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Biomedical subjects

H Waldmann

Publications and source records attributed to H Waldmann.

At least 163 records · Page 9Linked to original sources
PubMed1996

Treatment of refractory Wegener's granulomatosis with humanized monoclonal antibodies.

Conventional immunosuppression for systemic vasculitides is limited by substantial side-effects, cumulative drug toxicity and refractoriness in some patients. Six Wegener's granulomatosis patients who had been refractory to conventional therapy for at least 6 months, were treated with humanized monoclonal antibodies specific to lymphocyte CD52 or CD4 antigens. Diagnosis was on clinicopathological grounds, supported by the presence of autoantibodies to Proteinase 3. Histological evidence of persistent disease activity was obtained for each patient. Humanized monoclonal anti-CD52, with or without anti-CD4, was given intravenously up to 40 mg/day for up to 10 days. Remission, (programmed withdrawal of drug therapy without return of refractory disease) was achieved in all patients. Cytotoxic drugs were discontinued at the time of monoclonal antibody treatment and not used again; steroids were withdrawn gradually. Four patients relapsed at 1.5, 5, 10 and 18 months, and were treated successfully with further monoclonal antibody therapy alone. Three years after the study began, five patients are well; one patient died at surgery whilst in remission. Humanized monoclonal antilymphocyte antibodies may provide an effective treatment in patients with systemic vasculitis which is refractory to steroids or cytotoxic agents, or who are intolerant of these drugs.

Adoptive Transfer↗
PubMed1996

Mechanisms of peripheral tolerance and suppression induced by monoclonal antibodies to CD4 and CD8.

Over the last five years it has become increasingly clear that the peripheral immune system can maintain tolerance to both self and non-self antigens through a variety of mechanisms. Although clonal deletion may play an important part in limiting rapidly expanding responses, there are many examples where antigen reactive T cells remain. It has been proposed that tolerance is maintained in this situation either by the induction of anergy or by ongoing suppression. The phenomenon known as immune deviation, where non-inflammatory Th2 responses could suppress Th1 and positively reinforce themselves provided an attractive explanation for infectious tolerance, where tolerant T cells could guide further naive T cells also to tolerance. However, experiments to test this hypothesis in the models of CD4 and CD8 antibody-induced tolerance have given conflicting data, with no clear evidence of Th2 responses in tolerant mice. In this paper we review recent data that IL-4 plays a role in suppression, but that the source of IL-4 may not be the tolerant/suppressor T cell. We also discuss how infectious tolerance can operate on third party antigens if they are linked on the same antigen presenting cell and how CD4+ T cells can suppress CD8+ T-cell responses. Finally, we suggest a model of infectious anergy that is compatible with the available data.

Animals↗
PubMed1996

CAMPATH-IH in multiple sclerosis.

In a pilot study, seven patients with multiple sclerosis were treated with CAMPATH-IH which targets the CD52 antigen present on lymphocytes and monocytes. There was a substantial reduction in disease activity as measured by gadoliunium-enhancing lesions on MRI. Encouraged by this result a further seven patients have been treated with CAMPATH-IH; four also received anti-CD4 antibody. Lymphopaenia developed rapidly and was sustained for at least one year. In 12 patients, the first infusion of antibody was characterised by significant exacerbation or re-awakening of pre-existing symptoms lasting several hours. These clinical effects of antibody treatment correlated with increased levels of circulating cytokines. Peak levels of tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) occurred at 2 h whereas the rise in interleukin-6 (IL-6) was significantly delayed and peaked at 4 h after starting antibody treatment. The neurological symptoms could not be attributed directly to pyrexia and were not provoked (in one patient) by an artificial rise in temperature. In the remaining two patients, a single pre-treatment with intravenous methylprednisolone (500 mg) prevented both the transient increase in neurological symptoms and the cytokine release. Our results suggest that soluble immune mediators contribute to symptom production in multiple sclerosis by directly or indirectly blocking conduction through partially demyelinated pathways.

Adrenal Cortex Hormones↗
PubMed1996

Recent results using CAMPATH-1 antibodies to control GVHD and graft rejection.

Recent data from the CAMPATH users group are reported. Different protocols have been tested using the CD52 antibodies Campath-1M and Campath-1G for prevention of GVHD and graft rejection in allogeneic transplants from both sibling and volunteer unrelated donors. Leukaemia relapse remains a significant problem for patients with CML, but in other diseases the recent results using T cell depletion appear to be as good as, or better than, published data with conventional GVHD prophylaxis. In addition, the morbidity and mortality associated with chronic GVHD are substantially reduced. Future collaborative studies to consolidate these findings include a randomised trial of the humanised antibody Campath-1H organised under the auspices of the EBMT. There are also plans to carry out experimental studies using Campath-1 antibodies to deplete T cells from peripheral blood stem cell harvests.

