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Biomedical subjects

G S Pinkus

Publications and source records attributed to G S Pinkus.

At least 37 records · Page 2Linked to original sources

In vivo expression of B7-1 and B7-2 by follicular lymphoma cells can prevent induction of T-cell anergy but is insufficient to induce significant T-cell proliferation.

Expression of B7 family costimulatory molecules on B cells defines their capacity to function as antigen presenting cells (APCs). B cells that do not express B7 costimulatory molecules induce T-cell tolerance. Therefore, the expression of B7 costimulatory molecules on malignant B cells might be critical for their recognition by anti-tumor-specific T cells. Here we show that virtually all germinal center (GC)-derived B-cell lymphomas including follicular lymphoma (FL) and diffuse large cell lymphoma, but not mantle cell lymphoma or small lymphocytic lymphomas (SLL/CLL), express B7-1 (CD80) and B7-2 (CD86) on their cell surface in situ, although at extremely low levels. Despite their expression of low levels of B7-1 and B7-2, FL cells could not induce significant allogeneic T-cell proliferation. However, B7 costimulatory molecules on FL appeared to be functional because they were capable of increasing T-cell proliferation of preactivated T cells in a secondary allogeneic mixed lymphocyte response. Moreover, low B7 expression was sufficient to prevent the induction of alloantigen-specific anergy in vitro. Therefore, we postulate that whereas low-level expression of B7 is not sufficient to initiate a productive antilymphoma T-cell response, it might be sufficient to prevent T-cell tolerance in vivo.

Antigens, CD↗

The development of a model for the homing of multiple myeloma cells to human bone marrow.

Prior in vitro studies have suggested a role of adhesion molecules, bone marrow stromal cells (BMSCs), and cytokines in the regulation of human multiple myeloma (MM) cell growth and survival. Although in vivo models have been developed in severe combined immunodeficient (SCID) mice that support the growth of human MM within the murine BM microenvironment, these xenograft models do not permit a study of the role of adhesion proteins in human MM cell-human BMSC interactions. We therefore established an in vivo model of human MM using SCID mice implanted with bilateral human fetal bone grafts (SCID-hu mice). For the initial tumor innoculum, human MM derived cell lines (1 x 10(4) or 5 x 10(4) ARH-77, OCI-My5, U-266, or RPMI-8226 cells) were injected directly into the BM cavity of the left bone implants in irradiated SCID-hu mice. MM cells engrafted and proliferated in the left human fetal bone implants within SCID-hu mice as early as 4 weeks after injection of as few as 1 x 10(4) MM cells. To determine whether homing of tumor cells occurred, animals were observed for up to 12 weeks after injection and killed to examine for tumor in the right bone implants. Of great interest, metastases to the right bone implants were observed at 12 weeks after the injection of 5 x 10(4) MM cells, without spread of human MM cells to murine BM. Human MM cells were identified on the basis of characteristic histology and monoclonal human Ig. Importantly, monoclonal human Ig and human interleukin-6 (IL-6), but not human IL-1beta or tumor necrosis factor-alpha, were detectable in sera of SCID-hu mice injected with MM cells. In addition, specific monoclonal Ig light chain deposition was evident within renal tubules. This in vivo model of human MM provides for the first time a means for identifying adhesion molecules that are responsible for specific homing of human MM cells to the human, as opposed to murine, BM microenvironment. Moreover, induction of human IL-6 suggests the possibility that regulation of MM cell growth by this cytokine might also be investigated using this in vivo model.

Animals↗

Umbilical cord 'pseudo-vasculitis' following second trimester fetal death: a clinicopathological and immunohistochemical study of 13 cases.

