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Biomedical subjects

S Cobbold

Publications and source records attributed to S Cobbold.

49 records · Page 3Linked to original sources
PubMed1987

Monoclonal antibodies for the depletion of specific subpopulations of lymphocytes.

A number of rat monoclonal antibodies of the IgG2b subclass have been used to deplete mice of T lymphocyte subsets. It has been possible to produce long-term depletion where antibodies are administered to mice thymectomized in their adult life, or short-term depletion in euthymic animals. It is therefore feasible to ablate a T lymphocyte subpopulation at any stage in the course of an immune response and to examine in detail the role of a particular subset in the induction or effector phases of that response. We have used such ablative procedures to define the T cell subsets which participate in graft rejection, graft-versus-host disease, antigenic competition and antiviral and anti-self immunity and have attempted to exploit such knowledge to establish immunological tolerance in an adult animal.

Animals↗
PubMed1987

CD4 monoclonal antibody pairs for immunosuppression and tolerance induction.

A pair of rat anti-mouse CD4 monoclonal antibodies (mAb) have been selected which bind to different epitopes of the molecule. Both the mAb are rat IgG2b and show clear synergistic activity in complement lysis in vitro. When injected together in vivo, they exhibit an improved immunosuppressive effect, compared to each antibody alone, on allogeneic graft rejection, humoral responses and on tolerance induction. Limiting dilution analysis indicates that the in vivo depletion of interleukin 2-producing cells is improved using both mAb by 2-3-fold over that obtained with the individual antibodies. As little as 60 ng per mouse of the CD4 antibody pair was sufficient to allow the induction of tolerance to human gamma-globulin, even without elimination of the CD4+ cells. The results suggest that appropriate antibody pairs may be good candidates for effective immunosuppressive serotherapy in man.

Animals↗
PubMed1987

Human leukocyte differentiation antigens: monoclonal antibody computer databases as a tool for the future.

The immunofluorescence results of the Third International Workshop on Human Leukocyte Antigens have been used as the basis of a microcomputer database system. As well as providing a convenient means to access data on individual antibodies and the antigens identified by the Workshop (designated as 'clusters of differentiation' or CD antigens), it can be used to help characterize and identify new monoclonal antibodies. The ability to continue adding to this database means that it should become an increasingly powerful tool for both immunologists and haematologists. The philosophy behind the methods described should also be of interest to anyone making monoclonal antibodies to differentiation antigens.

Antibodies, Monoclonal↗
PubMed1987

Do L3T4+ T cells act as effector cells in protection against influenza virus infection.

This study aimed to analyse the roles of Lyt 2+ and L3T4+ memory T-cell subpopulations in murine influenza infection. Previous work has shown that Lyt 2+ cytotoxic T-cell (Tc) clones can adoptively transfer protection. We therefore wished to see whether L3T4+ (Th) cells could also act as protective effector cells. Donors for adoptive cell transfer were thymectomized mice, depleted in vivo of either Lyt 2+ or L3T4+ T cells with monoclonal antibodies (MAb) and then infected with influenza virus (A/X31). Primed spleen cells, after removal of the B cells, were transferred into irradiated hosts infected simultaneously or persistently with a heterologous influenza virus and the effect on lung virus replication determined. Depletion of L3T4+ T cells suppressed the formation of IgG antibodies after influenza virus infection, indicating significant depletion of T-helper function. Yet Lyt 2+ class I MHC-restricted Tc cells were effectively primed in these mice, albeit to half the normal level. Adoptive transfer of the Lyt 2+ memory T cells cleared virus in a persistent infection within 6 days. Spleen cells selected for L3T4+ T cells cleared virus within 21 days of transfer in a simultaneous infection and reduced viral titres in a persistent infection, but not as effectively as L3T4+-depleted spleen cells. Although no Lyt 2+ cells were detected by fluorescence staining in Lyt 2+-depleted spleens, we could detect low levels of class I MHC-restricted influenza-specific Tc memory cells in host spleens following influenza infection. Therefore, whether the early viral clearance is solely due to L3T4+ T cells is not clear. Lyt 2+ memory T cells appear more efficient in this respect than L3T4+ memory T cells.

Animals↗
PubMed1987

L3T4 and Lyt-2 T cells are both involved in the generation of low-dose streptozotocin-induced diabetes in mice.

