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B D Hock

Publications and source records attributed to B D Hock.

At least 19 recordsLinked to original sources
PubMed2006

Circulating levels and clinical significance of soluble CD86 in myeloma patients.

Circulating soluble CD86 (sCD86) levels are elevated in a number of leukaemias and are an independent prognostic factor in acute myeloid leukaemia. We investigated the clinical significance of circulating sCD86 in 299 patients from the UK Medical Research Council myeloma VIth trial, where patients received ABCM [adriamycin, carmustine (BCNU), cyclophosphamide, melphalan] either alone or with prednisolone (ABCM + P). Serum levels of sCD86 were significantly elevated (P = 0.0001) in myeloma patients and using the median normal donor level (0.621 ng/ml) as a cut-off point, 70% of patients had elevated levels (range = 0.015-15.87 ng/ml, median = 1.1 ng/ml). In univariate analysis elevated sCD86 levels were associated with significantly shorter (P < 0.001) survival (median = 22 vs. 51 months) and event-free survival (median = 14 vs. 31 months) in ABCM + P but not ABCM patients. Multivariate analysis demonstrated that sCD86 was a significant, independent prognostic marker of both overall [risk ratio (RR) = 2.04, P = 0.0006] and event-free (RR = 1.95, P = 0.0004) survival in ABCM + P patients. In conclusion, this study demonstrated that sCD86 levels are a significant independent prognostic marker in at least some myeloma treatment groups and its biological role and prognostic value should be further investigated.

Adult↗
PubMed2006

Levels of the soluble forms of CD80, CD86, and CD83 are elevated in the synovial fluid of rheumatoid arthritis patients.

The release of soluble forms of CD80 (sCD80), CD86 (sCD86), and CD83 (sCD83) provide a potentially powerful immunoregulatory mechanism. We therefore investigated the potential presence and relative levels of these molecules in the synovial fluid (SF) and serum of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum and SF levels were measured by enzyme-linked immunosorbent assay. Serum levels of sCD80, sCD86, and sCD83 in RA and OA patients were similar to those present in normal donor serum (NDS) and the SF of OA patients. In contrast, when compared with NDS and OA SF levels, almost all RA SF samples had elevated sCD83 levels (32/35, >0.63 ng/ml) and a substantial proportion had elevated sCD80 (13/29, >0.22 ng/ml) or sCD86 (16/33, >2.31 ng/ml) levels. Analysis of matched pairs of serum and SF from RA patients demonstrated that the SF/serum ratio for sCD80 (95% CI = 1.7-3), sCD86 (95% CI = 1.5-3.1), and sCD83 (95% CI = 3.6-7.8) levels was >1 in almost all patients. In conclusion, this study shows that the SF from almost all RA patients contain elevated levels of sCD83 and the majority of these samples also contain elevated levels of sCD80 and/or sCD86. These molecules may play a role in modulating immune responses within the rheumatoid joint.

Adolescent↗
PubMed2004

Identification of a circulating soluble form of CD80: levels in patients with hematological malignancies.

The release of soluble forms of CD80 provides a potentially powerful mechanism for the modulation of anti-tumor responses. In this report we investigated whether a soluble form of CD80 (sCD80) circulates in vivo and whether levels are altered in patients with hematological malignancies. Circulating sCD80 was detected by ELISA in all normal donor (0.024-0.318 ng/ml) and patient (0.02-3.75 ng/ml) blood analyzed. The majority of acute myeloid leukemia (13/17) and multiple myeloma (11/12) patients had normal sCD80 levels. Significantly elevated levels were detected in chronic lymphocytic leukemia (CLL, P = 0.0001) and mantle cell lymphoma (MCL, P = 0.0002) patients. MCL patients had the highest levels with 8/9 having levels > 0.318 ng/ml. Increased sCD80 levels in CLL were significantly associated with poor prognosis markers such as low platelet (P = 0.01) and hemoglobin (P = 0.002) levels, elevated WBC counts (P = 0.03) and expression of CD38 (P = 0.048). The immunoreactivity of the sCD80 in both normal and patient plasma was inhibited by the presence of CTLA-4-Ig, suggesting sCD80 is functional. Comparison of sCD80 and soluble CD86 levels demonstrated that these molecules were independently elevated in 39% of patients. The finding that a proportion of CLL and the majority of MCL patients contain elevated levels of sCD80 and the demonstration that sCD80 can interact with CTLA-4-Ig suggests a potential role for sCD80 in modulating anti-tumor responses during the malignant process.