Amniotic fluid bacterial infection is an occasional cause of second trimester septic abortion. We describe an autolysis-related histological artifact, umbilical cord 'pseudo-vasculitis', which can erroneously implicate amniotic bacterial infection in fetal death. Clinicopathological features of 13 second trimester fetal deaths with umbilical cord pseudo-vasculitis are reported. In four cases (31%), an incorrect pathological diagnosis of umbilical vasculitis had initially been rendered. Umbilical cords from five cases of pseudo-vasculitis and one comparison fetus (18-week septic abortion with true umbilical vasculitis), were studied with chloroacetate esterase and with immunohistochemical staining for myeloperoxidase, muscle-specific actin (HHF35) and smooth muscle actin. Histologically, umbilical pseudo-vasculitis exhibited numerous small, rounded, degenerating cells with irregular, multilobed nuclei (closely resembling neutrophils) located within the umbilical vessel wall. Immunohistochemical studies demonstrated that all cells resembling neutrophils were of smooth muscle origin. Moderate to severe fetal autolysis was present in all cases of umbilical pseudo-vasculitis, suggesting that this finding represents autolysis of umbilical vascular smooth muscle secondary to post moderate fetal retention. Vascular smooth muscle in other fetal and placental locations did not demonstrate the finding, suggesting that this striking degenerative artifact of smooth muscle is restricted to the umbilical cord.

Actins↗

T-cell blast crisis in chronic myelogenous leukemia. Immunophenotypic and molecular biologic findings.

T-cell blast crisis in chronic myelogenous leukemia is rare. We examined three patients (ages 35 to 72 years) in whom T-cell blast crisis developed 11 to 36 months (mean, 25 months) after diagnosis of chronic myelogenous leukemia and who died 4 to 12 months (mean, 7 months) thereafter. Two patients had diffuse lymphadenopathy, and the third had marked lymphocytosis (white blood cell count 217,000/microL, with 90% circulating blasts). In all three patients, neoplastic cells had the appearance of lymphoblasts and were immunoreactive for T-cell markers by immunohistochemical or flow cytometric analysis or both. Molecular diagnostic studies revealed the presence of a bcr-abl oncogene rearrangement in all three cases, but none exhibited a clonal T-cell receptor delta, beta, or gamma chain gene rearrangement. One case exhibited deletion of the J delta 1 region of both delta chain genes. The significance of these findings is discussed, and they are compared with those of other reported cases of T-cell blast crisis in chronic myelogenous leukemia.

Adult↗

Fascin, a sensitive new marker for Reed-Sternberg cells of hodgkin's disease. Evidence for a dendritic or B cell derivation?

Immunohistochemical localization of human fascin, a distinct 55-kd actin-bundling protein, was determined for a wide variety of lymphoid tissues (364 specimens total). In non-neoplastic tissues, reactivity was highly selective and localized predominantly in dendritic cells. In the thymus, this protein was distinctly localized to medullary dendritic cells. In reactive nodes, interdigitating reticulum cells of T zones, cells in subcapsular areas, and cells of the reticular network were reactive, with variable reactivity observed for follicular dendritic cells. Splenic dendritic cells of the white pulp and sinus-lining cells of the red pulp were reactive. Endothelial cells of all tissues exhibited variable reactivity. Lymphoid cells, myeloid cells, and plasma cells were uniformly nonreactive. In the peripheral blood, only dendritic (veiled) cells were reactive for fascin. A striking finding was observed for cases of Hodgkin's disease (total 187 cases). In all cases of nodular sclerosis (132), mixed cellularity (34), lymphocyte depletion (2), and unclassified types (5), all or nearly all Reed-Sternberg cells and variants were immunoreactive for fascin. Neoplastic cells exhibited strong diffuse cytoplasmic staining and frequently assumed dendritic shapes, particularly in the nodular sclerosis type, producing an interdigitating meshwork or syncytial network of cells. In cases of mixed cellularity type, neoplastic cells generally appeared more discrete. In all 14 cases of nodular lymphocyte predominance type, L&H variants were nonreactive. By contrast, neoplastic lymphoid cells of only 24 of 156 (15%) other lymphoid neoplasms (127 B cell, 27 T cell, and two null cell evaluated) were reactive for fascin. Fascin represents a highly effective marker for detection of certain dendritic cells in normal and neoplastic tissues, is an extremely consistent marker for Reed-Sternberg cells and variants of Hodgkin's disease (except L&H types), and may be helpful to distinguish between Hodgkin's disease and non-Hodgkin's lymphoma in difficult cases. The staining profile for fascin raises the possibility of a dendritic cell derivation, particularly an interdigitating reticulum cell, for the neoplastic cells of Hodgkin's disease, notably in nodular sclerosis type. However, as fascin expression may be induced by Epstein-Barr virus infection of B cells, the possibility that viral induction of fascin in lymphoid or other cell types must also be considered in Epstein-Barr virus-positive cases.

