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Biomedical subjects

C E Grossi

Publications and source records attributed to C E Grossi.

At least 19 recordsLinked to original sources
PubMed1992

Adhesion molecule-mediated signals regulate major histocompatibility complex-unrestricted and CD3/T cell receptor-triggered cytotoxicity.

Appropriate experimental conditions were devised to demonstrate that CD58 (LFA-3), CD54 (ICAM-1) and CD11a/CD18 (LFA-1) adhesion molecules are the source of signals that regulate nonspecific major histocompatibility complex-unrestricted and CD3/T cell receptor (TcR)-triggered cytotoxicity. Using anti-LFA-3 monoclonal antibody (mAb)-treated, interleukin-2 (IL-2)-cultured peripheral blood lymphocytes (PBL) or cloned CD3+/CD8+ cells as lymphocyte-activated killer (LAK) effectors, and ligand (CD2)-negative tumor cell lines as targets, a down-regulation of CD3- and CD3+ cell-mediated LAK activity was consistently observed. Anti-LFA-3 mAb also down-regulated tumor cell lysis when T cell clones were triggered to kill P815 cells through stimulation of the CD3/TcR complex by an anti-CD3 mAb. The inhibitory effect of anti-LFA-3 mAb was not prevented by stimulatory anti-CD2 mAb. Anti-ICAM-1 mAb treatment of IL-2-cultured PBL consistently up-regulated LAK cytotoxicity against tumor target cells. However, this effect was only exerted on CD3- LAK effectors. Anti-LFA-1 mAb blocked conjugate formation between effector cells and tumor target cells, thus rendering this model unsuitable to evaluate the regulatory role of LFA-1. Therefore, a cytotoxicity model system was applied in which a hybrid anti-CD3/anti-human red blood cell (HuRBC) mAb triggers cytolytic T cells to lyse HuRBC. In these experiments, anti-LFA-1 mAb markedly up-regulated the lytic ability of IL-2-cultured PBL. We conclude that mAb against LFA-3, ICAM-1 and LFA-1 molecules deliver regulatory signals for LAK cells and cytotoxic T lymphocytes. As these stimuli may be delivered by ligands expressed on tumor targets as well as on other immune competent and inflammatory cells, the present observations are relevant in the context of both the host's immune response against tumors and the general functioning of the immune system.

Antibodies, Monoclonal↗
PubMed1992

Functional and morphologic characterization of human T lymphocytes expressing the TCR gamma/delta.

A minor subset of T lymphocytes express a TCR composed of gamma and delta chains. This subset differs from conventional T cells for a number of phenotypic and functional characteristics. TCR gamma/delta+ cells simultaneously lack both CD4 and CD8 antigens. Cloning of CD4-8- peripheral blood lymphocytes, under limiting dilution conditions, revealed that they are homogeneously composed of cytolytic cells which efficiently lyse tumor target cells. Formal proofs have been provided that TCR gamma/delta+ cells are able to recognize antigens. For example, they proliferated in response to allogeneic mixed lymphocyte culture (MLC); in addition, MLC-derived TCR gamma/delta+ cells specifically lysed PHA-induced blast cells bearing the stimulating alloantigens. The selection of monoclonal antibodies specific for TCR gamma/delta molecules allowed to identify two distinct subsets of TCR gamma/delta+ cells. Both of these mABs, termed BB3 and delta TCS-1 respectively, induced specific activation of cloned cells expressing the corresponding antigenic determinants (as assessed by measurements of intracellular Ca++ and/or lymphokine production or cytolytic activity). Analysis of the distribution of subsets expressing different forms of TCR gamma/delta, showed that the BB3-reactive form is prevalent in the peripheral blood. In contrast, delta-TCS-1-reactive cells are relatively infrequent in peripheral blood but represent the majority of TCR gamma/delta+ cells in tissues.

Humans↗
PubMed1992

Localization of a novel integrin of the beta 1 subfamily in human tissues.

We have previously described a novel integrin composed of a beta 1-chain non-covalently linked to an alpha-chain which is biochemically different from those known so far (i.e., alpha 1-alpha 7 and alpha v). This molecule has been identified with a monoclonal antibody (MAb) termed 10.1.2 raised against long-term cultured human thymic epithelial cells (TEC). In this study we analyzed the immunohistochemical distribution of this new integrin in a variety of human tissues. MAb 10.1.2 stains several types of endothelial and epithelial cells. Among the endothelia, a strong reaction was detected in the HEV of lymphoid organs including thymus, lymph node, tonsil, and mucosa-associated lymphoid tissue. Epithelial localizations of note were those in the basal layer of the epidermis and of other stratified squamous epithelia, where the lateral and apical but not the deep surfaces of most cells were stained. A variety of water-electrolyte transporting cells in sweat glands, salivary glands, and kidney were also stained at their deep surface. The latter findings suggest that this molecule may subserve other functions in addition to those related to cell adhesion.

