular mass of approximately 40 to 64 kDa. At the electron microscopy level, this cell surface-expressed antigen was found to be associated with intracellular vesicles. The subcellular distribution of the CD37 antigen may reflect a function of this antigen both at the cell surface and in the cytoplasm. We found that, both due to its peculiar biochemical structure and its ultrastructural distribution, the CD37 antigen closely resembles the 46-kDa species of the mannose 6-phosphate receptor. The implications of this possible congruence for the function of the CD37 antigen are discussed.

Animals↗
PubMed1988

Complement-mediated cytolysis: quantification of B cell surface antigen molecules and role of cell cycle.

Complement (C')-mediated cytolysis is currently used for the purging of autografts in autologous bone marrow transplantation (ABMT). However, a number of factors influencing the efficiency of lysis remain to be explored. In this report, firstly using a Scatchard analysis, the number of surface antigen molecules for CD19 and CD20 on 3 B cell lines has been quantified. This demonstrated that with CD20 a higher number of antigen molecules was required as compared to CD19 to produce an equally effective cytolysis. Secondly, the role of cell cycle has been investigated: cytolysis was not affected by cell phase. Moreover, CD19- and CD20-deficient cells escaping lysis displayed no difference in cell phase and possessed an identical growth pattern as controls.

Antigens, CD19↗
PubMed1988

Reduction or loss of HLA-A,B,C antigens in colorectal carcinoma appears not to influence survival.

Primary colorectal carcinomas of an unselected group of 159 patients 126 of whom could be curatively resected were examined for the expression of MHC class I antigens with monoclonal antibody W6/32 directed against a non-polymorphic determinant of HLA-A,B,C heavy chain. One hundred and nine (68.6%) were found to express HLA-A,B,C antigens in normal quantities, 33 (20.8%) showed a substantial reduction in expression, while 17 (10%) lacked these antigens either completely or incompletely. The loss of HLA-A,B,C was inversely correlated with the degree of differentiation. The tendency of mucinous carcinomas to lack class I antigens was statistically not significant. Tumours with distant metastatic spread at the time of operation tended to be normal with respect to HLA-A,B,C expression. Within the curatively resected group, poor differentiation and mucus production were risk factors for survival as could be shown by life table analysis after a maximum follow-up of 39 months. In contrast, the mode of HLA-A,B,C expression of the primary tumour did not influence survival within this time of observation. We conclude that in spite of increasing experimental data suggesting the contrary, the presence or absence of MHC class I antigens does not seem to profoundly modify tumour biology, at least in human colorectal carcinoma.

Adenocarcinoma↗
PubMed1988

B-cell proliferative and differentiative responses after autologous peripheral blood stem cell or bone marrow transplantation.

In this study the authors have evaluated B-cell function after autologous peripheral-blood stem cell transplantation (ABSCT) and autologous bone marrow (ABMT) transplantation. The B-enriched fractions of peripheral blood from ten normal subjects and 22 autografted patients (11 patients after ABMT, eight patients after ABSCT, and three patients after ABSCT followed by ABMT) were investigated. Time postgrafting ranged from 1 to 34 months. Proliferative responses to anti-mu antibody, Staphylococcus aureus Cowan 1 (SAC), and low molecular weight (mol wt) 12-Kd B-cell growth factor (BCGF) were measured. Differentiative responses to the same factors were assessed by quantifying in vitro immunoglobulin (IgG/IgM) production. The authors found no difference in B-cell function between the ABMT and the ABSCT patient groups. Compared to the B cells of normal subjects, only five out of 22 autografted patients showed a normal proliferative response to all agents used, while nine out of 22 did not respond to any signals. Eight out of 22 patients displayed various defects of B-cell response. However, in vitro IgG/IgM secretion of predominantly IgG subclass was normal in 19 out of 22 patients. This in vitro ability to produce Ig was reflected by the patients' normal serum IgG/IgM levels, whereas serum IgA levels were low. The authors speculate that there may be 2 B-cell populations: the normal in vitro Ig production and in vivo serum IgG may come from the stimulation of a small number of re-infused pre-committed memory B cells while, in parallel, immature B cells develop from autografted hematopoietic progenitor cells.

Adult↗
PubMed1988

Functional evaluation of CD19- and CD22-negative variants of B-lymphoid cell lines.

