Antigen-presenting cells and T cell activation.
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Animals↗
Biomedical subjects
M Kennedy
Publications and source records attributed to M Kennedy.
A bone marrow transplant with an acquired anti-Le(a): a case study.
A patient with aplastic anemia received an ABO incompatible bone marrow transplant (BMT) from an HLA identical sibling. Weekly HLA antibody screens were performed as part of the BMT protocol. At the time of transplant, a hemolytic anti-Le(a) was detected in the Le (a-b-) donor. The Le (a-b+) recipient had no red cell or LCT antibody. A hemolytic anti-Le(a) was detected in the recipient on day 8, but no LCT reactivity was noted at this time. On day 15, the LCT panel demonstrated reactivity with 9 of 50 panel cells without apparent HLA specificity. Graft vs. host disease (GVHD) was present on the skin at this time. The dose of cyclosporin A was increased, but by day 20 the GVHD worsened and the LCT titers increased to 8. This strong reactivity was noted only in the Le (a+) panel members (12/50) and was neutralized with commercial Lewis substance. On day 34 there was no evidence of GVHD, but the lymphocytotoxic anti-Lea continued to be present. The patient began experiencing renal and gastrointestinal difficulties by day 48, and expired on day 60. In renal transplants the kidneys retain their Lewis type and secrete Lewis substance in the urine. In our experience BMT patients retain their Lewis type regardless of the type of the donor. The Lewis system has been linked to renal allograft rejection, and Lewis antigens may function as transplantation antigens in BMT patients as well. In addition, lymphocytotoxic Lewis antibodies can mask other significant HLA antibodies and must be identified when screening patients in need of plateletpheresis products.
Anemia, Aplastic↗
Reserpic acid as an inhibitor of norepinephrine transport into chromaffin vesicle ghosts.
Reserpic acid, a derivative of the antihypertensive drug reserpine, inhibits catecholamine transport into adrenal medullary chromaffin vesicles. Since it does not affect the membrane potential generated by the H+-translocating adenosine triphosphatase but inhibits ATP-dependent norepinephrine uptake with a Ki of about 10 microM, reserpic acid must block the H+/monoamine translocator. Because reserpic acid is much more polar than reserpine, it does not permeate the chromaffin vesicle membrane, nor is it transported into chromaffin vesicle ghosts in the presence of Mg2+-ATP. Although it inhibits norepinephrine transport when added externally, reserpic acid does not inhibit when trapped inside chromaffin vesicle ghosts. Therefore, reserpic acid must bind to the external face of the monoamine translocator and should be a good probe of the translocator's structural asymmetry.
Adrenal Medulla↗
Monozygotic twins with alpha 1-antitrypsin deficiency.
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Diseases in Twins↗
Evaluation of accessory cell heterogeneity. I. Differential accessory cell requirement for T helper cell activation and for T-B cooperation.
Several Ia+ tumor cell lines and peritoneal exudate macrophages were tested as accessory cells (AC) for the activation of antigen-specific T cells and for T-B cooperation. The macrophages and all the Ia+ tumor lines tested induced the release of lymphokines from T cells in a major histocompatibility complex (MHC)-restricted fashion and reconstituted the antibody responses of AC-depleted spleen cells or of purified T and B cells. However, only the normal macrophages but none of the tumor lines induced carrier-specific T helper (Th) cells which help B cells for specific antihapten antibody responses by linked recognition. For T-B cooperation accessory cells were also required, but in contrast to Th cell activation any type of Ia+ AC (e.g. macrophage or tumor line) was effective. Strong MHC-restriction between the lymphocytes and the AC was seen if antigen-pulsed AC were added into the AC-depleted T-B cooperation cultures. If the AC and antigen were concomitantly added to the AC-depleted T-B cultures, MHC-restriction was less obvious. Concanavalin A supernatant reconstituted the response of AC-depleted T-B cultures provided antigen-specific Th cells and the hapten-carrier conjugate were present. If, however, tumor line-activated T cells were added instead of macrophage-induced Th cells, no cooperation with B cells took place even in the presence of Con A supernatant. The results obtained demonstrate a differential AC requirement for the induction of Th cells depending on the differentiation stage of the Th cells.
