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H Waldmann

Publications and source records attributed to H Waldmann.

At least 181 records · Page 10Linked to original sources
PubMed1995

Ex-vivo whole blood cultures for predicting cytokine-release syndrome: dependence on target antigen and antibody isotype.

Ex-vivo whole blood assays have been evaluated for their ability to accurately predict the risk of a first-dose cytokine reaction developing in vivo following therapeutic antibody infusion. Tumour necrosis factor alpha (TNF alpha) release was rapidly detected in cultures incubated with either anti-CD52 antibodies of the human IgG1 or rat IgG2b isotype, and to a lesser extent with a human IgG4 isotype. Endotoxin contamination of the antibodies was not responsive for cytokine release, since polymixin B failed to inhibit cytokine release using concentrations of this antibiotic which neutralized the enhanced cytokine release seen from LPS-spiked antibody. A rat IgG2b antibody to CD45 and a human IgG1 anti-CD3 also induced significant TNF release, however, an aglycosyl anti-CD3 mutant devoid of adverse side-effects in vivo, did not result in cytokine release in vitro. Since the pattern of cytokine release seen following the clinical use of these antibodies was in good agreement with the findings of the ex-vivo whole cultures, this demonstrates the usefulness of this assay to predict cytokine release in vivo.

Adult↗
PubMed1994

Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis.

The central nervous system lesions of multiple sclerosis (MS) can be detected by magnetic resonance imaging (MRI) and the initial perivascular inflammatory component is distinguished by the presence of gadolinium enhancement. To assess the effect of systemic lymphocyte depletion on disease activity, seven patients with MS received a 10-day intravenous course of the humanised monoclonal antibody CAMPATH-1H (anti-CDw52). With some variations in the protocol, enhanced cerebral MR images were obtained monthly for 3-4 months before and at least 6 months after treatment. 28 enhancing areas were detected on the first series of 7 scans; 51 additional active lesions were identified on 18 scans before treatment; 15 were detected on 20 scans done over the next 3 months, but only 2 active lesions were seen on 23 scans during follow-up beyond 3 months. The difference in lesion incidence rate before and after treatment varied and the rate ratio was significantly reduced in only three patients. Collectively, in a "meta-analysis", the rate ratios were 0.15 [corrected] (95% CI 0.09-0.24) for all seven patients and 0.24 (0.14-0.42; p < 0.001) with exclusion of the patient whose scanning schedule differed. The effect of CAMPATH-1H on disease activity provides direct, but preliminary, evidence that disease activity in MS depends on the availability of circulating lymphocytes and can be prevented by lymphocyte depletion. It is too early to say anything about the clinical results of treatment with this agent.

Antigens, CD↗
PubMed1994

Mechanisms in CD4 antibody-mediated transplantation tolerance: kinetics of induction, antigen dependency and role of regulatory T cells.

CBA/Ca mice may be made tolerant to minor histoincompatible B10.BR skin grafts by treatment with a short course of non-depleting anti-mouse CD4 and CD8 monoclonal antibodies (mAb), during the transplantation period. We wished to determine when, in relation to antibody therapy, the T cells became tolerant. This was investigated by a series of adoptive transfer experiments in which mAb-treated cells were removed from therapeutic antibody at defined times after skin grafting, and exposed to fresh antigen in the absence of further mAb treatment. We show here that T cells do not become fully tolerant until 5 weeks after skin grafting. If antibody therapy is continued for the full 5 weeks, T cell tolerance can still be established, suggesting that antibody therapy does not prevent lymphocytes from registering the presence of antigen. Once the tolerant state is established, it is difficult to break that tolerance by lymphocyte infusions from normal donors. This "resistance" is mediated by T cells of the tolerant host. We show that the maintenance of both tolerance and "resistance" requires a continuous supply of antigen. When tolerant cells were "parked" in T cell-depleted mice, tolerance and "resistance" were eventually lost by 6 months. In contrast, "parked" cells exposed to fresh antigen at any time up to 4 months remained tolerant and "resistant" indefinitely. Finally, we wished to establish whether "resistance" was peculiar to this form of peripheral tolerance, or whether it might also be present in tolerance considered to be classically central. We observed resistance to be greater in the mAb-treated peripherally tolerant group, but noted that some of the centrally tolerant animals also exhibited a level of resistance above that of T cell-ablated controls. This suggests that a tolerance mechanism whose role is only minor in central tolerance may have a major role in antibody-mediated peripheral tolerance.