In order to determine the role of different T lymphocyte subsets in the pathogenesis of low-dose streptozotocin (LD-Sz) induced diabetes, we treated mice with Sz together with repeated injections of rat monoclonal antibodies (MoAb) with specificity towards the mouse T cell differentiation markers L3T4 ('helper/inducer' T cells and some macrophages), Lyt-2 ('cytotoxic/suppressor' T cells and NK cells) and Thy-1 (pan T lymphocytes). Treatment depleted target cells in peripheral blood and spleen; decreased the ability of spleen cells to respond to mitogens; and, in the case of depletion of the L3T4 T cell subset, prevented a humoral immune response to SRBC. Treatment with MoAb against either of the two T cell subtypes could protect from hyperglycaemia and loss of body weight, suggesting that both T cell subsets were implicated in the development of LD-Sz induced diabetes. Immunocytochemical analysis of pancreatic sections showed that both L3T4+ and Lyt-2+ cells participated in islet infiltration together with macrophages. Treatment with MoAb markedly reduced islet infiltration by both L3T4+ and Lyt-2+ cells but not by macrophages. The suppressive effect of MoAb against either L3T4 or Lyt-2 on diabetes development suggests that the pathomechanism involved is different from that in experimental autoimmune neuritis and adjuvant arthritis where Lyt-2 cells are not involved.

Animals↗
PubMed1986

Unexpected mobilisation of lead during cisplatin chemotherapy.

During an investigation by X-ray fluorescence of platinum uptake in the kidney after chemotherapy with cisplatin, lead was found to have accumulated in the kidney in four subjects. The average kidney lead burden in one case exceeded 800 micrograms/g. Although two of the subjects had been occupationally exposed to lead, the other two had not. The tibia lead burden was also high in the two subjects in whom it was measured. The origins of this mobilised lead and the implications for cisplatin nephrotoxicity are discussed.

Aged↗
PubMed1986

Immunoglobulin heavy chain locus of the rat: striking homology to mouse antibody genes.

DNA encoding the rat diversity segment (D), joining segment (JH), and constant (C) region mu, gamma 2a, gamma 1, gamma 2b, epsilon and alpha of the Ig heavy chain has been isolated from a cosmid library. Restriction mapping allowed us to identify two gene clusters: D-JH-C mu and C gamma 1-C gamma 2b-C epsilon-C alpha in addition to a single C gamma 2a gene. Analysis of genomic DNA by Southern blotting permitted identification of the C gamma 2c gene and led to the proposal of the following gene order for the rat Ig heavy chain locus: D-JH-C mu-C delta-(C gamma 2c, C gamma 2a)-C gamma 1-C gamma 2b-C epsilon-C alpha. There is striking homology between the rat and mouse Ig heavy chain loci as regards gene order and distance between CH genes. Partial DNA sequencing confirms this homology and shows that exon sequences are more conserved than are intron sequences. One of the most conserved intron regions between rat and mouse is that spanning the Ig heavy chain enhancer (91% homology). However, the relationship between the different C gamma subclasses in rat differs from that in mouse. Comparison of the C gamma CH3 domains shows that the rat C gamma 2b gene is most homologous to mouse C gamma 2a/b, whereas the rat C gamma 1 and C gamma 2a genes, both very similar to each other, are most homologous to the mouse C gamma 1 gene.

Amino Acid Sequence↗
PubMed1986

Skin allograft rejection by L3/T4+ and Lyt-2+ T cell subsets.

The L3/T4+ and Lyt-2+ T-cell subsets can be depleted from mice, using selected monoclonal antibodies in vivo, at different times during rejection of, or priming to, allogeneic skin grafts. Although L3/T4+ cells are sufficient to reject skin grafts in naive Lyt-2-depleted mice, we show that Lyt-2+ cells can become involved, after an initial delay, in intact mice. Furthermore, these Lyt-2+ cells are primed to dominate the accelerated rejection of a normal secondary response. Mice depleted of L3/T4+ cells cannot be primed in this way, suggesting that priming of Lyt-2+ cells is dependent on help from L3/T4+ cells. However, in mice depleted of Lyt-2+ cells, priming for rapid rejection can be achieved, presumably via the L3/T4+ population. This suggests that the rejection of skin allografts in a given situation reflects different contributions of multiple effector mechanisms.

Animals↗
PubMed1986

Monoclonal antibodies for the prevention of graft-versus-host disease and marrow graft rejection. The depletion of T cell subsets in vitro and in vivo.