Adult↗
PubMed1992

Expression of adhesion molecules in lymphoproliferative disorders.

We review the role of adhesion molecule expression on malignant lymphoid cells as delineated by experimental studies and clinical observation. Adhesion molecules of the Ig superfamily, integrins, selectins, and the lymphocyte homing receptor CD44 mediate cell-to-cell and cell-to-extracellular matrix interactions. These molecules have been investigated with the aim (i) of defining certain biological features of the malignant cells, (ii) of providing a rationale to understand tumor organization, metastasis and organ specificity, and (iii) of detecting disease subsets and prognostic groups.

Animals↗
PubMed1991

Emergence of a B-cell lymphoblastic lymphoma in a patient with B-cell chronic lymphocytic leukemia: evidence for the single-cell origin of the two tumors.

A patient is described who presented with a chronic lymphocytic leukemia (CLL) and later developed a lymphoblastic lymphoma. The cells from the CLL were typical mature B lymphocytes as could be assessed by morphologic, cytochemical, and surface marker analyses. The cells from the lymphoblastic lymphoma were immature B cells that expressed CD10, CD20, and HLA-DR markers, but not surface Ig or cytoplasmic mu chains, and were negative for terminal deoxynucleotidyl transferase (TdT). The cells of two continuous cell lines, obtained from the bone marrow and the peripheral blood of the patient, had the same phenotype as the lymphoblastic lymphoma cells, did not contain the Epstein-Barr virus genome, and displayed malignant features in vitro, including the capacity to form colonies in agar. The two cell lines also shared identical chromosomal abnormalities, a finding which suggests that they derived from the same malignant cell already present in vivo. Such chromosomal abnormalities were not seen in the karyotype of the peripheral blood cells at the onset of the disease. Analysis of the Ig heavy chain genes using a DJ-specific probe showed the very same monoclonal rearrangement in the cells from the B-CLL, the lymphoblastic lymphoma and the two cell lines, thus demonstrating their common clonal origin. By contrast, a monoclonal rearrangement of the lambda chain gene locus was found in the B-CLL cells only, a finding consistent with their exclusive capacity to express surface IgM lambda. This patient represents a rare case in whom a chronic lymphoproliferative disorder with mature malignant cells transforms into a lymphoblastic lymphoma characterized by cells frozen at a very early maturational stage. The possible mechanisms leading to such transformation within the same cell clone are discussed.

Adult↗
PubMed1991

A novel integrin involved in thymocyte-thymic epithelial cell interactions.

Thymocytes differentiate in the thymic microenvironment into immunocompetent T cell through the interaction with a variety of accessory cells, including thymic epithelial cells (TEC). TEC plays an important role in the selection process presenting self antigens in association with major histocompatibility complex (MHC) molecules to the maturing T cells. The T cell receptor recognizes the self antigen-MHC complex, but other surface molecules help stabilize this interaction. Thus, the CD2/LFA-3 and LFA-1/intercellular adhesion molecule 1 pairs have been shown to participate in the binding between lymphoid cells and TEC. Here we describe an integrin of the very late activation antigen subfamily composed by the known beta 1 chain and by a novel alpha chain. This adhesion molecule is expressed on the surface of medullary TEC and is involved in the adhesion between TEC and thymocytes, but not peripheral blood T lymphocytes.

Antibodies, Monoclonal↗
PubMed1991

Morphological features of cloned lymphocytes expressing gamma/delta T cell receptors.