Abatacept↗
PubMed2002

Differential effects of G-CSF mobilisation on dendritic cell subsets in normal allogeneic donors and patients undergoing autologous transplantation.

It has been suggested that the immunological properties of cytokine primed PBSC may reflect the presence of altered levels of cellular components. In this study the changes induced in blood dendritic cell (DC) subsets following G-CSF mobilisation are analysed. Analysis of normal donors (n = 64) demonstrated considerable individual variation in the absolute numbers (x10(6)/l) of resting blood CD11c(-) DC (1.2-26.2) and CD11c(+) DC (0.9-34.7) as well as in the CD11c(-)/CD11c(+) DC ratio (0.29-4.13). G-CSF therapy increased CD11c(-) DC numbers to above the normal range in all normal donors analysed (n = 6) and the CD11c(-)/CD11c(+) ratio was also increased to >2.0 in all donors. Patients undergoing autologous PBSCT showed a heterogeneous response to mobilisation and although total DC and CD11c(-) DC numbers were increased in the majority (8/14), they remained within the normal range post mobilisation. The CD11c(-)/CD11c(+) ratio decreased in 5/15 patients and only three patients had ratios >2.0 post mobilisation. Post G-CSF the DC from all normal donors and 13/14 patients had an immature phenotype. These results demonstrate that G-CSF mobilisation induces relatively consistent changes in the number and ratio of DC subsets in normal donors, but considerable variation is seen in the response of patients undergoing mobilisation for autologous PBSCT.

Adult↗
PubMed2002

Human plasma contains a soluble form of CD86 which is present at elevated levels in some leukaemia patients.

Cell surface expression of CD86 (mCD86) provides an important co-stimulatory signal which profoundly influences immune responses. In this report, we investigated the potential presence of a circulating soluble form of CD86 (sCD86) in normal individuals and patients with acute myeloid leukaemia (AML) or B cell chronic lymphocytic leukaemia (B-CLL). Circulating sCD86 was detected in the plasma of all normal individuals (1.04 +/- 0.33 ng/ml, n = 51) and patients analysed. Plasma collected from AML patients in remission (n = 6) contained only low levels of sCD86 but significantly elevated levels (> or =2.65 ng/ml, P < 0.0001) were detected in 10/24 AML patients analysed at the time of presentation or relapse. Significantly elevated levels of sCD86 were also detected in 2/17 B-CLL patients. There was no correlation between sCD86 levels and other clinical parameters. RT-PCR analysis demonstrated that normal monocytes and dendritic cells, as well as isolated AML (n = 2) and B-CLL (n = 4) cells, expressed an alternatively spliced transcript of CD86 which encoded a soluble form absent in normal T, B and NK cells. The finding that a proportion of leukaemia patients contain elevated levels of sCD86 and that at least some leukaemic cells express sCD86 transcript suggests a potential role for sCD86 in modulating mCD86 signalling during the malignant process.

Acute Disease↗
PubMed2001

Phenotypic characterization of five dendritic cell subsets in human tonsils.

Heterogeneous expression of several antigens on the three currently defined tonsil dendritic cell (DC) subsets encouraged us to re-examine tonsil DCs using a new method that minimized DC differentiation and activation during their preparation. Three-color flow cytometry and dual-color immunohistology was used in conjunction with an extensive panel of antibodies to relevant DC-related antigens to analyze lin(-) HLA-DR(+) tonsil DCs. Here we identify, quantify, and locate five tonsil DC subsets based on their relative expression of the HLA-DR, CD11c, CD13, and CD123 antigens. In situ localization identified four of these DC subsets as distinct interdigitating DC populations. These included three new interdigitating DC subsets defined as HLA-DR(hi) CD11c(+) DCs, HLA-DR(mod) CD11c(+) CD13(+) DCs, and HLA-DR(mod) CD11c(-) CD123(-) DCs, as well as the plasmacytoid DCs (HLA-DR(mod) CD11c(-) CD123(+)). These subsets differed in their expression of DC-associated differentiation/activation antigens and co-stimulator molecules including CD83, CMRF-44, CMRF-56, 2-7, CD86, and 4-1BB ligand. The fifth HLA-DR(mod) CD11c(+) DC subset was identified as germinal center DCs, but contrary to previous reports they are redefined as lacking the CD13 antigen. The definition and extensive phenotypic analysis of these five DC subsets in human tonsil extends our understanding of the complexity of DC biology.

CD13 Antigens↗
PubMed2001

A soluble form of CD83 is released from activated dendritic cells and B lymphocytes, and is detectable in normal human sera.