Animals↗
Evaluation of accessory cell heterogeneity. II. Failure of dendritic cells to activate antigen-specific T helper cells to soluble antigens.
The activation of antigen-specific T cells requires Ia+, antigen-presenting accessory cells (AC). Dendritic cells (DC) and macrophages (M phi) isolated from spleen an peritoneal exudate were tested as AC for the activation of the activation of T helper cells and the induction of T cell proliferation. The cell separations to obtain DC and splenic M phi were performed by discontinuous bovine serum albumin gradients, adherence on petri dishes and rosetting with opsonized sheep erythrocytes. DC as well as the M phi were able to induce antigen-specific T cell proliferation, but only the M phi and not the DC activated antigen-specific T helper cells which help B cells for antibody production to soluble antigens. Keyhole limpet hemocyanin-specific T cells repeatedly stimulated with DC and antigen also did not express helper activity. The failure of DC to induce T helper cells was not due to the activation of a suppressor pathway. Thus, dendritic cells, although very efficient as AC in the induction of various T cell functions, are not able to activate T helper cells required for carrier-specific T-B cooperation and therefore cannot be the sole accessory cells. Based on these results and on previous data using Ia+ tumor cell lines as AC, we confirm the existence of functional AC heterogeneity.
Animals↗
The design of a model for a three dimensional stress analysis of the cement layer beneath the medial plateau of a knee prosthesis.
Factors which have influenced the design of a large scale model for an analysis of the strain in three dimensions of the cement layer beneath the medial plateau of a knee prosthesis are discussed. Materials were selected to model the medial tibial plateau, underlying cement and bone for a typical prosthesis and a two dimensional finite element analysis was used to indicate where the strain gauges should be embedded in the model.
Bone Cements↗
Marrow transplantation for leukemia following fractionated total body irradiation. A comparative trial of methotrexate and cyclosporine.
Fifty-six patients, 30-47 yr of age, with leukemia in relapse received allogeneic marrow transplants from HLA-identical siblings. All patients were treated with cyclophosphamide (120 mg/kg) and 7 daily fractions of 2.25 Gy of total body irradiation (TBI) for seven consecutive days. Nine patients (16%) are currently alive and free of disease 324-845 days from transplantation. The actuarial relapse and survival rates at 2 yr were 56% and 9.5% respectively. These data were not remarkably different from those in previous studies using 10 Gy of TBI administered as a single dose. Thirty patients were randomized to receive methotrexate (MTX) and 26 to receive cyclosporine (CSP) as postgrafting prophylaxis for acute graft-versus-host disease (GVHD). The probability of developing significant acute GVHD by day 100 post-transplant was 71% for patients in the MTX group and 45% for patients in the CSP group (p less than 0.05). The probability of relapse was 37% for patients in the MTX group and 70% for patients in the CSP group (p less than 0.05). Transplant-related deaths were more frequent in the MTX group and leukemic deaths were more frequent in the CSP group although this may have been related to an uneven distribution of high-risk patients. Long-term disease-free survival was comparable. Patients in the MTX group had more severe mucositis, more alveolar pneumonias and possibly more deaths due to complications of acute and chronic GVHD. Patients in the CSP group had a higher incidence of hypertension, neurological complications and renal dysfunction.
Adult↗
Graft-versus-host disease in murine bone marrow transplantation. I. Modification of GVHD by preimmunization of recipients with spleen cells of primary recipients undergoing GVHD.
Lethally irradiated (1000 rad) CBA/J mice were transplanted with anti-Thy 1 treated BALB/c bone marrow. Under these conditions, we uniformly observed the development of pathology suggestive of acute graft-vs.-host disease (GVHD), i.e. weight loss, diarrhoea, hypogammaglobulinemia and thymic hypoplasia. If, 2 wk before irradiation, the recipients were preimmunized with spleen cells taken from mice undergoing acute GVHD, these symptoms were avoided. Instead, such animals seemed to show long term survival either with or without signs of chronic GVHD (hypergammaglobulinemia, splenomegaly, lymphoid hyperplasia). The ability to show long term survival with bone marrow allografts was dependent upon successful immunization of the recipient mice. Long term survivors contain a splenic population not bearing detectable host MHC antigens, which can elicit a memory anti-host cytotoxic response from a population of quiescent donor lymphocytes previously immunized in vitro against host MHC antigens.