We have analyzed the morphological characteristics of human T lymphocytes bearing CD3-associated T cell receptor (TcR) gamma and delta chains. BB3 and delta-TCS1 monoclonal antibodies (mAb) were used to identify two distinct, nonoverlapping populations of TcR gamma/delta + cells which express the products of V delta 2 and V delta 1 gene segments, respectively. In the peripheral blood, most V delta 1+ (delta TCS-1+) lymphocytes express the non-disulfide-linked form of receptor whereas V delta 2+ (BB3+) cells express the disulfide-linked form. The majority of cloned TcR gamma/delta + cells exhibit a growth pattern different from that of conventional TcR alpha/beta + cells as they adhere promptly to surfaces and undergo morphological changes which can be summarized as follows: cells spread on the surface, form a distinct uropod and, in the final phase of adherence, emit long filopodia ending with adhesion plaques. Immunofluorescence studies of TcR gamma/delta + clones demonstrated the presence of submembraneous actin microfilaments and actin-binding protein confirming that these cells are capable of active motility which is related to the propensity of TcR gamma/delta + cells to home to epithelia. Scanning electron microscope analyses of effector/target cell conjugates showed that in TcR gamma/delta + cells the region of the uropodia next to the cell body is responsible for the binding to tumor target cells. Interestingly, immunofluorescence analyses revealed that LFA-1 molecules are predominantly distributed in the uropodium whereas they are virtually absent in the cell bodies. These morphological characteristics of TcR gamma/delta + cells may pertain to defensive mechanisms the mucosal level.

Actinin↗
PubMed1991

X-linked codominant genes control all types of non-major histocompatibility complex-restricted cytotoxicity.

In most individuals, natural killer (NK) activity is abolished after lymphocyte irradiation with 3,000 cGy, while lymphocytes from a minority of males retain 100% NK activity and lymphocytes from some females retain 50% NK activity after this dose. Radiation sensitivity of NK activity is controlled by X-linked codominant genes. The frequency of the allele that imparts resistance is 7%. We studied a unique family in which both parents have the resistant allele such that the father is completely resistant and the mother is partially resistant. The three offspring of this couple were one sensitive male, one partially resistant female, and one completely resistant female. The radiation sensitivity of nonspecific cytotoxic functions mediated by various types of effector cells from all five family members were evaluated in order to determine whether other cytotoxic functions were controlled by the same set of genes. The cytotoxic functions investigated were: NK and lymphokine-activated killing, anomalous killing and lectin-dependent cellular cytotoxicity, and antibody-dependent cell-mediated cytotoxicity. Our data indicate that the radiation sensitivity of all types of nonspecific cytotoxic cells is under the same genetic control.

Adult↗
PubMed1991

Russell bodies: a general response of secretory cells to synthesis of a mutant immunoglobulin which can neither exit from, nor be degraded in, the endoplasmic reticulum.

Dilated cisternae of the ER resembling Russell Bodies (RBs) are induced in light (L) chain producing myeloma cell lines by transfection of a mu heavy (H) chain gene lacking the first constant domain (mu delta CH1). RBs do not appear to be tissue specific, since they are also induced in a rat glioma cell line transfected with mu delta CH1 and L chain genes. Efficient RB biogenesis requires H-L assembly and polymerization. The mutant Ig is partially degraded in a pre-Golgi compartment. The remnant, however, becomes an insoluble lattice when intersubunit disulphide bonds are formed. The resulting insoluble aggregate accumulates in RBs. Replacing the COOH-terminal cysteine of mu delta CH1 chains with alanine reverses the RB-phenotype: the double mutant mu ala delta CH1 chains assemble noncovalently with L and are secreted as H2L2 complexes. Similarly, secretion of mu delta CH1 chains can be induced by culturing transfectant cells in the presence of reducing agents. The presence of RBs does not alter transport of other secretory or membrane molecules, nor does it affect cell division. Resident proteins of the ER and other secretory proteins are not concentrated in RBs, implying sorting at the ER level. Sorting could be the result of the specific molecular structure of the insoluble lattice. We propose that RBs represent a general response of the cell to the accumulation of abundant, nondegradable protein(s) that fail to exit from the ER.

Amino Acid Sequence↗
PubMed1990

Cytolytic function of clonable T cells after human bone marrow transplantation.

We evaluated T-cell mediated lymphokine activated killer (LAK) function during the late (greater than 5 months) reconstitution phase after T cell-depleted allogeneic bone marrow transplantation (BMT) for hematologic malignancy. Since LAK cells are sustained by interleukin-2 (IL-2), we also investigated the ability of post-BMT T cells to produce IL-2. These functions were investigated at the clonal level. More than 200 T-cell clones from six long-term BMT recipients were generated and compared with 60 T-cell clones derived from two normal controls. Almost all the CD8+ clonal cultures from BMT recipients expressed cytolytic activity in a lectin-dependent cellular cytoxicity assay. Interestingly, a higher proportion of BMT recipient-derived cytolytic clones were able to mediate LAK activity in comparison with control clones (28% versus 4%, P less than .05). However, T-cell clones from BMT recipients, as opposed to control clones, were largely incapable of producing IL-2. Given the high proportions of post-BMT circulating CD8+ T cells, it appears that, in long-term BMT recipients, the precursors of nonspecific LAK effectors are present at above normal levels. However, their function may be defective in vivo due to poor IL-2 production.

