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Biomedical subjects

H Waldmann

Publications and source records attributed to H Waldmann.

At least 199 records · Page 11Linked to original sources
PubMed1994

Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases.

Campath-1 (CDw52) antibodies (IgM and IgG2b) have been used in vitro and in vivo for control of GVHD and prevention of rejection following bone marrow transplantation. Results of 951 patients with malignant disease transplanted from HLA-matched siblings are reported. Both Campath-1M and Campath-1G are shown to be effective when used in vitro for prevention of graft-versus-host disease (GVHD). Graft failure was reduced by addition of cyclosporin A (CsA) post-transplant and possibly also by total lymphoid irradiation (TLI) pre-transplant. However, treatment of the recipient with Campath-1G to deplete residual lymphocytes was more effective, reducing the incidence of graft failure from 21% to 9% (in the absence of CsA). GVHD was virtually eliminated and leukaemia-free survival was improved. However, the risk of relapse was increased by T cell depletion, certainly in CML and to a lesser extent in AML. Addition of donor T cells to the depleted bone marrow or early post-transplant restored the risks of GVHD, graft failure and relapse to much the same as without T cell depletion. One problem associated with the use of Campath-1G in vivo was a significant delay (by up to 7 days) in neutrophil engraftment. This was unlikely to be caused by toxicity to progenitor cells and we argue that small numbers of lymphocytes may be required to assist early engraftment, possibly by cytokine production. If this problem can be overcome, T cell depletion of donor and recipient may be a good alternative to conventional GVHD prophylaxis for matched sibling transplants, resulting in a superior quality of life for the survivors. It is also likely to be particularly beneficial in transplants for non-malignant diseases and transplants from unrelated donors.

Adult↗
PubMed1993

A humanized CD18 antibody can block function without cell destruction.

Leukocyte integrins are intimately involved in transient adherence of leukocytes to endothelium and to each other in the processes of extravasation and cell activation. In this study, seven mAb directed against human CD11a and two mAb directed against human CD18, the alpha- and beta-chains of the leukocyte functional Ag-1 molecule, respectively, were analyzed for their ability to inhibit several leukocyte functional Ag-1-mediated interactions. The best blocking mAb in these studies, a rat anti-human CD18, YFC51.1, was subsequently humanized by complementarily-determining region grafting, associated with human C regions and expressed. The humanized mAb was shown to maintain binding for human CD18. Even though the humanized mAb was an IgG1 isotype it still retained the functional blocking characteristics of the rat mAb while failing to mediate cell killing. The IgG1 mAb was unable to bind human Clq and could block but did not mediate antibody-dependent cellular cytotoxicity.

Animals↗
PubMed1993

Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchored glycoprotein which is an exceptionally good target for complement lysis.

CAMPATH-1 antibodies recognize a unique molecule on human lymphocytes and are unusually efficient at causing cell lysis with homologous complement. They have been successfully used for lymphocyte depletion in vivo in a variety of diseases. We find that the antigen is a very small glycosylphosphatidylinositol (GPI)-anchored glycoprotein with a mature peptide comprising only 12 amino acids. It can be separated into two distinct antigenic fractions which differ in their susceptibility to phosphatidylinositol-specific phospholipase C. There is one N-linked glycosylation site, but no evidence for O-glycosylation despite the presence of several serine and threonine residues. The antibodies were found to bind, albeit with a generally reduced affinity, to a proteolytic fragment containing the C-terminal tripeptide and the GPI anchor. We postulate that one of the reasons why the CAMPATH-1 antibodies are so good for cell lysis is because they bind to an epitope which is likely to be very close to the lipid bilayer.

Amino Acid Sequence↗
PubMed1993

Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy.

Monoclonal antibodies that target T cells offer an alternative to conventional immunosuppressive drugs in the management of autoimmune disease. "Humanisation" of such monoclonal antibodies makes their clinical use less likely to be prone to the risk of cross-species sensitisation than treatment with rodent antibodies. We describe humanised monoclonal antibody therapy in four patients with severe systemic vasculitis unresponsive to immunosuppressive drugs. Substantial and sustained benefit was seen in three of the four patients, although one of these three patients developed anti-idiotypic antibodies that had to be removed by plasma exchange.

Antibodies, Anti-Idiotypic↗
PubMed1993

"Infectious" transplantation tolerance.

The maintenance of transplantation tolerance induced in adult mice after short-term treatment with nonlytic monoclonal antibodies to CD4 and CD8 was investigated. CD4+ T cells from tolerant mice disabled naïve lymphocytes so that they too could not reject the graft. The naïve lymphocytes that had been so disabled also became tolerant and, in turn, developed the capacity to specifically disable other naïve lymphocytes. This process of "infectious" tolerance explains why no further immunosuppression was needed to maintain long-term transplantation tolerance.

Animals↗
PubMed1993

CD4 and CD8 monoclonal antibody therapy: strategies to prolong renal allograft survival in the dog.