CD83 is an inducible glycoprotein expressed predominantly by dendritic cells (DC) and B lymphocytes. Expression of membrane CD83 (mCD83) is widely used as a marker of differentiated/activated DC but its function and ligand(s) are presently unknown. We report the existence of a soluble form of CD83 (sCD83). Using both a sCD83-specific ELISA and Western blotting, we could demonstrate the release of sCD83 by mCD83(+) B cell and Hodgkin's disease-derived cell lines, but not mCD83(-) cells. Inhibition of de novo protein synthesis did not affect the release of sCD83 during short-term (2 h) culture of cell lines although mCD83 expression was significantly reduced, suggesting sCD83 is generated by the release of mCD83. Isolated tonsillar B lymphocytes and monocyte-derived DC, which are mCD83(low), released only low levels of sCD83 during culture. However, the differentiation/activation of these populations both up-regulated mCD83 and increased sCD83 release significantly. Analysis of sera from normal donors demonstrated the presence of low levels (121 +/- 3.6 pg/ml) of circulating sCD83. Further studies utilizing purified sCD83 and the analysis of sCD83 levels in disease may provide clues to the function and ligand(s) of CD83.

Antigens, CD↗
PubMed1999

Human dendritic cells express a 95 kDa activation/differentiation antigen defined by CMRF-56.

Despite the unique functions of dendritic cells (DC), only two cell surface antigens (CMRF-44 and CD83) with relatively restricted expression on human DC have been described to date. We describe a third mAb, CMRF-56, which recognizes another DC early activation/differentiation antigen with limited expression on other haemopoietic cell populations. Circulating blood leukocytes did not express the CMRF-56 antigen and, following either in vitro culture or activation of PBMC populations, CMRF-56 antigen expression was detected only on DC and a subpopulation of CD19+ lymphocytes. Circulating blood DC were CMRF-56 but induced expression within 6 h of in vitro culture. This, together with the finding that tonsil and synovial fluid DC upregulate the antigen following short-term in vitro culture, confirmed that CMRF-56 recognizes an early activation antigen on DC. Isolated Langerhan's cells, dermal DC, migratory dermal DC and monocyte derived DC (GM-CSF/IL-4/TNFalpha) also express the CMIRF-56 antigen. Antigen modulation studies demonstrated that the amount of cell surface bound CMRF-56 and CMRF-44 (but not CD83) mAb was dramatically reduced by short-term incubation at 37 degrees C. This effect was not due to internalization and the reduction in CMRF-56 binding was a reversible, temperature-dependent process. In contrast, the decrease in CMRF-44 binding was irreversible, suggesting that following ligation the CMRF-44 antigen undergoes an irreversible conformational change or shedding at 37 degrees C. Western blotting confirmed that CMRF-56 recognizes a previously undescribed 95 kDa activation antigen whose cellular distribution and expression kinetics overlaps with, but is clearly distinguishable from, that of the CD83 and CMRF-44 antigens. CMRF-56 therefore provides a useful additional marker for studies on human DC.

Antibodies, Monoclonal↗
PubMed1998

Human dendritic cells express functional interleukin-7.

Interleukin-7 (IL-7) supports the proliferation of mature T lymphocytes, however, the cellular source of IL-7 for T lymphocyte activation has not been well established. We therefore investigated whether human peripheral blood dendritic cells (DC) produce IL-7 as a contribution towards T lymphocyte activation. Human CMRF-44+/CD14-/CD19- low density DC, purified after overnight tissue culture, contained IL-7 transcripts, detected by direct cell reverse transcription-polymerase chain reaction. Intracytoplasmic staining confirmed IL-7 protein in at least a subpopulation of cultured low density DC. In contrast, resting/immature DC, isolated directly by immunodepletion of lineage marker positive cells, contained no IL-7 mRNA. Thus, the expression of IL-7 by DC follows the pattern described previously for CD80, CD86 and CD40. However, tissue culture of purified resting/immature DC, in contrast to CD80, CD86 and CD40, failed to induce IL-7 transcripts. The functional importance of DC IL-7 expression was demonstrated in an allogeneic mixed leukocyte reaction (MLR). Neutralising mAb to IL-7 significantly inhibited T lymphocyte proliferation when low DC numbers were used, but at higher stimulator numbers, anti-IL-7 mAb failed to inhibit an allogeneic MLR. This suggests, that when DC are in excess, other co-stimulatory pathways can compensate for the lack of IL-7. Addition of IL-7 to a MLR caused a significant increase in the proliferative response stimulated by monocytes and B lymphocytes but not by DC. These data support the concept of an initial phase of antigen uptake by DC followed by the optimisation of DC co-stimulatory potential. The co-stimulatory repertoire expressed, including IL-7, may be regulated by exogenous stimuli, thereby ensuring DC flexibility in mounting a response appropriate to the environmental changes.