Bone Marrow Transplantation↗
PubMed1990

Immunoreactive lactoferrin in resting, activated, and neoplastic lymphocytes.

Lactoferrin (Lf) in lymphocytes was assessed with immunofluorescence/flow cytometric technique. Surface Lf was detected primarily among B-cell-enriched preparations. Tonsillar B-cells of different densities expressed surface Lf similarly. Very small percentages of CALLA+ ALL, HCL, or EBV-transformed B-cells expressed surface Lf, whereas B-CLL lymphocytes had the highest percentages of surface Lf positivity. Few resting, cultured, or neoplastic T-lymphocytes expressed Lf. The pattern of immunofluorescence and analyses of surface and total cellular immunoreactive Lf indicated that Lf is associated primarily with the lymphocyte surface. The percentage and/or intensity of surface Lf-specific fluorescence were not significantly altered in B- or T-cells by incubation with physiologic concentrations of differric Lf, and the percentages of Lf-positive cells detected in respective subjects remained stable over time. Surface Lf positivity was unrelated to the expression of other surface antigens (except those marking B- or T-cell lineage) or cell cycle. Expression and/or binding of Lf in B-lymphocytes may become increased during certain stages of cell maturation.

B-Lymphocytes↗
PubMed1990

Individual NK cell clones lyse both tumor cell targets and herpes simplex virus-infected fibroblasts in the absence of interferon.

The target specificity of natural killer (NK) cells for either tumor cells or virus-infected cells has been investigated. Lymphocyte clones with the surface phenotype of NK cells (CD3-, CD16+) were obtained by limiting dilution of peripheral blood mononuclear cells stimulated with PHA, Herpes simplex virus type 1 (HSV-1), or Varicella-Zoster antigens. Clones were maintained in media with recombinant interleukin 2 (IL-2). Both NK-sensitive (K562 cells) and NK-resistant (Raji cells) targets were lysed by three cloned lines of NK cells. The ability to lyse NK-resistant target cells was largely lost when the cloned lymphocytes were cultured overnight in the absence of IL-2. Effector cells from all three clones were also capable of specifically lysing HSV-1 infected human fibroblasts in comparison with uninfected fibroblasts. We also showed that lysis of HSV-1 infected targets by NK cloned cells was independent of interferons in the culture system.

Adult↗
PubMed1990

T gamma delta-cell subsets in cord and adult blood.

A minor population of T cells expresses a heterodimeric antigen receptor composed of gamma and delta chains (TcR-1). In blood from adults, two subsets of T gamma delta cells can be identified by the monoclonal antibodies (MoAb) BB3 and A13. Little is known about the distribution and markers of these subsets early in life. We have therefore examined both the frequencies of these cells in cord blood and their expression of the cytotoxicity-associated marker serine esterase (SE), using immunocytochemical techniques. Our data show lower percentages of TcR-1+ cells in the blood of newborns compared with that in adults. However, the ratio of the A13+/BB3+ cells was significantly higher in cord than in adult blood. Whereas virtually all the adult TcR-1+ cells in blood were SE-positive, only a small proportion of the cord blood cells carried this enzyme. This was restricted to the BB3+ T gamma delta-cell subset in the cord. Our data suggest different characteristics of the TcR-1+ cells in blood from newborns compared with adult blood, and study of the functions of the different subsets, e.g. cytotoxicity, will be important in understanding their particular role in immunity.

Adult↗
PubMed1990

T gamma delta cells and their subsets in blood and synovial tissue from rheumatoid arthritis patients.

We have examined the frequencies of T gamma delta cells in blood, synovial fluids, and synovial membranes of patients with rheumatoid arthritis (RA) and in blood from age-matched controls. Immunocytochemical and immunohistochemical techniques were used with monoclonal antibodies BB3 and A13 to define a major and minor blood subset of T gamma delta cells respectively. Together, these antibodies identify the majority (if not all) of the peripheral blood T gamma delta cells. Significantly lower levels of T gamma delta cells were found in the blood of RA patients compared with controls, whilst higher but not significant numbers were found in the synovial fluids of paired samples. Scattered T gamma delta cells were found only in some synovial membranes with a distribution similar to the T alpha beta cells. Analysis of the two different T gamma delta-cell subsets indicated a ratio of BB3 to A13 of about 5:1 in control and RA blood. However, this ratio was less than 1:1 in the RA synovial fluids and membranes. The migratory nature of the A13+ cells could account for their predominance in these sites. The possible pathological significance of these cells in the rheumatoid synovial fluid and synovial membranes is discussed.

