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Biomedical subjects

H Waldmann

Publications and source records attributed to H Waldmann.

At least 325 records · Page 18Linked to original sources
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↗
PubMed1986

Ex vivo T-cell depletion with the monoclonal antibody Campath-1 plus human complement effectively prevents acute graft-versus-host disease in allogeneic bone marrow transplantation.

We have developed a rapid and simple procedure for the elimination of mature T-cells from the donor marrow using a single incubation with the monoclonal antibody Campath-1 and donor complement. This resulted in a reduction of T-cell contamination to a mean of 1%. This regimen reduced the incidence of acute graft-versus-host disease significantly in 21 consecutive bone marrow grafts in 18 patients with leukaemia and non-Hodgkin's lymphoma. Purging was responsible for an increased incidence of graft rejection in HLA-identical transplants (13%).

Adolescent↗
PubMed1986

Successful haploidentical mismatched bone marrow transplantation in severe combined immunodeficiency: T cell removal using CAMPATH-I monoclonal antibody and E-rosetting.

Six patients with severe combined immunodeficiency were transplanted with bone marrow from their HLA haploidentical parents. T-lymphocytes were removed by complement mediated lysis with a monoclonal antibody (CAMPATH-I) followed by rosetting with sheep erythrocytes. The patients were pre-conditioned with marrow ablative chemotherapy, using busulphan and cyclophosphamide. There was graft take in five patients, with evidence of transient acute graft-versus-host disease only. Three patients are alive and well greater than 5 months after transplant, and one who is 12 months post graft has full reconstitution of cell mediated and humoral immunity, including specific antibody response to immunization. Transplantation across major histocompatibility barriers can be successfully achieved using this method of treatment of donor marrow.

Antibodies, Monoclonal↗
PubMed1986

Bone marrow transplantation for patients with chronic myeloid leukaemia: T-cell depletion with Campath-1 reduces the incidence of graft-versus-host disease but may increase the risk of leukaemic relapse.

Between December 1983 and November 1985 we treated 39 patients with chronic myeloid leukaemia by chemoradiotherapy and transplantation from HLA-identical sibling donors using bone marrow that had been depleted of T cells ex vivo with the rat monoclonal antibody Campath-1. Twenty-eight of the patients were in the chronic phase (good-risk group) and 11 patients were in more advanced phases of the disease (accelerated phase or blastic transformation; poor-risk group). Of the patients of good risk 23 (82%) survive; the median duration of follow-up is 461 (range 111-776) days; of the 11 patients of poor risk four survive; the median duration of follow-up is 280 (range 189-658) days. Acute graft-versus-host disease (GVHD) of grade II or greater occurred in three (11%) of the patients of good risk and in six (55%) of the patients of poor risk. In the patients of good risk haematological evidence of relapse was seen in four and cytogenetic evidence of persisting or relapsed leukaemia (based on the finding of Philadelphia-chromosome-positive marrow metaphases more than 6 months after transplant) was seen in three other patients. In comparison with the patients of good risk transplanted with untreated marrow between February 1981 and December 1983, the incidence of acute GVHD was reduced significantly (P less than 0.001) but the risk of leukaemic relapse (including patients with only cytogenetic evidence of relapse) was increased (P less than 0.005). We conclude that T-cell depletion used in this manner may be associated with an increased risk of leukaemic relapse.

Actuarial Analysis↗
PubMed1985

Identification of macrophages and smooth muscle cells in human atherosclerosis using monoclonal antibodies.

Sections of human atherosclerotic plaques were stained by the indirect immunoperoxidase technique using three rat anti-human monoclonal antibodies: YAML 501.4 (anti-'leukocyte-common' (T200) antigen; YTH 8.18 (antimacrophage cytoplasm); and YPC 1/3 . 12 (anti-smooth muscle cell). The cells of diffuse intimal thickening were almost all smooth muscle cells but there were rare subendothelial macrophages. Focal lesions, in contrast, contained numerous macrophages as well as smooth muscle cells. Macrophage 'foam cells' were particularly numerous in fatty streaks and in advanced fibro-fatty plaques, but were less conspicuous in focal fibro-elastic lesions. The results confirm that macrophages are an important component of atherosclerotic plaques and suggest that they may have a significant role in atherogenesis in man.

Adult↗
PubMed1985

Therapeutic potential of monoclonal antibodies to the leukocyte-common antigen. Synergy and interference in complement-mediated lysis.

A series of rat monoclonal antibodies against the human leukocyte-common antigen were isolated and, by means of competitive binding assays with purified antigen, two distinct groups were defined that recognize different epitopes of the molecule. None of these antibodies were lytic with human complement, but when antibodies against each of these two epitopes were used in combination, synergistic lysis with human complement could be obtained. Synergistic lysis was only seen when each antibody of the pair was of the IgG2b subclass. IgG2a antibodies could not synergize, and in fact could interfere with lysis obtained by the pair of IgG2b antibodies. Although synergy has so far only been studied for rat monoclonal antibodies we also show that it is possible with mouse antibodies or with combinations of mouse and rat antibodies. The information about the principles of synergy and its interference should provide a rationale for using well-planned cocktails of monoclonal antibodies for therapy rather than a shotgun polyclonal antiserum.

Animals↗
PubMed1985

Reactivity of rat monoclonal antibody CAMPATH-1 with human leukaemia cells and its possible application for autologous bone marrow transplantation.