Cells, Cultured↗
PubMed1997

Isolation of human blood dendritic cells using the CMRF-44 monoclonal antibody: implications for studies on antigen-presenting cell function and immunotherapy.

Dendritic cells (DC) are potent antigen-presenting cells (APC) with the capacity to stimulate a primary T lymphocyte immune response and are therefore of interest for potential immunotherapeutic applications. Freshly isolated DC or DC precursors may be preferable for studies of antigen uptake and the potential control of APC costimulator activity. In this report, we report that the monoclonal antibody CMRF-44 can be used to detect early DC differentiation. The majority of DC circulating in blood do not express any known DC lineage specific markers, but can be identified by CMRF-44 labeling after a brief period of in vitro culture. The sequential acquisition of DC activation antigens allows the identification of two stages of DC maturation/activation. Cytokines, especially granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)alpha, enhance both phases of this process, whereas CD40-ligand trimer preferentially enhances the final DC maturation to a fully mature, activated phenotype. DC positively selected using CMRF-44 possess potent allostimulatory activity and are efficient at the uptake, processing, and presentation of soluble antigens for both primary and secondary immune responses. CMRF-44+ DC are also more potent than other APC types at restimulation of a chronic myeloid leukemia peptide specific T-cell clone. The use of a purified population of freshly isolated DC may be advantageous in attempts to initiate, maintain, and direct immune responses for immunotherapeutic applications.

Animals↗
PubMed1997

Hodgkin's cells express CD83, a dendritic cell lineage associated antigen.

Hodgkin's cells (HC) are considered to be the malignant cells of Hodgkin's disease (HD), but despite extensive studies, no conclusive evidence has emerged regarding their non-malignant counterpart and the ontogeny of these cells remains controversial. The analysis of a possible dendritic cell (DC) origin of HC has been hampered to date by the lack of a DC lineage specific marker. The expression of the two DC-associated antigens CD83 and CMRF-44, the B lymphocyte restricted molecule CD79, and the costimulator molecule CD86, was examined in lymph nodes from 23 HD patients using immunohistological techniques. The majority of HC expressed the CD83 (22/23) and CD86 antigens (20/23), whereas expression of the CMRF-44 antigen was variable (10/23) and usually only a subpopulation of HC stained. In contrast, the CD79 antigen was absent from most HC (17/23). The presence of the CD83 antigen on HC in the absence of the CD79 antigen supports a possible DC lineage origin for some HC. Regardless of its role in lineage assignment, CD83 may become a useful immunohistological marker for HD as the CD83 antigen was present on most HC.

Antibodies, Monoclonal↗
PubMed1996

Human T lymphocytes and hematopoietic cell lines express CD24-associated carbohydrate epitopes in the absence of CD24 mRNA or protein.

The CD24 surface antigen is a small glycophosphatidylinositol (GPI)-anchored glycoprotein found on human granulocytes and most B lymphocytes. Many CD24 monoclonal antibodies (MoAbs) have been described that identify several epitopes, with the majority of them related to carbohydrate structures associated with the CD24 molecule. Considerable variation has been observed in the apparent tissue distribution of the CD24 antigen depending on the MoAb used, and hence the CD24 epitope studied. In this study, CD24 expression by human cell lines and normal hematopoietic call populations was assessed using a panel of carbohydrate and protein core-specific CD24 MoAbs and reverse transcriptase polymerase chain reaction (RT-PCR) analysis. A number of CD24 carbohydrate epitope-reactive MoAbs bound to both T lymphocytes and several hematopoietic cell lines, despite the absence of concomitant CD24 mRNA or detectable surface CD24 core protein in the same cells. This additional CD24 MoAb reactivity on T lymphocytes was, in common with that observed on granulocytes (CD24 protein+), specifically inhibited by the presence of both sialyllactose and mucin. Similarly, the binding of carbohydrate epitops-reactive CD24 MoAb was reduced on both T lymphocytes and granulocytes by pretreatment with phospholipase C, pronase, or neuraminidase. Together, the data indicate that a number of CD24-associated carbohydrate epitopes have a broader tissue distribution than the CD24 protein and are expressed on additional GPI-linked molecule(s). These findings have immediate implications for both leukemia phenotyping and attempts to examine CD24 function with CD24 MoAb.