B-Lymphocytes↗

CD99 (p30/32MIC2) immunoreactivity in the diagnosis of leukemia cutis.

The diagnosis of leukemia cutis and distinction of early myeloid cells and blasts from lymphoblasts or other lymphoid cells can be difficult, particularly if only fixed tissue is available. O13, a monoclonal antibody that recognizes CD99, the p30/32MIC2 gene product, has been used to identify a number of cell types, including lymphoblasts, in paraffin sections. To evaluate the usefulness of CD99 immunoreactivity in the diagnosis of leukemia cutis, we analyzed cases of cutaneous involvement by acute lymphoblastic leukemia/lymphoblastic lymphoma and acute myelogenous leukemia for the presence of this marker. Without the use of antigen retrieval methods, lymphoblasts in cases of cutaneous involvement by acute lymphoblastic leukemia/lymphoblastic lymphoma were immunoreactive for CD99 in 9 of 9 cases. Myeloblasts and early myeloid cells in cases of cutaneous involvement by acute myelogenous leukemia were immunoreactive for CD99 in 12 (80%) of 15 cases. We conclude that CD99 is a sensitive but nonspecific marker for cutaneous involvement by acute lymphoblastic leukemia/lymphoblastic lymphoma and that CD99 is immunoreactive in the vast majority of cases (21 [88%] of 24 cases) of leukemia cutis.

12E7 Antigen↗

The role of follicular and interdigitating dendritic cells in HIV-related lymphoid hyperplasia: localization of fascin.

Fascin is a 55-kDa, actin-bundling protein expressed in follicular and interdigitating dendritic cells (DCs). Because these cells play a pivotal role in the pathogenesis of human immunodeficiency virus-related lymphoid hyperplasias (HLP), we evaluated them in 49 cases by immunohistochemical localization of fascin, and we related the findings to the histologic stage of disease. Fifteen cases of early HLP revealed strong localization of fascin within DCs of hyperplastic follicles and intense staining in interdigitating DCs and their processes in the interfollicular zones. Some follicles revealed focal disruption of the fascin-positive dendritic framework. DCs were also aligned beneath the peripheral sinuses of the node. In 15 cases of progressive HLP with partial follicular involution, 3 cases revealed findings similar to those described above. Twelve cases revealed loss of follicular dendritic staining, which was moderate in five cases and marked in seven. Residual clusters of DCs remained after partial dissolution. Interfollicular dendritic staining was reduced in 13 cases, and perisinusoidal staining was reduced in 7. In late-stage HLP, staining of both follicular and interdigitating DCs was reduced or absent. Nine cases of diffuse immunoblastic or angioimmunoblastic lymphadenopathy-like proliferation had markedly reduced or absent follicular DCs, but prominent staining was present in interfollicular DCs, which formed a meshwork throughout the node in eight cases. Two cases of hyaline-vascular lymphoid hyperplasia had increased follicular DCs forming a tight syncytial network. In most cases, there was reduction of dendritic fascin-expressing cells with advanced disease and destruction of the dendritic framework of the node. Diffuse hyperplasia of fascin-positive interdigitating cells occurred in cases with angioimmunoblastic morphologic features, and cases of hyaline-vascular lymphoid hyperplasia had increased follicular dendritic histiocytes forming a tight syncytial network. Destruction of DCs and, in some cases, interdigitating cell hyperplasia might be associated with the variable clinical course of HLP.

