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Biomedical subjects

H Waldmann

Publications and source records attributed to H Waldmann.

At least 289 records · Page 16Linked to original sources
PubMed1988

The potential of hybrid antibodies secreted by hybrid-hybridomas in tumour therapy.

Using a simple method for the selection of hybrid cell growth from the cell fusion of pairs of existing hybridoma cell lines, 2 different hybrid-hybridoma cell lines were produced. Both hybrid-hybridomas secreted bi-specific antibody with similar specificity for human CD3 and for mouse Thy-l but in one case the parental antibody isotypes were both IgG2b and in the other case the CD3 antibody was IgG2b and the anti-Thy-l antibody was IgG2c. In a model in vitro system both bi-specific antibodies were able to elicit potent cell killing of a Thy-l expressing mouse tumour cell line by human effector cell blasts. The cell blasts were generated from resting peripheral blood mononuclear cells using a mitogenic monoclonal antibody (MAb) (YTH361). The parental anti-Thy-l IgG2b but not the IgG2c antibody was also able to mediate cell killing by ADCC. This ADCC killing was inhibited by a MAb to the CD16 Fc receptor but the killing elicited by the bi-specific antibodies was not. Both mechanisms of tumour cell killing may be of great potential in human tumour therapy with MAbs.

Animals↗
PubMed1988

Delay in onset of insulitis in NOD mice following a single injection of CD 4 and CD 8 antibodies.

Non-obese diabetic (NOD) mice injected with 500 micrograms of both CD 4 and CD 8 antibodies at 5 weeks of age did not develop insulitis until 18 weeks of age, 12 weeks later than the onset of insulitis in parallel uninjected controls. Injection with both antibodies at 2 weeks or 4 weeks of age protected from insulitis for 10 and 14 weeks respectively. Insulitis was not delayed in onset in animals injected at any age with one antibody only, or who were injected at birth. Injection after the onset of insulitis achieved partial but incomplete clearing of islet infiltrates. Salivary gland infiltrates (sialitis) were also delayed in animals injected with both CD 4 and CD 8 antibodies though the degree of protection was less pronounced than that seen for insulitis.

Age Factors↗
PubMed1988

Monoclonal antibodies for organ transplantation: prospects for the future.

Monoclonal antibodies (MoAbs) have the potential to facilitate the induction of transplantation tolerance. Realization of this potential requires both a better understanding of the cellular events concerned with rejection and tolerance, and a more detailed approach to improving antibodies for therapy. This report reviews work in our laboratory directed toward these goals.

Animals↗
PubMed1988

Universal bispecific antibody for targeting tumor cells for destruction by cytotoxic T cells.

Previous studies have demonstrated that bispecific hybrid antibodies produced by cell-cell fusion or chemically conjugated heteroaggregates can direct cytotoxic T lymphocytes to kill target cells for which they have no intrinsic specificity, a phenomenon we call effector cell retargeting (ECR). These studies used bispecific reagents with one specificity directed to CD3 or Ti on the effector cell and the other directed to a target cell antigen. To avoid the need to create different hybrid hybridomas for each target antigen we have developed a universal means to elicit ECR through the use of an antiglobulin step. We have constructed a bispecific hybrid antibody with dual specificity for CD3 and a rat immunoglobulin light chain allotype. This bispecific antibody could mediate ECR to a range of target cells, each coated with distinct surface-binding rat monoclonal antibodies. A particular advantage of targeting to surface-bound monoclonal antibodies is that all other available effector systems may also attack the same antibody-coated target cell.

Animals↗
PubMed1988

The repopulation capacity of bone marrow grafts following pretreatment with monoclonal antibodies against T lymphocytes in rhesus monkeys.

Complement-mediated lysis of (subsets of) T lymphocytes in bone marrow grafts is increasingly used to prevent acute graft-versus-host disease in human bone marrow transplant recipients, especially in case of major immunogenetic disparity between donor and recipient. Since T lymphocyte depletion has resulted in an increased frequency of allogeneic engraftment failures, its effect on hemopoietic reconstitution was measured in rhesus monkeys. The reactivity patterns of commonly used types of antihuman T lymphocyte monoclonal antibodies (MCAs) with rhesus monkey lymphocytes was analyzed using a double-label cytofluorometry technique and found to be very similar to those with human lymphocytes. The antibodies investigated included CAMPATH-1 (recognizing an antigen present on virtually all lymphocytes and monocytes), OKT4 + 4a (CD4, helper/inducer T lymphocytes), B9 (CD8, suppressor/cytotoxic T lymphocytes), WT-1 (CD7, pan-T), and anti-DR MCAs as stem cell toxic controls. Their possible toxicity to hemopoietic stem cells was studied by using a semiquantitative autologous regeneration assay. Cytotoxic lysis of cells in the bone marrow grafts reacting with the T lymphocyte purging MCAs did not result in delayed regeneration compared to untreated autologous grafts. It is concluded that T lymphocyte depletion using anti-T-lymphocyte MCAs does not influence the repopulating capacity of an autologous bone marrow graft.