Animals↗
PubMed1995

Activation of human peripheral blood dendritic cells induces the CD86 co-stimulatory molecule.

Maximal T lymphocyte responses require presentation of antigen by major histocompatibility complex molecules and delivery of one or more co-stimulatory signals. Interaction of the CD28 molecule on T lymphocytes with its ligands on antigen-presenting cells (APC) initiates a critical co-stimulatory pathway inducing T lymphocyte proliferation and cytokine secretion. Dendritic cells (DC) are potent APC for a primary T lymphocyte response and potential CD28/CTLA-4 ligands on DC are, therefore, of particular functional relevance. In these experiments, the expression and function of the CD28/CTLA-4 ligands B7.1 (CD80) and B7.2 (CD86) were examined on human blood DC. Resting DC populations directly isolated by immunodepletion of lineage marker-positive cells lacked cell membrane expression of CD80 and expressed little or no CD86, although CD86, but not CD80 mRNA was detected by reverse transcription-polymerase chain reaction analysis. In contrast, low-density DC isolated after culture in vitro strongly expressed CD86 surface protein, but expressed limited or no CD80, although mRNA for both molecules were detected. Short-term culture of directly isolated DC up-regulated both CD80 and CD86 expression. Analysis of the kinetics of CD28/CTLA-4 ligand induction showed that surface CD86 was present within 8 h, whereas CD80 antigen was first detected after 24 h of culture. The functional importance of CD28/CTLA-4 ligand up-regulation on DC during T lymphocyte interactions was demonstrated by the ability of both CTLA-4Ig and CD86 monoclonal antibodies (mAb), but not CD80 mAb, to block an allogeneic mixed lymphocyte reaction stimulated by DC populations initially negative for CD80 and CD86. These results demonstrate that CD86 is both the earliest and functionally the predominant co-stimulatory CD28/CTLA-4 ligand on DC.

Abatacept↗
PubMed1994

Characterization of a novel leucocyte activation antigen recognized by the antibody CMRF-37.

We describe a novel activation antigen recognized by the monoclonal antibody CMRF-37, which is absent or only weakly expressed on resting cells but is rapidly induced on T cells, B cells and monocytes following stimulation. Its kinetics of expression (12-24 h after the addition of the inductive signal) indicate that it is an early activation antigen. The cellular distribution and expression kinetics of the CMRF-37 antigen differ from other known activation antigens and as such should be a useful marker of human leucocyte activation.

Animals↗
PubMed1994

Characterization of CMRF-44, a novel monoclonal antibody to an activation antigen expressed by the allostimulatory cells within peripheral blood, including dendritic cells.

Dendritic cells (DC) are the most potent antigen-presenting cells (APC) involved in the initiation of primary T-lymphocyte responses. However, despite their importance, no DC-specific surface marker has been identified in humans and many aspects of their ontogeny and the mechanisms underlying their potent functional activity remain unknown. In this report we describe a novel monoclonal antibody (mAb), CMRF-44, which recognizes an early activation antigen expressed by human DC and acts as a marker of allostimulatory activity within preparations of peripheral blood mononuclear cells (PBMC). The CMRF-44 antigen was expressed strongly on DC isolated from blood and tonsil by standard techniques, but was not detectable on Langerhans' cells within skin or on DC isolated directly from blood using a cell-sorting method which involves minimal DC manipulation/activation. Normal resting peripheral blood leucocytes did not label with CMRF-44, although weak staining of a small subpopulation (15%) of blood B lymphocytes was identified by double labelling. However, following overnight culture at 37 degrees, moderate staining of a subpopulation of PBMC was detected. Confirmation that CMRF-44 recognized an early marker of activated DC and hence allostimulatory activity was obtained by sorting cultured cell preparations on the basis of CMRF-44 reactivity. A marked enrichment of allostimulatory activity was observed in the CMRF-44-positive cellular population, whereas the CMRF-44-negative cells showed only minimal stimulatory activity. Activation studies established that the CMRF-44 antigen was an early activation marker, expressed constitutively on the majority of tonsil B lymphocytes, which can be induced on peripheral blood B lymphocytes and subpopulations of monocytes. Expression of the CMRF-44 antigen on cell lines was similarly restricted, CMRF-44 antigen being detected only on Hodgkin's disease-derived and B-lymphoid lines. The cellular distribution, expression kinetics and biochemical characteristics of the CMRF-44 antigen identify it as a new early marker of activated allostimulatory (DC) populations.

Animals↗