Biopsy↗

Cytologic diagnosis of primary serous lymphoma.

Lymphomas arising primarily in serosal surfaces have recently been described. Although these "body-cavity" lymphomas usually present as an effusion, the role of cytologic diagnosis has not been fully explored. The authors present seven cases of primary serous lymphoma. All were large cell lymphomas (5 B cell types, 2 T cell types). Three distinct clinical presentations were seen. Four patients had the rapid onset of pleural effusions without an associated mass in the setting of immunodeficiency (3 with AIDS, 1 with Castleman's disease). Cytologic examination of the effusion was positive in all cases for B-cell lymphoma. All four patients died of their disease in less than 6 months. Two other patients with AIDS and T-cell lymphomas both of which were associated with a serosal mass as well as an effusion. Although cytologic examination revealed numerous atypical lymphoid cells, clonality could not be demonstrated. One patient survived for more than 1 year, the other lymphoma was an incidental finding at autopsy. Finally, one B-cell lymphoma arose in a patient with chronic pleuritis. Pleural decortication was required to identify the neoplastic cells. The authors conclude that primary serosal lymphomas have characteristic clinical presentations, and that although cytologic and flow cytometric examination of effusions is necessary for the diagnosis of immunodeficiency associated B-cell lymphomas, tissue biopsy will likely be required in patients with immunodeficiency-associated T-cell lymphomas or lymphomas associated with chronic pleuritis.

Acquired Immunodeficiency Syndrome↗

Circulating human dendritic cells differentially express high levels of a 55-kd actin-bundling protein.

This study was initiated to examine the differential expression of an evolutionary conserved human 55-kd actin-bundling (p55) protein that is induced in B lymphocytes by Epstein-Barr virus infection. Our study demonstrates that p55 is specifically expressed at constitutively high levels in human peripheral blood dendritic cells and lymph node (interdigitating) dendritic cells. Blood dendritic cells constitute a minority (< 2%) of all blood leukocytes but are a distinct population of potent antigen-presenting cells. Immunofluorescence microscopy with a monoclonal antibody specific for p55 showed that 87% of peripheral blood dendritic cells stained brightly in the cytoplasm and in the veiled cytoplasmic extensions. In contrast, monocytes, granulocytes, T cells, and B lymphocytes showed no expression of the p55 protein. Western blot analysis confirmed that only the dendritic cell component of peripheral blood expressed high levels of p55. Staining of human lymph node sections demonstrated selective expression of the p55 antigen by dendritic cells in the T-cell-dependent areas but not in the B cell follicles. p55 is likely to be involved in the organization of a specialized microfilament cytoskeleton in the dendritic cells, and the anti-p55 antibody should be useful for further characterization of this important population of antigen-presenting cells in clinical transplantation, HIV-1 pathogenesis, and autoimmune diseases.

Actins↗

Follicular lymphomas can be induced to present alloantigen efficiently: a conceptual model to improve their tumor immunogenicity.

In the tumor-bearing host, T cells invariably fail to induce a clinically significant antitumor immune response. Although model systems support the existence of tumor peptide antigens, the molecular interactions critical for antigen presentation by the tumor cell remain unresolved. Here, we demonstrate that human follicular lymphoma cells are highly inefficient at presenting alloantigen despite their strong expression of major histocompatibility complex and low-to-intermediate expression of some adhesion and B7 costimulatory molecules. Activation of follicular lymphoma cells via CD40 induces or up-regulates both adhesion and B7 costimulatory molecules essential to repair this defect. More importantly, once primed, alloreactive T cells efficiently recognize unstimulated follicular lymphoma cells. Thus, correction of defective tumor immunity requires not only expression of major histocompatibility complex but also sufficient expression of multiple adhesion and costimulatory molecules.

Antigen-Antibody Reactions↗

Synovial tissue response to treatment with Campath-1H.