Animals↗
Evaluation of accessory cell heterogeneity. III. Role of dendritic cells in the in vitro activation of the antibody response to soluble antigens.
Dendritic cells and macrophages obtained from spleen and peritoneal exudate were tested as accessory cells for the activation of lymphokine production by T cells, for supporting T-B cooperation and for the induction of antigen-specific T helper cells. Dendritic cells as well as macrophages were able to activate T cells for interleukin-2 secretion and functioned as accessory cells in T-B cooperation, but only macrophages induced T helper cells, which cooperate with B cells by a linked recognition interaction, to soluble antigens. Dendritic cell- and antigen-activated T cells also did not help B cells in the presence of Con A supernatants which contained various T cell- and B cell-stimulatory factors. The failure of dendritic cells to differentiate memory into functional T helper cells, but their efficient accessory cell function in T-B cooperation, where functional T helper cells are already present, can be best explained by a differential accessory cell requirement for T helper cell activation dependent on the differentiation stage of the T helper cell.
Animals↗
Cimetidine reverses tumor growth enhancement of plasmacytoma tumors in mice demonstrating conditioned immunosuppression.
Mice were given repeated injections, at 21 day intervals, of cyclophosphamide paired with a novel taste (saccharin) in the drinking water. Subsequent challenge with a syngeneic plasmacytoma tumor led to elevated tumor growth and mortality only in conditioned mice that were reexposed to saccharin. This effect was abolished by conditioned exposure to a histamine type II-receptor antagonist.
Animals↗
The binding of human IgM paraprotein from cases of polyneuropathy associated with benign monoclonal gammopathy to specific neurons of the rodent brain.
Human sera from patients with IgM paraproteinaemia were screened for IgM binding to frozen sections of the rat cerebellum by the indirect immunoperoxidase procedure. Out of 18 patients with a benign IgM gammopathy and associated demyelinating polyneuropathy (PPN), 17 showed binding to the surface of specific neurons, i.e. those of the deep cerebellar nuclei and the intermediate cell of Lugaro. Examination of other regions of the mouse brain suggests that the reactivity is restricted to cells of certain nuclei of the sensory-motor system. The use of F(ab)2 and monoclonal anti-idiotype antibodies demonstrate that the binding involves the antigen binding sites of the paraprotein. This reactivity indicates that some neurons have on their surface an antigen having an hapten in common with human myelin-associated glycoprotein (MAG) and the pi granules of human Schwann cells and furthermore is an additional serological characteristic of this group of patients. In addition 3 sera from the PPN group stained a particulate component in the cytoplasm of all medium-sized and large neurons. A similar staining was found with 7 out of 52 other unselected IgM paraproteinaemias.
Animals↗
Comparison of alprazolam with imipramine and placebos.
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Alprazolam↗
Alterations in lymphocyte recognition repertoire during ageing. I. Analysis of changes in immune response potential of B lymphocytes from non-immunized aged mice, and the role of accessory cells in the expression of that potential.
The repertoire of specificities recognized by endogenous plaque-forming cells of young or aged mice has been examined, as well as the repertoire of specificities represented by mitogen-activated B cells of those animals. Significant changes occur in both polyclonal endogenous plaque-forming cells and polyclonal B cell responsiveness, as well as reactivity for antigens expressed on bromelain-treated mouse erythrocytes and mouse Ig-coupled sheep erythrocytes. Adoptive transfer experiments suggest that these changes reflect a role for the differentiative environment in the regulation of the B cell recognition repertoire. Additional analysis of changes in antigen-presenting cells in aged mice suggest that alterations in the manner of presentation of environmental antigens in vivo may control the expressed B cell repertoire. Indeed, under experimental conditions it has proven less easy to induce B cell/macrophage restriction (for antigen presentation and induction of antibody formation) in cells of old animals than in cells of younger mice.
Aging↗
Immune responses to myelin antigens in Guillain-Barré syndrome.
