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Biomedical subjects

H Waldmann

Publications and source records attributed to H Waldmann.

394 records · Page 22Linked to original sources
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Therapeutic potential of monovalent monoclonal antibodies.

One therapeutic use for monoclonal antibody technology is the elimination of categories of unwanted cells by virtue of their distinct cell surface antigens. The efficiency of cell destruction by complement lysis or opsonization depends on a number of factors such as antibody specificity and isotype as well as certain properties of the target antigen. In some instances cells can escape destruction by redistributing and eventually losing the antigen-antibody complexes from their surface. This process, known as antigenic modulation, generally depends on bivalent antibody binding. Starting from the observation that rabbit antisera can be made more effective at killing tumour cells if they are first rendered univalent by limited proteolysis, we have now prepared a number of monovalent rat monoclonal antibodies to human cell-surface antigens. We find that these antibodies are no longer able to bring about modulation of their target antigens and have an enhanced facility for lysis with human complement. These special properties should greatly increase the therapeutic potential of monoclonal antibodies.

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Self tolerance is H-2-restricted.

H-2 restriction is an established characteristic of T-cell behaviour and, in effect, it means that mouse T cells are activated against foreign antigens only if those antigens are presented in a membrane association with molecules of the mouse major histocompatibility complex, H-2. Whether T-cell inactivation or tolerance is also H-2-restricted is a question which has been tested directly and indirectly several times in the past. In each case the answer was 'No' but in each case the answer was inconclusive. Doubts arose because of the observation that activation of T cells, in vivo, is an H-2-restricted event which appears unrestricted because of antigen processing by the host. If antigen processing is involved in the induction of tolerance, then tolerance might also be an H-2-restricted process disguised to appear unrestricted. We report here a study designed to minimize antigen processing in which we find that T-cell tolerance induction to 'self' minor histocompatibility (H) antigens is indeed H-2-restricted.

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Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo.

A major aim in immunology has been to understand how the immune system evokes characteristic responses to infection, foreign tissue grafts and tumours. The current view of immunoregulation is based mainly on studies of lymphocyte subsets, either in vitro or by adoptive transfer to irradiated recipients. Many reagents are available for defining T-cell subsets, but only recently have there been helper T-cell-specific antibodies against the mouse equivalent of the Leu3/T4 (man) and W3/25 (rat) antigens. It is clear that monoclonal antibodies will eventually replace antilymphocyte globulin for immunosuppression in organ grafting, but although there has been some clinical success, most monoclonal reagents cause only transient reductions in their target cells in vivo. This uncertainty in the potency of monoclonal antibodies has led some workers to consider them as targeting agents for such highly cytotoxic drugs as ricin A (ref. 21). We show here that unmodified monoclonal antibodies can be extremely effective at depleting cells in vivo and can be used for the selective manipulation of different aspects of the immune response.

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Induction of tolerance by monoclonal antibody therapy.

A major goal in immunology has been to find a means of selectively abolishing an individual's potential to mount an immune response to certain antigens, while preserving responsiveness to others. The facility to induce such specific immunological unresponsiveness in an adult would have major implications for tissue-grafting, the control of allergy and for treatment of autoimmune disease. Classical work has shown that immunosuppressive regimes, such as irradiation, anti-lymphocyte globulin or thoracic duct drainage, may facilitate tolerance induction. We describe here a technique by which the immune system of mice can be manipulated to be tolerant to certain protein antigens by administering these during a brief pulse of treatment with a monoclonal antibody directed to the L3T4 molecule on helper T lymphocytes. This technique has the potential to form the basis of a novel generalized means of tolerance induction.

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Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance.

Allogeneic reactions are the major limitation to organ transplantation. These are manifested as rejection of the grafted tissue, and also, in the case of bone marrow transplantation (BMT), graft-versus-host disease (GVHD). Recent methods of avoiding GVHD, by depleting T cells from donor marrow, have led to an increased incidence of marrow graft rejection. Current recipient conditioning protocols involving drugs or irradiation cannot safely be increased, so alternatives must be found. Monoclonal antibodies can be used to control immune responses in vivo, and would be useful in this context if we could define and deplete the cells responsible for marrow rejection. We show here that elimination of residual L3T4+ and Lyt-2+ cells from mice receiving fully mismatched bone marrow abrogates rejection and promotes tolerance to donor-type skin grafts, even in sub-lethally irradiated recipients.

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CAMPATH-1H in inflammatory arthritis.

CAMPATH-1H is a humanised mAb directed against lymphocytes. This mAb has been used to treat patients with rheumatoid arthritis. Clinical improvement with reduction in the Ritchie index and joint score has lasted for up to 8 months in some patients. A profound and prolonged lymphopaenia is induced by the mAb, with CD4+ numbers remaining suppressed for up to one year.

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