OBJECTIVE: Therapeutic trials in rheumatoid arthritis with the monoclonal antibody Campath-1H have demonstrated recurrent clinical synovitis in some patients, despite profound depletion of circulating lymphocytes. This study was undertaken to examine the cellular infiltrates in synovial tissue at a time of persistent peripheral lymphopenia. METHODS: Immunohistochemical staining of synovial tissue and peripheral blood lymphocyte phenotyping. RESULTS: Synovial tissues from 2 patients with recurrent synovitis after Campath-1H therapy contained significant T lymphocytic infiltrates at a time when circulating T lymphocytes were markedly depleted. CONCLUSION: These results demonstrate that peripheral blood analysis may not accurately reflect the synovial tissue response to monoclonal antibody therapy.

Antigens, CD↗

Accelerated healing of duodenal ulcers by oral administration of a mutein of basic fibroblast growth factor in rats.

BACKGROUND/AIMS: Human basic fibroblast growth factor (bFGF) is an endothelial mitogen that stimulates angiogenesis and proliferation of other cells such as fibroblasts and smooth muscle cells. After this peptide was stabilized to acid and pepsin by site-specific mutagenesis, it was tested whether bFGF might accelerate the healing of experimental duodenal ulcers. METHODS: This mutein peptide (bFGF-CS23) was administered orally in comparison with cimetidine to rats with chronic duodenal ulcers previously induced by cysteamine. RESULTS: Oral bFGF-CS23 therapy maintained for 21 days at 100 ng/100 g twice daily resulted in (1) significant acceleration of healing of duodenal ulcers, i.e., reduction of mean ulcer area by 83% in the bFGF-CS23-treated rats compared with only 61% for cimetidine therapy and 40% for untreated controls; (2) complete healing with no residual ulcer in 62% of the bFGF-CS23-treated rats compared with only 7% of untreated rats; and (3) a ninefold increase in angiogenesis in the ulcer bed compared with untreated controls. A single dose of the bFGF-CS23 mutein had no effect on gastric output of hydrochloric acid or pepsin, but daily treatment for 2 or 3 weeks resulted in enhanced acid and pepsin outputs. CONCLUSIONS: Chronic duodenal ulcers can be healed rapidly by stimulating angiogenesis and other wound-healing processes in the ulcer bed without reduction of gastric acid.

Administration, Oral↗

Bcl-2 oncogene protein is preferentially expressed in Reed-Sternberg cells in Hodgkin's disease of the nodular sclerosis subtype.

One hundred three cases of nodular sclerosis (NS) and mixed-cellularity Hodgkin's disease were evaluated for expression of bcl-2 oncogene protein, because previous studies have revealed expression of bcl-2 in these subtypes but only rarely in the nodular lymphocyte-predominance subtype. Reed-Sternberg (RS) cells and lacunar variants were positive for bcl-2 in 51 of 86 NS cases and 4 of 17 mixed-cellularity cases. In individual cases of NS, the percentage of RS cells and lacunar variants positive for bcl-2 ranged from minimal (in 5 cases) to 100% positive (mean, 34%). By univariate analysis, expression of the bcl-2 gene product in RS cells was observed in a significantly greater proportion of NS Hodgkin's disease cases than MC cases (P < .009), a finding that may have implications on the pathogenesis of this disorder.

Adolescent↗

Immunohistochemical detection of Epstein-Barr virus-encoded latent membrane protein in Reed-Sternberg cells and variants of Hodgkin's disease.