Animals↗
PubMed1988

T cell depletion with CAMPATH-1 in allogeneic bone marrow transplantation.

A total of 282 patients with leukemia have been treated by transplantation from HLA-matched siblings using marrow depleted of T cells with CAMPATH-1 and autologous complement. The incidence of graft-versus-host disease (GVHD) of grades 2-4 was only 12% but the maximum incidence of graft failure was 15%. A significant increase in relapse cannot yet be detected in acute leukemia but relapse in chronic granulocytic leukemia (CGL) was substantially above that reported before T cell depletion. The most important predictive factor for relapse in CGL appeared to be slow engraftment. This finding suggests an alternative explanation for the graft-versus-leukemia effect other than a direct attack on leukemia cells. This is that donor T cells may affect the balance of competition between donor and recipient haemopoesis by preventing a rejection reaction to donor stem cells. Recipient leukemic cells would benefit (i.e. relapse) if recipient hemopoiesis gained an advantage. If this explanation were true we would expect extra immunosuppressive preconditioning of recipients to reduce the incidence of relapse, as well as preventing graft rejection.

Acute Disease↗
PubMed1987

Comparison of the effector functions of human immunoglobulins using a matched set of chimeric antibodies.

Cell lines have been established that secrete a matched set of human chimeric IgM, IgG1, IgG2, IgG3, IgG4, IgE, and IgA2 antibodies that are directed against the hapten 4-hydroxy-3-nitrophenacetyl. These chimeric antibodies secreted from mouse plasmacytoma cells behave exactly like their authentic human counterparts in SDS-PAGE analysis, binding to protein A and in a wide range of serological assays. The antibodies have been compared in their ability to bind human C1q as well as in their efficacy in mediating lysis of human erythrocytes in the presence of human complement. A major conclusion to emerge is that whereas IgG3 bound C1q better than did IgG1, the chimeric IgG1 was much more effective than all the other IgG subclasses in complement-dependent hemolysis. The IgG1 antibody was also the most effective in mediating antibody-dependent cell-mediated cytotoxicity using both human effector and human target cells. These results suggest that IgG1 might be the favoured IgG subclass for therapeutic applications.

Animals↗
PubMed1987

Isolation of low-frequency class-switch variants from rat hybrid myelomas.

Class-switch variants have been isolated from rat-rat hybrid myelomas by sib selection using a simple assay based on red cell-labelled antiglobulins. The variants detected are consistent with the gene order deduced from molecular cloning. They appear to arise spontaneously at a rate approximately ten-fold lower than for mouse cell lines but the rate of switching back to the parental isotype is substantial in comparison. An IgG2b variant antibody having the same specificity as CAMPATH-1 for human lymphocytes and monocytes is active in antibody-dependent cell-mediated killing (unlike the parental IgG2a) and may prove to be a valuable therapeutic antibody for immunosuppression and treatment of leukaemia and lymphoma.

Animals↗
PubMed1987

Functional analysis of T lymphocyte subsets in antiviral host defense.

The role of different T cell subsets in antiviral host defense was investigated by treating thymectomized C57BL/6 and CBA/J mice with monoclonal rat anti-Lyt-2 or anti-L3/T4 IgG 2b antibodies 14 and 10 days before infection. This treatment depleted the respective T cell subsets to undetectable levels in peripheral blood when assayed by immunofluorescence. In mice treated with anti-Lyt-2, induction of cytotoxic T cells was reduced to less than 1 to 2% after intravenous infection with Armstrong strain of lymphocytic choriomeningitis virus (LCMV). In addition, no primary swelling of the footpad could be detected following local inoculation of the virus. In animals treated with anti-L3/T4, antiviral cytotoxic T lymphocyte responses were reduced by a factor of 10. These L3/T4+ cell-depleted mice showed delayed footpad swelling after local injection of LCMV Armstrong. After intracerebral infection with LCMV, anti-Lyt-2-treated mice were resistant and those injected with anti-L3/T4 were totally susceptible to LCMV Armstrong-triggered immunopathologic disease. Virus could be detected in the blood of antibody-treated mice 7 days after inoculation; however, no virus could be measured in the blood of surviving anti-Lyt-2-treated animals 15 days after intracerebral infection. Serum titers of interferon-alpha,beta induced by viral infection remained unaffected by depletion of T cell subsets. Anti-L3/T4 antibody-treated C57BL/6 mice failed to generate IgG antibodies against the New Jersey strain of vesicular stomatitis virus, whereas Lyt-2+ cell-depleted mice had normal antivesicular stomatitis virus (New Jersey strain) IgG antibody titers.

Animals↗
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↗