The value of CD4 and CD8 monoclonal antibody therapy in tolerance induction has been demonstrated in rodent transplant models. In this paper the immunosuppressive potential of CD4 and CD8 monoclonal antibodies for dog renal allografts was evaluated as a preliminary to tolerogenic studies in this large animal model. Monoclonal antibodies were given for a maximum of 10 days after transplantation. Therapy was stopped prematurely following adverse reactions associated with the recipient developing an antibody response against the foreign (rat) therapeutic monoclonal antibody. Blood trough levels of CD4 and CD8 antibodies indicated that saturating doses were achieved. Although neither CD4 nor CD8 alone prolonged allograft survival (rejection by day 7), combination of CD4 and CD8 antibodies resulted in good graft function for a median of 14 days. The effect of removing circulating T lymphocytes was also assessed using a lytic Thy-1 monoclonal antibody. Alone Thy-1 had little effect but, when combined with CD4, the median allograft survival time was increased to 15.5 days. Reduction of the number of circulating T lymphocytes appears complementary to blockade of CD4 for immunosuppression, while blockade of CD4 combined with removal of CD8 also favours allograft survival.

Animals↗
PubMed1993

The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties.

CD3 antibodies are proven immunosuppressants capable of reversing transplant rejection episodes. Their general application has been limited both by their immunogenicity and, in particular, by the "first-dose" cytokine-release syndrome experienced by patients after the initial administration of antibody. We have produced a set of variants of the humanized YTH 12.5 CD3 monoclonal antibody (mAb) (Routledge et al., Eur. J. Immunol. 1991. 21: 2717) bearing different human heavy (H) chain constant regions, with the intention of finding a form of the antibody that is not able to activate T cells. Comparison of the variants having gamma 1, gamma 2, gamma 3 and gamma 4 H chains in a competitive binding assay showed that antibody avidity was not affected by IgG subclass. Using a sensitive indicator of FcR binding activity (the capacity of the CD3 mAb to redirect cytotoxic T cells to kill the monocytic cell line U-937) we demonstrated a functional hierarchy of gamma 1 = gamma 4 > alpha 2 =/> gamma 3 mb >> gamma 2. An aglycosyl version of the gamma 1 CD3 mAb, produced by site-directed mutagenesis (Asn297 to Ala), still had considerable activity in this assay (intermediate to the gamma 1 and alpha 2 CD3 mAb), albeit at a level approximately 10-fold lower than that of the parental gamma 1 form. When we tested their ability to stimulate T cell proliferation in vitro in the presence of 5% human serum, all of the wild-type immunoglobulin isotypes were found to be active, although there were T cell donor-dependent variations in the extent of the responses. The aglycosyl gamma 1 mAb was, however, completely non-mitogenic in all of ten donors tested, unless the assay was performed in IgG-free medium. Despite being non-stimulatory, this mAb was also able to inhibit the mixed lymphocyte reaction responses of both naive and primed T cells. Comparison of the gamma 1 and aglycosyl gamma 1 mAb in an experimental mouse model for CD3 mAb-induced cytokine release indicated that removal of the carbohydrate moiety from the gamma 1 constant region reduced the in vivo tumor necrosis factor-alpha response by a factor of at least 16-fold. These data suggest that the aglycosyl gamma 1 CD3 mAb is a promising candidate for immunosuppressive therapy without "first dose" side effects.

Animals↗
PubMed1993

Active suppression induced by anti-CD4.

Treatment with a non-depleting monoclonal antibody to CD4 in the presence of mouse thyroglobulin (MTg) inhibits the development of murine autoimmune thyroiditis. This unresponsiveness was transferrable since such treatment generated a population of donor cells which could suppress the thyroiditis induced in lightly irradiated recipients by subsequent challenge with specific antigen. The suppression appears to be both antigen specific and antigen dependent and seems to discriminate between TH1 and TH2 helper subsets in that there is no significant effect on anti-MTg autoantibodies after challenge.

Animals↗
PubMed1993

Structural motifs involved in human IgG antibody effector functions.

A humanized IgG antibody to CAMPATH-1 antigen (CDw52) is known to be lympholytic both in vitro and in vivo. So as to improve therapeutic potency through protein engineering strategies, we wish to define the structural motifs underlying some of the documented differences in function between human (h) IgG1 and IgG4 forms of the antibody. By the creation of heavy chain domain-switch and intra-domain recombinant antibodies we have established an important role for the carboxy-terminal half of the CH2 domain in determining differential behaviour in antibody-dependent cytotoxicity (ADCC) and in complement lysis. If this same region were necessary for the effector mechanisms that operate in vivo, then it might be possible to improve antibody effector functions by construction of novel antibodies that possess within the one molecule multiple copies of the crucial hinge-CH2 associated structures. Although our previous work suggested that the hIgG4 CAMPATH-1 antibody was ineffective at ADCC, we found this to be so only in some individuals. In others, IgG4, and indeed all the IgG subclasses were able to mediate ADCC. Overall, though, hIgG1 remains the best choice isotype for lytic therapy in vivo.

Amino Acid Sequence↗
PubMed1993

Prevention of diabetes but not insulitis in NOD mice injected with antibody to CD4.