By co-cultivating lymphoid B-cell lines with ricin-A conjugates of CD19 and CD22 monoclonal antibodies, we generated cell line variants that selectively lacked CD19 or CD22 antigens. The expression of other B-cell antigens was not affected by the treatment. Loss of the CD19 antigen did not result in alterations in growth ability of the cells, while CD22-negative variants had an impaired colony formation ability, as detected by a sensitive clonogenic assay. Cell cycling properties of both CD19- and CD22-negative variant lines did not differ from those of parental lines. These results are in line with previous observations that correlate the presence of CD22 antigens on the membrane with the ability of B cells to proliferate. Besides inducing the loss of cell surface reactivity, CD22-ricin-A treatment induced also the loss of CD22 intracytoplasmic expression. The antigen-negative cell lines restored their original phenotype in 20-40 days after discontinuing co-cultivation with ricin-A conjugates. With the return of CD22 positivity, cells recovered their colony-formation ability. These results further underline the importance of CD22 in regulating the growth of B cells.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1987

The influence of major histocompatibility complex class I antigens on tumor growth and metastasis.

The work described here demonstrates the importance of major histocompatibility complex class I antigens for the control of tumor growth and metastasis by the host's immune system. In certain murine tumor cells which have lost expression of H-2 class I antigens, a de novo expression of H-2 can be achieved by transfection with syngeneic class I genes. In contrast to the parental cells the transfected tumors do not grow any more in syngeneic mice, or in other cases they do not form metastases. The studies suggest that the de novo expression of the H-2 antigens renders the tumors highly immunogenic and leads to effective recognition of a tumor-associated antigen in conjunction with the transfected H-2 antigen. These conclusions were confirmed in other tumor systems. For example, separation of a heterogeneous tumor into clones expressing high or low amounts of H-2 showed that only the tumor cell with low H-2 grew well in syngeneic mice, whereas the H-2 high tumor clones were rejected. In other studies in vitro induction by IFN-gamma of H-2 antigen on H-2 negative tumors led to reduced tumor growth in vivo which was due to the increased immunogenicity. About 10% of human tumors are also low or defective for HLA class I expression and often these tumors appear to be more malignant. The class I negative tumors could either have arisen from class I low or negative tissues or are HLA loss variants which escaped the attack of the immune system. Altogether, our studies and the data of other laboratories demonstrate the important role of class I antigens for anti-tumor immunity and they suggest that modulation of class I expression by gene transfection or by induction with soluble mediators could be a useful tool for the manipulation of tumor immunity.

Animals↗
PubMed1987

B-cell lymphomas of high-grade malignancy frequently lack HLA-DR, -DP and -DQ antigens and associated invariant chain.

The expression of HLA-DR, HLA-DP and HLA-DQ antigens was studied in an unselected series of 66 B-cell lymphomas by means of immunohistology using monoclonal antibodies against non-polymorphic determinants in a sensitive immunoperoxidase technique. In addition, the expression of the MHC class-II antigen-associated invariant chain (li) was examined. The tumors were classified according to the Kiel classification, 30 being of high-grade and 36 being of low-grade malignancy. Only 6 lymphomas of high-grade and 16 lymphomas of low-grade malignancy showed coordinate strong expression of all HLA class-II antigens and invariant chain as observed in the normal peripheral B cell. Six further tumors of high-grade and 8 tumors of low-grade malignancy contained tumor-cell subsets with reduced expression of one or several of the antigens. Eighteen lymphomas of high-grade and 12 lymphomas of low-grade malignancy contained varying tumor-cell subsets that were negative for HLA-DR, -DP, -DQ and li in a selective or combined manner. Three highly malignant tumors were devoid of all class-II antigens and li; 2 highly malignant tumors expressed invariant chain only. The presence of high-grade malignancy was significantly correlated with the occurrence of tumor cells lacking HLA-DR (p = 0.004), HLA-DP (p = 0.013), HLA-DQ (p = 0.007) or li (p = 0.024).

B-Lymphocytes↗
PubMed1987

Defective expression of MHC class I antigens is frequent in B-cell lymphomas of high-grade malignancy.

An unselected series of 66 immunohistologically proven B-cell lymphomas was examined for the expression of MHC class I antigens with monoclonal antibodies directed against non-polymorphic determinants of HLA-A,B,C heavy chain and beta 2-microglobulin. The tumors were classified according to the Kiel classification. No significant differences were observed in the reaction for HLA-A,B,C and beta 2m which may be indicative of a coordinate expression in our lymphoma series. In 37 cases (56%), all tumor cells exhibited strong staining for class I antigens as observed in normal B cells. The remaining 29 cases (44%) showed abnormally low or undetectable class I expression in varying tumor cell subsets; 13 cases were completely devoid of HLA-A,B,C. Twenty-two out of 30 lymphomas of high-grade malignancy but only 7/36 lymphomas of low-grade malignancy presented defective class I expression. This difference in proportion is highly significant (p less than 0.00002). Eleven of the 13 class I-negative lymphomas belonged to the group of high-grade malignancy. Centrocytic lymphoma, which has the poorest prognosis among the B-cell lymphomas of low-grade malignancy, was defective in 40% of the cases examined. The lymphoblastic type represented an exception within the lymphomas of high-grade malignancy as no defective expression was observed. In addition to the correlation between the high-grade malignancy and defective class I expression, defects occurred more frequently in lymphomas with an extra-nodal primary manifestation (p less than 0.05). The grade of malignancy, however, was not correlated with the primary site of the lymphoma.