A total of 186 specimens of Hodgkin's disease of various histologic types (127 nodular sclerosis, 39 mixed cellularity, 14 lymphocyte predominance, 3 lymphocyte depleted, and 3 unclassified) were evaluated for the presence of latent membrane protein (LMP) and Epstein-Barr virus nuclear antigen-2, two Epstein-Barr virus encoded gene products that appear to play important roles in cell transformation and oncogenesis. Immunoreactivity for LMP was observed in Reed-Sternberg cells and variants of 27/39 (69%) cases of mixed cellularity type, 18/127 (14%) of nodular sclerosis type, 2/3 cases of lymphocyte depleted type, and 1/3 cases of unclassified type. All cases of lymphocyte predominance Hodgkin's disease were nonreactive for LMP. In cases that were reactive for LMP, staining was restricted to Reed-Sternberg cells and variants. Other cells within the proliferation, e.g., lymphocytes, histiocytes, eosinophils, fibroblasts, etc., were nonreactive. The pattern of immunoreactivity for LMP was characterized by strong diffuse cytoplasmic staining, occasionally with membrane accentuation and/or paranuclear staining. Reactivity for LMP was demonstrated in cryostat sections and was also well preserved in paraffin sections of B5- or formalin-fixed tissues. Five of six specimens of Hodgkin's disease (4 mixed cellularity and 2 nodular sclerosis type) that occurred in HIV-positive patients exhibited immunoreactivity for LMP in Reed-Sternberg cells and variants. Cryostat section studies for Epstein-Barr virus nuclear antigen-2 using monoclonal antibody PE-2 failed to reveal staining for 43 cases (26 nodular sclerosis, 12 mixed cellularity, and 5 lymphocyte predominance) after a 2-h incubation with primary antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗

Distinction between small lymphocytic and mantle cell lymphoma by immunoreactivity for CD23.

Immunoreactivity for CD23, a B-cell activation antigen, was compared in 22 cases of B-cell small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) and 15 cases of mantle cell lymphoma (MCL) (intermediate lymphocytic lymphoma or centrocytic lymphoma) to determine if the presence of this antigen can be used as a criterion to distinguish between these two low-grade B-cell lymphoproliferative processes. CD23 immunoreactivity was observed in 21 of 22 cases (95%) of SLL/CLL, whereas only 2 of 15 cases (13%) of MCL were reactive for this antigen; therefore, lack of CD23 reactivity is statistically significantly associated with MCL (P < 0.0001). In addition, lack of CD23 immunoreactivity is also statistically significantly associated with SLL with plasmacytoid differentiation in comparison with typical SLL (P < 0.0003), although only a small number of cases were evaluated. SLL/CLL, MCL, and SLL with plasmacytoid differentiation cases were all uniformly immunoreactive for pan-B-cell antigens such as CD20 and CD22. Immunoreactivity for CD23 appears to be a useful marker to aid in distinguishing SLL/CLL from MCL and may be helpful in routine immunophenotypic screening of low-grade B-cell derived lymphoproliferative processes.

Adult↗

Lineage-restricted chromosome translocation in a benign fibrous tumor of the breast.

We describe a clonal chromosome rearrangement, t(4;14)(q24-25;q24.3), in a benign fibrous tumor of the breast. This is the first reported cytogenetic analysis of a fibrous tumor of the breast and the first evidence for clonality in these lesions. A combined immunohistochemical/cytogenetic study demonstrated that cells with the clonal translocation were mesenchymal. Epithelial cells, in contrast, had normal chromosomes.

Adult↗

Small lymphocytic non-Hodgkin's lymphoma of suppressor/cytotoxic T-cell phenotype [CD4(-), CD8(+)].

An unusual case of small lymphocytic non-Hodgkin's lymphoma of suppressor/cytotoxic T-cell phenotype is described. The patient presented with significant involvement of the spleen, lymph nodes, and bone marrow, but without a leukemic phase. Most small lymphocytic lymphomas are of B-cell phenotype, and those of T-cell origin are overwhelmingly of T-helper/inducer phenotype. Furthermore, T-cell lymphoproliferative lesions of suppressor/cytotoxic phenotype generally present as leukemias comprising large granular lymphocytes. This case reveals that suppressor/cytotoxic T lymphocytes may give rise to a lymphoproliferative disorder with a distinctive phenotype and presentation.

CD4 Antigens↗