Animals↗
PubMed1994

What can be done to prevent graft versus host disease?

Graft versus host disease presents a major obstacle to the widespread application of allogeneic bone marrow transplantation despite improvements in drug prophylaxis. Although animal models are providing an understanding of the biology of the process, opportunities for exploitation of that knowledge for therapeutic purposes are still limited. One way to overcome this impasse is to build on the positive benefits of T-cell purging of marrow, by combining it with intelligent correction of the known negative effects.

Animals↗
PubMed1994

CAMPATH-1 monoclonal antibodies in bone marrow transplantation.

CAMPATH-1 (CDw52) antibodies recognize a very small lipid-anchored glycoprotein that is expressed on the surface of human lymphocytes. They are remarkably lytic with human complement. In addition, CAMPATH-1G (rat IgG2b) and CAMPATH-1H (human IgG1) bind to human Fc receptors and are very effective for cell lysis in vivo. CAMPATH-1M (rat IgM) and CAMPATH-1G have been used to control GVHD and graft rejection in bone marrow transplantation by depletion of the T cells of the donor and recipient. Depletion of donor T cells alone gave excellent control of GVHD but up to 20% of the patients transplanted from HLA-matched siblings, and 51% of those transplanted from nonsibling donors, experienced graft failure caused by immunological rejection. Graft rejection could be partly overcome by additional immunosuppression either with CsA or total lymphoid irradiation (TLI). More effective was the use of CAMPATH-1G in vivo to deplete residual host lymphocytes. Preliminary results from current protocols of antibody depletion give two year actuarial leukemia-free survival as good as or better than similar studies with conventional GVHD prophylaxis, as well as a decreased morbidity from chronic GVHD, although engraftment was delayed by about 5 days. We propose that prophylactic T cell depletion with CAMPATH-1 antibodies is a simple and valid alternative to drug-based immunosuppression that may be particularly applicable to patients with acute leukemia or nonmalignant diseases transplanted from HLA-matched siblings as well as any patients transplanted from unrelated donors. Future developments of antibody-based immunosuppression may allow the extension of marrow transplantation for tolerance induction to organ transplants or in autoimmune diseases.

Amino Acid Sequence↗
PubMed1994

Immunosuppression of canine renal allograft recipients by CD4 and CD8 monoclonal antibodies.

A state of tolerance to MHC mismatched allografts can be generated in rodents by treatment with CD4 and CD8 monoclonal antibodies (mAb). In order to transpose this type of therapy to large animals and ultimately to the clinic, a suitable model is required. To this end we have generated a series of mAb to the canine CD4, CD8, and Thy-1 antigens and have tested their ability to prevent rejection of renal allografts. Donor-recipient pairs were selected from a colony of mongrel dogs in which untreated rejection of two haplotype-mismatched kidneys occurred by day 7 (defined as a serum creatinine > 300 mumol/l). Therapy with either the CD4 or the CD8 mAb, using no other immunosuppression, did not prolong graft survival. Depletion of T cells by a Thy-1 mAb prior to surgery only extended graft survival to day 9. However, treating with combinations of mAb up to day 10 (CD4 plus Thy-1; CD4 plus CD8; or CD4 plus CD8 plus Thy-1) prolonged renal allograft function up to 25 days. Combination of the triple mAb therapy with a sub-therapeutic immunosuppressive drug regimen (cyclosporin A plus azathioprine that alone gave a median survival of 15 days) favored survival to a median of 38 days. This protocol also inhibited the antiglobulin response that had curtailed the effects of mAb treatment, opening the way to more extended, and potentially tolerizing, mAb plus drug regimens.

Animals↗
PubMed1994

CD4 and CD8 monoclonal antibody therapy in canine renal allografts.