Antibodies, Monoclonal↗
PubMed1987

Immunohistochemical study of the expression of a Mr 34,000 human epithelium-specific surface glycoprotein in normal and malignant tissues.

Monoclonal antibody HEA125 was used to study the tissue distribution of an epithelial cell surface glycoprotein of Mr 34,000 (Egp34). A large panel of normal and neoplastic tissues was examined for immunoreactivity with HEA125 by means of a sensitive immunoperoxidase technique. HEA125 labeled most epithelial cell types throughout the body but did not label any nonepithelial tissue. Major exceptions were epidermal keratinocytes, gastric parietal cells, hepatocytes, thymic cortical epithelial, and myoepithelial cells. Normal mesothelial cells were unreactive. In normal glandular epithelia and tubular adenocarcinomas exclusively the basolateral cell membranes were stained. HEA125 intensely reacted with all tested carcinoma specimens derived from colorectum, stomach, pancreas, liver, lung, mammary gland, ovary, thyroid, kidney, urinary bladder, and prostate including a number of anaplastic, diffusely infiltrating carcinomas. Metastatic lesions of these tumors were consistently positive. Generally, the staining of tumor cells was very homogeneous. The majority of squamous cell carcinomas were less strongly labeled than adenocarcinomas; keratinizing areas of the tumor masses were negative. Germ cell tumors and mesotheliomas of epithelioid type focally expressed the antigen. Egp34 was found to be absent from sarcomas, lymphomas, melanomas, and neurogenic tumors. Hence, HEA125 is a useful reagent for the distinction of carcinomas from nonepithelial neoplasms, even at very low degrees of histological differentiation. Furthermore, HEA125 allows the immunohistochemical detection of micrometastases originating from carcinomas. The antigen is detectable in formalin-fixed paraffin sections.

Antibodies, Monoclonal↗
PubMed1987

CD19 monoclonal antibody HD37 inhibits anti-immunoglobulin-induced B cell activation and proliferation.

The 95 Kd CD19 antigen is the broadest lineage specific surface marker for B cells: it is present on the surface of virtually all B lymphocytes, including early B progenitor cells. In this study we have evaluated the function of the CD19 antigen by using the CD19 mAb HD37. Binding of HD37 mAb to B cells at low doses (0.5 microgram/ml) induced a strong inhibition of the proliferative response to anti-Ig. This inhibition was not mediated by the Fc portion of the antibody, since F(ab')2 fragments were as effective as the whole antibody. Both dose-response curve analysis and experiments in which a cross-linking second step anti-mouse antibody was added suggested that cross-linking of CD19 antigens was necessary for optimal inhibition. Early phases in B cell activation were affected by the HD37 mAb: it significantly reduced the number of cells that left G0 and entered the G1 phase of the cell cycle upon triggering with anti-mu. The increase in free intracellular ionized calcium [Ca2+]i that is induced by anti-mu was also consistently reduced by CD19 mAb. Cross-linking was also crucial for this effect, suggesting that a causal relationship may exist between the inhibition of anti-Ig-mediated [Ca2+]i fluxes and inhibition of proliferation. A variable but clear increase in [Ca2+]i levels followed cross-linking of CD19 antigens by specific mAb. This evidence suggests that CD19 molecules may function in the downregulation of B cell growth and proliferation.

Antibodies, Anti-Idiotypic↗
PubMed1987

Amplification of human B cell activation by a monoclonal antibody to the B cell-specific antigen CD22, Bp 130/140.