The rat monoclonal antibody CAMPATH-1 recognizes a hitherto undefined antigen present on virtually all normal lymphocytes and monocytes. Its reactivity with 105 samples of fresh leukaemic cells and 13 cell lines was measured by indirect fluorescence and peroxidase staining to define in more detail which stages of differentiation it recognizes. It was found to bind to cells from virtually all cases of lymphoid leukaemia (B cell CLL, T cell ALL, cALL and the few examples of HCL, PLL, Sezary syndrome and CGL in lymphoid blast crisis). The single case of cALL in relapse and four of six cases of null ALL were negative. Binding to non-lymphoid leukaemia cells (AML, AMML, AMoL, APL, AEL and CGL in blast crisis) was weaker or undetectable. Binding to established lymphoid cell lines was generally weak compared with fresh cells but some lines (MOLT4, DAUDI and X308) expressed adequate amounts of antigen to be lysed by CAMPATH-1 with human complement. Because CAMPATH-1 is very effective at killing lymphocytes in the presence of human complement, it has been used for removal of T cells in allogeneic transplants. The present results suggest that it might also have a role in purging bone marrow of leukaemia cells prior to autologous transplantation for acute lymphocytic leukaemia.

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↗
PubMed1985

Therapeutic potential of rat monoclonal antibodies: isotype specificity of antibody-dependent cell-mediated cytotoxicity with human lymphocytes.

The ability of rat monoclonal antibodies to promote antibody-dependent cell-mediated cytotoxicity with human effector cells was tested by using a variety of antibodies against different human and mouse leukocyte antigens. It was found that only IgG2b antibodies were effective. This isotype has already been shown to be efficient in fixing human complement, which suggests that among rat monoclonal antibodies, the IgG2b subclass might be a good choice for attempts at serotherapy. Further studies with other antibody-mediated effector mechanisms as well as suitable clinical trials are merited.

Animals↗
PubMed1984

Elimination of graft-versus-host disease by in-vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (CAMPATH-1).

A new monoclonal rat anti-human lymphocyte antibody (CAMPATH-1) which lyses cells with autologous human complement was used for depletion of T lymphocytes from human bone-marrow allografts in vitro before transplantation in 11 high-risk patients. HLA-matched siblings were used as marrow donors. T-cell depletion was substantial when measured by E-rosette formation (0-0.18% residual T cells) and immunofluorescence with a monoclonal anti-T-cell antibody (0-0.5%). No anti-graft-versus-host disease prophylaxis was given after transplantation. Rapid engraftment was reported in all patients, and the post-transplantation course was uneventful. No signs of graft-versus-host disease developed in any of the patients, who were observed for a maximum period of 12 months. The method might be suitable for larger-scale studies in high-risk patients. The late graft failure seen in 2 patients may reflect residual host resistance uncompromised by GvHD.

Adolescent↗
PubMed1984

Immunohistological screening in the selection of monoclonal antibodies: the use of isotype-specific antiglobulins.

This paper describes the use of the immunoperoxidase technique for the screening of rat hybridoma culture supernatants on tissue sections. By combining the avidin-biotin system with mouse monoclonal antibodies specific to different rat immunoglobulin isotypes, it is possible to resolve the specificity patterns of complex mixtures of monoclonal antibodies from uncloned culture wells. This strategy is particularly useful in the derivation of monoclonal antibodies to cell surface antigens.

Animals↗
PubMed1984

Detection of monoclonal antibodies against cell surface antigens: the use of antiglobulins coupled to red blood cells.

An antiglobulin-coupled red cell assay is described for screening monoclonal antibodies against cell surface antigens. A monoclonal antibody specific for rat immunoglobulin kappa chains was coupled to red blood cells and used to detect binding of rat monoclonal antibodies to cells attached to the wells of microtitre plates. The method was found to be simpler and more rapid than the alternative enzyme-linked binding assay and useful for rapid screening and selection of antibodies for use as differentiation markers of human and mouse haemopoietic cells.

Animals↗
PubMed1984

Allosuppression: evidence for the involvement of both "noncytotoxic" and cytotoxic T cells.

Allogeneic suppressor cells were generated by priming to a minor histocompatibility antigen. C57BL/10 female mice were primed to the male-specific minor transplantation antigen, H-Y. After boosting, anti-male-primed cells could potently suppress the secondary antibody response of male spleen cells in vitro. Anti-male suppressor cells were H-2-restricted, radiation-resistant T cells which could act on either T or B cells in the responding population. Mapping the restriction elements for anti-male suppressor cells revealed two distinct subpopulations of effector cells. The majority subpopulation was restricted to H-Y in the context of the H-2Db molecule. These cells were probably cytotoxic T cells as they were inhibited by culture of the suppressor cells in pyrilamide (a histamine receptor antagonist, which prevents the maturation of cytotoxic T cells from their precursors). The second subpopulation of suppressor cells was restricted to H-Y in the context of H-2K or I region-coded molecules. as neither H-2Kb nor H-2Ib molecules can act as restriction elements for anti-male-specific cytotoxic T cells, this subpopulations was almost certainly not composed of conventional cytotoxic cells. Furthermore, these cells were not affected by culture in pyrilamide. Together these two populations act to completely inhibit the anti-trinitrophenyl (TNP) plaque-forming cell response of male spleen cells in vitro.

Animals↗