Therapy with CD4 and CD8 monoclonal antibodies was evaluated in dogs which received double-haplotype MHC-mismatched renal allografts. Neither CD4 nor CD8 monoclonal antibodies given alone prolonged allografts survival (creatinine > or = 300 micromol/l) beyond 7 days. However, combined therapy with CD4 and CD8 antibodies given up to day 10 did prolong allograft survival to a median of 14 days. A longer (21 day) course of CD4 and CD8 antibodies did not extend allograft survival further. The effect of prolonged antibody therapy was restricted by the occurrence of both an antiglobulin response and an anaphylactoid reaction to the monoclonal antibody preparation. When the CD4 and CD8 antibodies were combined with a pan-T-cell-depleting Thy-1 antibody, the survival of double-haplotype mismatched allografts was further prolonged (median 16 days). The median survival of single-haplotype mismatched renal allografts on this triple therapy was 21 days, with one surviving to day 36.

Anaphylaxis↗
PubMed1994

Depletion of CD4+ and CD8+ cells eliminates immunologic memory of thyroiditogenicity in murine experimental autoimmune thyroiditis.

Experimental autoimmune thyroiditis (EAT) develops in genetically susceptible mice after immunization with mouse thyroglobulin (MTg), and is mediated by T cells, both CD4+ and CD8+, infiltrating the thyroid. Previous work showed that depletion of CD4+, but not CD8+, cells with rat monoclonal antibodies (mAbs) interfered with EAT induction. To test if concomitant CD4+ cell depletion and immunization led to EAT resistance, mice were reimmunized at an interval of 15 or 43 days after injection of CD4 mAbs. No resistance had been established; disease severity and anti-MTg titers were comparable to mice with primary immunization. Previous work also showed that treatment during advancing EAT with only CD4 mAbs on days 21, 25 led to long-lasting, reduced severity in EAT, whereas administration of CD8 mAbs alone reduced the smaller CD8+ subset only. However, therapy with both mAbs was most efficacious; > 50% of thyroids were purged of all cellular infiltrate after only two doses. Moreover, T cells emerging subsequent to depletion were not retained in the thyroid, despite ongoing antibody production. To test if nondepleting CD4 and CD8 mAbs were similarly effective for therapy, mAbs of the IgG2a isotype were administered during advancing EAT. No effect on thyroidal infiltration was observed, indicating that modulation of the CD4 and CD8 antigen without depletion was insufficient for efficacious therapy. To determine if combined therapy with depleting mAbs reestablished self tolerance, treated mice were reimmunized on days 70, 77, when T cell recovery was nearly complete. Thyroiditis was comparable to controls given primary immunization, despite high antibody levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Engineering multiple-domain forms of the therapeutic antibody CAMPATH-1H: effects on complement lysis.

Antibody-mediated lysis of cells involves a complex interaction between the cell, the target antigen, the antibody and host effector mechanisms. One such mechanism, complement-mediated cell lysis, requires the interaction of C1q with the antibody heavy chain constant regions, and in particular the CH2 domain. Here we investigate the potential benefit of multiple-domain forms of the therapeutic monoclonal antibody CAMPATH-1H. This antibody is directed against the CDw52 antigen expressed by human lymphocytes and has proven lytic abilities both in vitro and in vivo. Using target cells with either high or low antigen density, engineered antibodies that contained additional domains in tandem (CH2, hinge-CH2 or Fc intramolecular repeats) showed no improvement in complement-mediated lysis when compared with controls. However, a homodimeric form of the antibody that was engineered by mutation of a serine residue to cysteine near the carboxy-terminal of the CH3 domain, exhibited markedly improved lysis using target cells expressing antigen at low density. Interestingly, no improvement was seen using cells expressing antigen at high density. These results suggest that dimeric forms of antibodies could be useful for converting cells with low density antigens into useful targets for therapy.

Alemtuzumab↗
PubMed1994

Helplessness as a strategy for avoiding antiglobulin responses to therapeutic monoclonal antibodies.