Antibodies↗
PubMed1996

Campath-1G in vivo confers a low incidence of graft-versus-host disease associated with a high incidence of mixed chimaerism after bone marrow transplantation for severe aplastic anaemia using HLA-identical sibling donors.

We have evaluated the effect of in vivo Campath-1G on engraftment and GVHD in 23 patients with severe aplastic anaemia transplanted from HLA-identical sibling donors. In 14 patients Campath 1g was given pre-transplant for up to 9 days in an attempt to overcome graft rejection (group 1). In nine patients Campath-1G was given pre-transplant, but also continued post-transplant until day +5 to reduce GVHD (group 2). There were three patients with late graft failure in group I following initial neutrophil engraftment, and four cases of grade II+ GVHD. In group II, two patients had early graft failure (no take), and there were no cases of acute GVHD out of seven evaluable patients. One patient in group I developed chronic GVHD of the liver, and two patients (one in each group) had transient localised chronic GVHD. PCR of short tandem repeats was used to evaluate chimaeric status in 13 patients. Of 11 patients with initial neutrophil engraftment, only one had 100% donor haemopoiesis at all times. The remaining patients had either transient mixed chimaerism or persistence of recipient (< 20%) cells. We conclude that in vivo Campath-1G is associated with a high incidence of mixed chimaerism which tips the balance away from GVHD but towards graft rejection.

Adolescent↗
PubMed1996

Monoclonal antibody therapy of diffuse cutaneous scleroderma with CAMPATH-1H.

A worker in a polyvinyl chloride factory with rapidly progressive diffuse cutaneous scleroderma was treated with the humanized monoclonal antibody (Mab) CAMPATH-1H. Treatment was followed by rapid and substantial improvement in skin score, which was maintained during followup without additional therapy. The mode of action of CAMPATH-1H and its relationship to clinical improvement are discussed.

Adult↗
PubMed1995

Bone marrow transplantation for chronic myeloid leukemia with volunteer unrelated donors using ex vivo or in vivo T-cell depletion: major prognostic impact of HLA class I identity between donor and recipient.

Between August 1985 and July 1994, we performed 115 volunteer unrelated donor (VUD) bone marrow transplants (BMT) for first chronic phase (n = 86) or advanced phase (n = 29) chronic myeloid leukemia (CML). Standard serologic HLA typing of potential donors and recipients was supplemented with one-dimensional isoelectric focusing (IEF) for class I proteins, allogenotyping for DR and DQ alleles using DNA restriction fragment length polymorphism (RFLP) analysis, and the measurement of antirecipient major histocompatibility complex (MHC) cytotoxic T-lymphocyte precursor cells in the donors' blood (CTLp assay). Recipients were conditioned for transplantation with a combination of high-dose chemotherapy and total body irradiation (n = 103) or high-dose chemotherapy alone (n = 12). Twenty eight recipients received ex vivo T-cell-depleted marrow, and 84 underwent some form of in vivo T-cell depletion. The probability of severe (grades III or IV) acute graft-versus-host disease (aGVHD) was 24%, and that of extensive chronic graft-versus-host disease (cGVHD), 38%. Proportional hazards regression analysis showed an association between low frequency CTLp and a reduced incidence of severe aGVHD (relative risk [RR], 0.28; P = .0035). The probability of relapse at 3 years was 23%, with first chronic phase disease being independently associated with a lower risk of relapse (RR, 0.71; P = .01). The overall leukemia-free survival (LFS) at 3 years was 37%; the LFS for the first chronic phase and advanced phase recipients was 41% and 26%, respectively. First chronic phase disease (RR, 0.56; P = .063) and the combination of recipient cytomegalovirus (CMV) seronegativity and an IEF-matched donor (RR, 0.48; P = .011) were both associated with improved LFS. The probabilities of survival and LFS for patients under 40 years of age transplanted in first chronic phase from an IEF-matched donor were 73% and 50%, respectively. We conclude that VUD BMT is a reasonable option for patients with CML; when using ex vivo or in vivo T-cell depletion, optimal results are achieved in patients transplanted in chronic phase with marrow from donors without demonstrable class I HLA mismatch and a low CTLp frequency.

Adolescent↗
PubMed1995

The effect of aglycosylation on the immunogenicity of a humanized therapeutic CD3 monoclonal antibody.