Antibodies to nerve antigens were sought in the sera of 17 patients with acute Guillain-Barré syndrome (GBS), 11 with chronic relapsing demyelinating poly-radiculoneuropathy (CRP), 20 with other neuropathies (ON), 15 with other neurological diseases (OND) and 19 normal subjects. Complement-fixing antibodies to a suspension of human peripheral nerve tissue were identified in only 2 patients with GBS and 1 with chronic progressive neuropathy. Five GBS sera gave complement fixation reactions with rabbit sciatic nerve. The sera were also tested for galactocerebroside (Gal-C) binding activity using a solid phase assay. The range of values in all groups was the same, although the mean values for patients with GBS, ON and OND were higher than those of normal subjects. In a radioimmunoassay for antibodies to bovine P2 slightly more radiolabelled antigen was precipitated by the GBS group of sera than by sera from the other groups, but only one serum from the GBS and another from the CRP patients precipitated more than 10% of the label. Addition of bovine P2 to cultures of peripheral blood mononuclear cells from 11 patients with GBS did not cause significant stimulation. Immunoassay for antibody to myelin basic protein (MBP) showed an increased proportion of sera with low binding activity in the GBS and CRP groups. The results suggest that humoral immune responses to potentially neuritogenic antigens are found with marginally increased frequency in patients with GBS and CRP.
Adolescent↗
Associative learning and regulation of immune responses.
Conventional genetically inbred mice were exposed to an immunologically inert stimulus (CS) along with a stimulus known to perturb immune functioning [either non-specifically, an immunosuppressive drug; or specifically, an antigen]. After repeated trials of this type subsequent re-exposure of such "conditioned mice" to the CS alone was found to produce a change in immune response potential. This phenomenon has been examined in situations as diverse as those in which the test antigenic challenge is a tumour cell innoculum, or a tissue allograft. Some possible clinical implications of these findings are discussed.
Animals↗
Monoclonal antibodies against SSEA-1 antigen: binding properties and inhibition of human natural killer cell activity against target cells bearing SSEA-1 antigen.
We describe the properties of three monoclonal antibodies (Mab) against stage-specific embryonic antigen-1 (SSEA-1) in terms of their binding activity to HL60, K562, OTF9, and SOTF9 tumor target cells and their functional activity in modulating human natural killer (NK) cytotoxicity assays in vitro against these target cells. Indirect binding, competition, and Western blot analyses indicate that the Mab AEC3A1-9 (3A1), ASSEA-1, and AECAB1-32 (AB1) recognize cell-defined SSEA-1 antigen with activity characteristic of the cell source (HL60 greater than OTF9 greater than K562 much greater than SOTF9). The addition of anti-SSEA-1 Mab to the NK cytotoxicity assay resulted in an inhibition of LU per 1 X 10(6) PBL that correlated closely with the expression of SSEA-1 antigen on the target cell. No significant inhibition was seen for seven other Mab. Inhibition of NK activity (greater than 30%) was observed in the presence of anti-SSEA-1 Mab for 18 of 21 and 6 of 7 human donors examined for HL60 and OTF9 target cells, respectively. The pretreatment of fixed competing cells with anti-SSEA-1 Mab reduced the efficacy of those cells to act as cold competitors in a standard NK cytotoxic assay. Taken together these data suggest that SSEA-1 determinants are important at some stage in the cytolysis produced by NK cells.
Animals↗
Recognition specificities, development and possible biological function of natural killer cells in the mouse. II. Changes in NK recognition during ontogeny and ageing, and examination of role of environment in controlling the expressed recognition repertoire.
We have used a spleen fragment assay to assess subpopulations of NK effector cells in individual mice and to analyse the patterns of inhibition of lytic activity seen in the presence of different sugars (mono-, di- and tri-saccharides). Our data suggest that during ontogeny the heterogeneity (diversity) of the NK effector population increases in a fashion which is somewhat characteristic of the individual strain under investigation. Furthermore, when a similar analysis was performed on NK cells in the spleen of lethally irradiated recipient mice receiving syngeneic or semi-allogeneic bone marrow stem cell precursors, we found that the phenotype of inhibition by different sugars was a characteristic of the bone marrow donor and not of the recipient. In so far as the assay described assesses target recognition by NK cells (and not subsequent parameters involved in the lytic event) these data can be interpreted in terms of a relative independence of the expressed recognition repertoire of NK cells from the environment in which their differentiation occurs.
Aging↗