Non-obese diabetic (NOD) mice were injected with a rat monoclonal antibody to CD4 from birth every two weeks through 6 months of age. These animals gained weight normally but < 11% of their spleen T cells were CD4+, compared with 28% of CD4+ in controls injected with polyclonal rat IgG. The reduction in CD4 cell percentage was associated with a reduction in the number of cells in the thymus and spleen following the injection. CD4+ cells which survived the injections were nevertheless able to enter cell cycle when stimulated by Con A. None of the CD4-treated NOD mice became diabetic by 6 months of age and none of the animals studied histologically at this time had insulitis. At 9 months of age (three months after stopping the CD4 injections) the mice made antibody to human IgG. At 1 year of age most of the male mice had insulitis, although none of the male or female mice had become spontaneously diabetic. Two thirds of animals injected with cyclophosphamide at 16 months became diabetic within 3 weeks. The results confirm that treatment with CD4 antibody in the first 6 months suffices to reduce the incidence of diabetes in NOD mice. The treatment does not prevent the subsequent development of insulitis in injected mice and does not prevent the accumulation of cells capable of causing overt diabetes after cyclophosphamide injection.

Animals↗
PubMed1993

Efficient complement-mediated lysis of cells containing the CAMPATH-1 (CDw52) antigen.

CAMPATH-1 antibodies recognise a unique molecule on human lymphocytes and are unusually efficient at causing cell lysis with homologous complement. They have been successfully used for lymphocyte depletion in vivo in a variety of diseases. The antigen is a small glycosylphosphatidylinositol (GPI)-anchored glycoprotein with a mature peptide comprising only 12 amino acids and one N-linked glycosylation site at Asn3. The antigenic epitope is found in a proteolytic fragment containing the C-terminal tripeptide and the GPI anchor. Both the native and deglycosylated antigen as well as the proteolytic fragment can be reincorporated into various target cells, conferring sensitivity to lysis by CAMPATH-1 antibodies. These results imply that the special feature of the antigen which makes it a good target does not reside in the N-linked sugar or the first nine amino acids: instead they support the hypothesis that the proximity of the antigenic epitope to the cell membrane is more important.

Amino Acid Sequence↗
PubMed1993

Control of immune-mediated disease of the central nervous system with monoclonal (CD4-specific) antibodies.

Chronic relapsing experimental allergic encephalomyelitis (CREAE) was induced in Biozzi AB/H (H-2dq1) mice by active sensitization with spinal cord antigens. A single i.p. injection of CD8-depleting (YTS169.4) monoclonal antibody (mAb) failed to affect the clinical course of CREAE when administered prior to and during the onset of both the initial clinical and subsequent relapse phase of the disease. By contrast similar treatment with both CD4-depleting (YTS191.1) or CD4-blocking/non-depleting (YTS177.9) mAb significantly inhibited disease progression. Treatment shortly before the anticipated onset of clinical EAE prevented the subsequent development of disease, although disease could be provoked following antigen-rechallenge. In contrast, treatment with these antibodies during post-acute remission phase mainly served to delay the incidence of relapse. This suggests that, unless tolerance can be re-induced, treatment of ongoing neuroimmunological disease will require 'pulse' therapy and thus potentiate the problems of long-term immunosuppresion. Despite the findings that CD4-specific antibodies can rapidly reverse overt clinical disease shortly after the onset of disease exacerbation, once neurological dysfunction becomes established anti-CD4 treatment fails to improve the animals clinically, possibly due to the inability to rapidly reverse established demyelination. Although this study does not exclude the potential central action of the injected mAb, the failure to significantly dissociate therapeutic benefit between mAb administered directly into the CNS and that given systemically suggests that a major action of these agents is probably by selectively removing T cells in the peripheral T cell pool.

Animals↗
PubMed1993

The use of monoclonal antibodies to achieve immunological tolerance.

Monoclonal antibodies are potentially useful immunosuppressive agents. Short course of CD4/CD8 monoclonal antibody can be used to guide the immune system of experimental animals to accept organ grafts and to arrest autoimmunity. This reprogramming, reviewed by Herman Waldmann and Stephen Cobbold, is accompanied by potent T-cell dependent, 'infectious' regulatory mechanisms. A goal for therapeutic immunosuppression should be to understand and harness these innate immunoregulatory mechanisms.

Animals↗
PubMed1993

The use of monoclonal antibodies to achieve immunological tolerance.

Monoclonal antibodies are potentially useful immunosuppressive agents. Short courses of CD4/CD8 monoclonal antibody can be used to guide the immune system of experimental animals to accept organ grafts and to arrest autoimmunity. This reprogramming is accompanied by potent T-cell dependent, 'infectious' regulatory mechanisms. A goal for therapeutic immunosuppression should be to understand and harness these innate immunoregulatory mechanisms.

Animals↗
PubMed1993

Monoclonal antibodies for the induction of transplantation tolerance.

Non-lytic antibodies to CD4 and certain other T cell adhesion receptors can guide the immune system to become tolerant to foreign antigens, and to regain tolerance in autoimmunity. Tolerance is maintained lifelong through the action of regulatory T cells that in turn can influence naive T cells to acquire the same regulatory properties. A fuller understanding of the molecular basis of infectious tolerance could lead to the design of better immunosuppressive protocols.

Animals↗