One of the major complications of allogeneic bone marrow transplantation is graft-versus-host disease. This can be avoided by removing the mature T cells from the marrow, most conveniently by the use of monoclonal antibodies. However, T cell purging results in an increased tendency for the recipient to reject the donor marrow. We have developed monoclonal antibodies to L3/T4 and Lyt-2 that specifically deplete functional T cell subsets in mice. We demonstrate that such reagents can be used to control both graft-versus-host disease and marrow rejection in mouse models of bone marrow transplantation across one-haplotype or two-haplotype major histocompatibility differences. Such strategies to abrogate host resistance, by administration of anti-T-cell monoclonal antibodies to the recipient, may complement marrow T cell purging for human allogeneic bone marrow transplantation.

Animals↗
PubMed1985

Antilymphocytic antibodies and marrow transplantation. VII. Two of nine monoclonal anti-Thy-1 antibodies used for pretreatment of donor marrow suppressed graft-versus-host reactions without added complement.

Eleven monoclonal antibodies of rat or mouse origin against the mouse pan T antigen Thy-1 were compared for their ability to reduce mortality from graft-versus-host disease (GVHD) when incubated with donor marrow. Spleen and bone marrow cells were transferred to F1 hybrids or to fully allogeneic (H-2 I-A incompatible) mice. Particular attention was paid to whether complement (rabbit) enhanced the anti-GVHD effect of the antibodies in homozygous histoincompatible chimeras: without complement, 5 IgM anti-Thy-1 and 2 IgG2a anti-Thy-1 did not reduce GVHD. With complement, acute GVHD was completely suppressed. Two of two rat IgG2b anti-Thy-1, however, suppressed acute GVHD without the need for added complement. One of the two also prevented chronic mortality following two haplotype-unmatched transplantation. This antibody, in contrast to other complement-fixing anti-Thy-1 antibodies, had previously been shown to delay rejection of skin allografts. Its specificity did not differ from other complement-dependent Thy-1 antibodies when tested in a cross-blocking radioimmunoassay, and it also had the lower affinity for Thy-1. It seems therefore that only a minority of the antibodies were able to fully exploit the marrow recipients' opsonizing capacity for suppression of GVHD. The important clinical implications of the remarkable difference in immunosuppression of various monoclonal antibodies with comparable specificity and capacity to fix complement in vitro are discussed.

Animals↗
PubMed1983

Separation of hemopoietic cells from adult mouse marrow by use of monoclonal antibodies.

Primitive hemopoietic progenitor cells from adult mouse marrow have been substantially enriched by virtue of a negative selection procedure with monoclonal antibodies. It has been possible to segregate erythroid progenitor cells at distinct stages of differentiation on the basis of their cell surface antigens. This has been achieved with two monoclonal antibodies reactive with the mature elements of bone marrow. YBM 34.3 binds to a heat-stable antigen expressed on B lymphocytes, neutrophils, and cells of the erythroid lineage. YBM 6.1 reacts with cells of the neutrophil, eosinophil, and monocyte series but does not bind to colony-forming cells. Separation is achieved by indirect immunoadsorption (panning) with YBM 34.3 on Protein-A-coated plastic plates followed by FACS II cell sorting with YBM 6.1. The combined procedures yield a marrow population containing 58% immature cells (blasts, promyelocytes, and myelocytes) and 9.5% clonogenic cells. In addition, differential binding of YBM 34.3 can be used to segregate erythroid progenitor cells at distinct stages of differentiation (day 7 BFU-E, day 5 BFU-E and CFU-E) either by cell sorting or panning. It is shown that both techniques give a comparable degree of resolution of the different cell types with, however, an appreciable advantage of panning over cell sorting in allowing the rapid handling of large numbers of cells.

Animals↗
PubMed1975

Lactic acidosis complicating treatment of ketosis of labour.

Hypertonic glucose, fructose, and sorbitol solutions were given intravenously to women in the first stage of labour who had ketonuria and ketonaemia as evidenced by a raised blood acetoacetate and 3-hydrosybutyrate. There was no difference in the antiketogenic action of these, which was rapid and effective, but when compared with a control group who were given normal saline they had a high incidence of hyperlactataemia, and nine out of 28 patients developed lactic acidosis after the infusions. The "lactatogenic" effect was shared by all three substrates, and when they are used in the treatment of ketosis of labour, and the mother develops lactic acidosis, they might exacerbate pre-existing lactic acidosis and precipitate fetal distress.

Acetoacetates↗