Adult↗
PubMed1990

Human lymphocytes expressing a TCR gamma/delta.

A minor subset of T lymphocytes express a TCR composed of gamma and delta chains. This subset differs from conventional T cells for a number of phenotypic and functional characteristics. TCR gamma/delta + cells simultaneously lack both CD4 and CD8 antigens. Cloning of CD4-8-peripheral blood lymphocytes, under limiting dilution conditions, revealed that they are homogeneously composed of cytolytic cells which efficiently lyse tumor target cells. Formal proofs have been provided that TCR gamma/delta + cells are able to recognize antigens. For example, they proliferated in response to allogeneic mixed lymphocyte culture (MLC), in addition MLC-derived TCR gamma/delta + cells specifically lysed PHA-induced blast cells bearing the stimulating alloantigens. The selection of monoclonal antibodies (MoAbs) specific for TCR gamma/delta molecules allowed to identify two distinct subsets of TCR gamma/delta + cells. These MoAbs, termed BB3 and delta-TCS-1 (or the equivalent A13) respectively, induced specific activation of cloned cells expressing the corresponding antigenic determinants (as assessed by measurements of intracellular Ca2+ and/or lymphokine production of cytolytic activity). Analysis of the distribution of subsets expressing different forms of TCR gamma/delta, showed that the BB3-reactive form is prevalent in the peripheral blood. In contrast, delta-TCS-1-reactive cells are relatively infrequent in peripheral blood, but represent the majority of TCR gamma/delta + in the tissues.

Animals↗
PubMed1989

Radiation sensitivity of resting and activated nonspecific cytotoxic cells of T lineage and NK lineage.

Natural killer (NK) cell-mediated killing of tumor cells is a radiation-sensitive function that in most subjects is completely abrogated by treatment of the effector cells with 3,000 cGy. The radiation sensitivity of LAK (lymphokine-activated killer) cells and their precursors, the bulk of which are NK cells, is undetermined. In this study, functional cytotoxicity assays and electron microscopy were used to determine the effect of radiation on the cytotoxic function of NK cells, LAK cells (generated by three-day culture of peripheral blood lymphocytes with IL-2), and LAK cell precursors (lymphocytes irradiated prior to culture with IL-2). For comparison, we analyzed the radiation sensitivity of lectin-dependent cell-mediated cytotoxicity (LDCC), which is primarily a function of CD3+ CD8+ granular lymphocytes. We also analyzed the radiation sensitivity of nonspecific cytotoxicity mediated by mitogen-activated T cells (AK activity). Following 3,000 cGy irradiation, NK cells retained their ability to bind to tumor cell targets but, as shown by both morphologic and functional analyses, they did not undergo activation after conjugate formation, and were unable to release the content of their granules. In order to evaluate LDCC, lymphocytes were depleted of CD16+ cells and tested in a cytotoxicity assay in the presence of Con A. The radiation sensitivity curve was comparable to that of NK cell-mediated cytotoxicity. IL-2-treated lymphocytes (LAK cells) were relatively radioresistant as compared with untreated NK cells, and their cytotoxic function was not abrogated until treatment with greater than 10,000 cGy. Cells receiving such radiation doses displayed cytoplasmic blebbing and damage of their cytoskeletal structures, with disruption of centrioles and microtubules, and disarray of the intermediate filaments. As was shown with NK cells, irradiated LAK cells formed conjugates with tumor targets but failed to degranulate. The radiation sensitivity of nonspecific cytotoxicity mediated by mitogen-activated T cells was identical to that of LAK effector cells. Doses up to 2,000 cGy did not prevent generation of LAK cells from blood lymphocytes, but 3,000 cGy did so. Blast transformation similar to that observed in IL-2-stimulated controls occurred when lymphocytes irradiated with 3,000 cGy were cultured with IL-2. These transformed cells were not cytotoxic and displayed a normal cytoskeletal apparatus but did not bear electron-dense granules.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytotoxicity, Immunologic↗