The B cell-specific antigen CD22 is a 130/140-Kd complex and is unique among human B cell antigens, since its surface expression is restricted to a subpopulation of Ig+ B cells. Here the function of the CD22 antigen was evaluated by using the mAb HD6, directed against one of the epitopes on the molecule. The HD6 antibody was constimulatory with anti-Ig in inducing small, dense tonsillar cells to proliferate; however, the antibody by itself was devoid of stimulatory activity. Anti-CD22 antibody also induced more anti-Ig-treated B cells to leave G0 and enter the G1 phase of the cell cycle. It also was constimulatory with low-m.w. BCGF and with an antibody to a 50-Kd polypeptide, Bp50, which mediates a BCGF-like activity. Results of kinetic experiments and analysis of different B cell fractions suggested that anti-CD22 acts during an early phase of B cell activation, probably by amplifying the anti-Ig signal. F(ab')2 fragments of anti-CD22 HD6 were as effective as the whole antibody in inducing augmentation of B cell proliferation, showing that the Fc portion of the molecule was not required for the activity. The results of these experiments, together with the intriguing distribution of the Bp 130/140 antigen in B cell ontogeny, suggest that this molecule plays an important role in the process that leads to B cell activation and proliferation.

Antibodies, Monoclonal↗
PubMed1987

Removal of cells from a malignant B-cell line from bone marrow with immunomagnetic beads and with complement and immunoglobulin switch variant mediated cytolysis.

In this report we describe the generation of complement (C') fixing IgG2b CD19 and CD22 monoclonal antibodies (mAbs) by the isolation of immunoglobulin (Ig) class switch variants using a simple and efficient method for the selection of spontaneously mutating hybridomas. The aim of this study was to compare the efficacy of C'-mediated cytolysis vs immunomagnetic (IB) depletion of tumor cells from mixtures of malignant B cells and normal bone marrow. In a clonogenic assay employing the B-cell lines Namalwa and OCI.LY1, we found that the use of immunomagnetic beads warranted a highly efficient tumor cell removal independent of the Ig isotype of the mAbs used. Elimination of up to 4 log was achieved using a cocktail consisting of CD19, CD20, CD22 and CD37 B-cell mAbs. A less efficient killing of 2 log was obtained by C' lysis using IgM mAbs, while only about 1 log tumor cell elimination was obtained using IgG2b mAbs. Immunomagnetic purging, besides being more effective than C'-mediated cytolysis, is easier to handle and more rapid.

Antibodies, Monoclonal↗
PubMed1987

Epithelium-specific surface glycoprotein of Mr 34,000 is a widely distributed human carcinoma marker.

An epithelial cell surface antigen is described which is defined by monoclonal antibody HEA125 (IgG1). The antibody was raised against the colon carcinoma cell line HT-29. Under reducing conditions HEA125 immunoprecipitates a surface glycoprotein of Mr 34,000 which was designated Egp34. The antigen does not contain disulfide-linked subunits. A slightly different migration behavior under non-reducing conditions (Mr 39,000) may be due to intrachain disulfide bonds. After enzymatic cleavage of N-linked carbohydrate residues the apparent molecular weight of the antigen was 29,000. Egp34 is a major cell surface component of HT-29 cells (10(6) molecules per cell). No antigen could be detected in the sera of colorectal cancer patients. A panel of malignant cell lines and normal cells was studied for surface expression of the antigen. 17/17 carcinoma lines of 6 different origins expressed the antigen, whereas 16/16 melanoma, neuroblastoma, sarcoma and lymphoma/leukaemia were unreactive as it was the case for normal fibroblasts and blood cells. Immunoperoxidase staining of frozen tissue sections with HEA125 demonstrated the presence of Egp34 in almost all normal epithelia and tumours derived therefrom. No reactivity with non-epithelial tissues was observed. Undifferentiated carcinomas of various origins homogeneously expressed Egp34. Therefore, HEA125 may become a valuable tool for the immunohistochemical diagnosis of carcinoma.

Animals↗
PubMed1987

Mediastinal lymphoma of clear cell type is a tumor corresponding to terminal steps of B cell differentiation.

This article reports eight primary mediastinal tumors occurring in young adults (19 to 43 years, mean 29.4 years), predominantly female (six of eight) adults. Most patients responded badly to aggressive therapy. Progression is presently noted in one patient; five patients died 10, 11, 13, 18, and 22 months after diagnosis. No patient developed leukemia. The tumors were highly proliferative, had a diffuse growth pattern, and comprised clear cells of variable size. They could not be classified histologically, but could, however, be immunohistologically characterized as B cell lymphomas. In all cases, the immunophenotype was LC+, cALLa-, CD19+, CD20+, CD21-, Ig (surface/cytoplasm)-, and PC-1+. In addition, the neoplastic cells exhibited variable defects in the expression of HLA-A,B,C and HLA-DR and inconstant expression of other B cell-restricted/associated antigens. This combination of immunophenotypical and clinical features suggests that the mediastinal clear cell lymphoma (MCCL) is a previously undescribed type of B cell lymphoma corresponding to the terminal steps of B cell differentiation.

Adult↗