The factors affecting the immunogenicity of a humanized gamma 1 CD3 monoclonal antibody (mAb) were investigated in transgenic mice that express the human CD3 antigen epsilon polypeptide (the mAb target antigen). Two derivatives of the mAb were employed, one with a normal, glycosylated Fc region (gamma 1 CD3 mAb), and the other with an aglycosylated Fc region (aglycosyl gamma 1 CD3 mAb). Comparisons of the antiglobulin responses elicited by the two derivatives in transgenic and nontransgenic mice demonstrated that Fab-mediated cell binding activity, dependent on target antigen expression, was a major positive determinant of CD3 mAb immunogenicity. A second positive factor was mAb Fc region glycosylation. At low dose levels the gamma 1 CD3 mAb consistently produced a higher antiglobulin response than the aglycosyl gamma 1 CD3 mAb. This was probably a result of the nonspecific, in vivo T cell activating property of the gamma 1 CD3 mAb, a consequence of its ability to cross-link T cells to Fc gamma receptor-bearing cells. (The aglycosyl gamma 1 CD3 mAb has a reduced Fc binding affinity for Fc gamma receptors and so does not activate T cells in vivo.) In support of this hypothesis, the gamma 1 CD3 mAb was able to nonspecifically enhance humoral immunity to an unrelated, coadministered antigen, whereas the aglycosyl gamma 1 CD3 mAb was not. The lower immunogenicity of the aglycosyl gamma 1 CD3 mAb correlated with a longer in vivo half-life and an improved capacity to block the target CD3 antigen. These results suggest that, as well as reducing the cytokine-induced side effects normally associated with CD3 mAb therapy, the nonactivating aglycosyl gamma 1 CD3 mAb will be less likely than the activating gamma 1 CD3 mAb to stimulate a neutralizing antiglobulin response.

Animals↗
PubMed1995

In vivo transfer of GPI-linked complement restriction factors from erythrocytes to the endothelium.

Many proteins are associated with the outer layer of the cell membrane through a posttranslationally added glycosyl phosphatidylinositol (GPI) anchor. The functional significance of this type of protein linkage is unclear, although it results in increased lateral mobility, sorting to the apical surface of the cell, reinsertion into cell membranes, and possibly cell signaling. Here evidence is presented that GPI-linked proteins can undergo intermembrane transfer in vivo. GPI-linked proteins expressed on the surface of transgenic mouse red blood cells were transferred in a functional form to endothelial cells in vivo. This feature of GPI linkage may be potentially useful for the delivery of therapeutic proteins to vascular endothelium.

Animals↗
PubMed1995

Human CD59 expressed in transgenic mouse hearts inhibits the activation of complement.

Porcine-to-human xenotransplantation offers a potential solution to the critical shortage of human organs. The major immunological barrier to xenotransplantation between these species is a rapid rejection process mediated by preformed natural antibodies and complement. Xenogeneic organ grafts are especially susceptible to complement mediated injury because complement regulatory proteins, which ordinarily protect cells from inadvertent injury during the activation of complement, function poorly in regulating activation of heterologous complement. Removal of xenoreactive antibodies or systemic inhibition of complement activity has been shown to prolong graft survival. As an alternative to the systemic inhibition of complement activity, we have established a model system using transgenic animals to test whether the expression of human membrane bound complement regulatory proteins on mouse endothelial cells can inhibit the activation of human complement. CD59, which acts at the terminal stage of complement activation by inhibiting the formation of the membrane attack complex, was used as a paradigm for this model. A CD59 construct containing the putative CD59 gene promoter linked to the CD59 coding region was used to demonstrate expression of the human CD59 protein in various tissues of transgenic mice, including endothelial cells in the heart. In addition, we show that the transgenic CD59 protein is biologically active as determined by the ability to inhibit the formation of membrane attack complex in transgenic mouse hearts perfused ex vivo with human plasma. These results demonstrate that expression of membrane bound complement regulatory proteins can achieve complement inhibition in a xenogeneic organ and suggest that this approach may be useful for successful xenotransplantation between discordant species.

Animals↗
PubMed1995

Prevention of immune-mediated corneal graft destruction with the anti-lymphocyte monoclonal antibody, CAMPATH-1H.

We report a patient with peripheral rheumatoid corneal melting who developed a corneal perforation in one eye requiring tectonic keratoplasty. Nine consecutive corneal grafts were rapidly destroyed despite systemic immunosuppression with corticosteroid, cyclophosphamide, azathioprine and cyclosporin A. A rejection episode was observed in one graft before it melted and allograft rejection may have contributed to the destruction of other grafts. Corneal graft survival was ultimately achieved by systemic immunosuppression with the anti-lymphocyte monoclonal antibody, CAMPATH-1H. A single episode of rejection developed in the early post-operative period which was easily reversed by topical corticosteroid. Corneal melting has not recurred and the graft has now remained intact and clear for 24 months. Anti-lymphocyte monoclonal antibodies may therefore provide effective immunosuppression in the treatment of refractory ocular disorders.

Aged↗