The antiglobulin (anti-Ig) response to therapeutic monoclonal antibodies (mAbs) poses a significant obstacle to their routine application in man. Whilst humanization has lessened the problem, repeated courses of humanized mAbs still sensitise some patients. Previous work suggested that unresponsiveness to cell-binding (therapeutic) mAbs could not be achieved due to an unexpected immunogenicity of their idiotypes (ids). The current work examines this phenomenon in more detail using CBA/Ca mice receiving rat antimouse CD8 mAbs as a model system. It is shown that the anti-Ig response is dependent on CD4+ T-cells. Furthermore, for at least some mAbs, most helper epitopes appear to reside within the mAb c-region. Consequently, when tolerance is induced to c-region (isotype), the anti-id response is extremely weak (induced helplessness). For one (weakly immunogenic) CD8 mAb concomitant administration of a CD4 mAb was sufficient to induce tolerance, whereas for another (more immunogenic) CD8 mAb, tolerance could only be achieved by prior concomitant exposure to both a CD4 mAb and an isotype-matched non-cell-binding mAb. The general applicability of these results is discussed and extrapolated to the clinical situation. Non-cell-binding variants of therapeutic mAbs could be usefully exploited to generate therapeutic unresponsiveness to any clinically useful mAb.

Animals↗
PubMed1994

Sparing of first dose effect of monovalent anti-CD3 antibody used in allograft rejection is associated with diminished release of pro-inflammatory cytokines.

The murine monoclonal antibody OKT3 is the best known of the anti-CD3 antibodies used for the prevention and treatment of renal allograft rejection. Use of this antibody is associated with improved graft outcome but it has a number of adverse effects thought to result from the massive release of pro-inflammatory cytokines. It has been postulated that OKT3 causes cytokine release because of cross-linking of CD3 molecules on the cell surface by bivalent anti-CD3 antibodies, such as OKT3, and the simultaneous binding of the Fc regions of these monoclonal antibodies to Fc receptors on other cells resulting in cell activation. Monovalent antibodies directed against the CD3 antigen should not, in theory, cause cell activation and cytokine release by this postulated mechanism. This study details the use of a monovalent anti-CD3 monoclonal antibody in the treatment of allograft rejection in five renal transplant recipients and documents the degree of TNF, IFN-g and IL6 release generated after antibody injection. Monovalent anti-CD3 monoclonal antibody reversed the rejection episode for which it was used and was well tolerated in all patients. TNF, IFN-g and IL6 measurement showed that little pro-inflammatory cytokine release occurred after this drug. It is likely that the relative lack of side-effects of monovalent anti-CD3 reflects the blunted release of pro-inflammatory cytokines. Monovalent anti-CD3 monoclonal antibody may be a useful addition to the reagents available to treat allograft rejection.

Acute Disease↗
PubMed1994

T cell depletion by exposure to Campath-1G in vitro prevents graft-versus-host disease.

Campath-1G is an immunosuppressive monoclonal antibody directed against human lymphocytes. Its effectiveness in preventing graft-versus-host disease (GVHD) by simple opsonisation of bone marrow T-cells has been studied in 36 consecutive allografts: in 17 for leukaemia, one for essential thrombocytosis and four for myeloma this was the sole means of GVHD prophylaxis. A further eight patients with aplastic anaemia received 3 months post-transplantation cyclosporin A (CsA) for this purpose whereas in the ninth and tenth the preparative regimen has been modified with this immunosuppressive agent now discontinued. Nucleated cells were harvested and after quantitative recovery of the mononuclear population on the Cobe 2997 separator they were exposed to 20 mg Campath-1G for 30 min at room temperature and then infused. Following standard conditioning, which included total lymphoid irradiation, the median days to reach 0.5 and 1.0 x 10(9)/l neutrophils were respectively 18 (range 9-34) and 28 (range 10-59); to 25 and 100 x 10(9)/l platelets the corresponding times were 17 days (range 5-32 days) and 27 days (range 13-127 days). In all, the day 14 trephine biopsy showed engraftment. At median follow-up of 20 months (range 5-44 months) only one patient has developed possible grade I cutaneous GVHD that responded promptly to corticosteroids: no chronic GVHD or CMV pneumonitis has been encountered. Of those with haematological malignancy transplanted in remission only two with acute leukaemia have relapsed. In aplastic anaemia graft loss initially occurred but this has been overcome by adding Campath-1G in vivo and omitting CsA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