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Biomedical subjects

H Waldmann

Publications and source records attributed to H Waldmann.

At least 217 records · Page 12Linked to original sources
PubMed1993

CAMPATH-1 monoclonal antibody therapy in severe refractory autoimmune thrombocytopenic purpura.

Six patients with autoimmune thrombocytopenic purpura (three of whom had CLL/NHL and one previous Hodgkin's disease) refractory to conventional therapy were treated with an antilymphocyte monoclonal antibody directed at CDw52 (CAMPATH-1). We observed response in four of the five evaluable patients; in three patients the response has lasted more than 4-9 months. However, response did not occur in most cases until 4-6 weeks after the commencement of the antibody therapy, suggesting that the mechanism of action is probably that of immune modulation.

Adult↗
PubMed1993

Tolerance to IDDM induced by CD4 antibodies in nonobese diabetic mice is reversed by cyclophosphamide.

IDDM can be induced in nonobese diabetic (NOD) mice in several ways, including high doses of cyclophosphamide and transfer of diabetic spleen cells to sublethally irradiated recipients. It has previously been established that transferred diabetes can be prevented by treatment with a nondepleting CD4 monoclonal antibody; however, we report herein that cyclophosphamide-induced diabetes also can be prevented using this antibody. The protection induced by CD4 monoclonal antibody to transferred diabetes is maintained for a long period after cessation of antibody treatment. However, cyclophosphamide can abrogate this induced tolerance and we report that this abrogation does not require new T-cells. During the course of the experimental work described, we observed that the thymus had a suppressive effect on the expression of transferred disease. Mice that were depleted of their peripheral T-cells showed a doubling of the time for disease expression if they were euthymic, compared with thymectomized mice.

Animals↗
PubMed1993

In vitro and in vivo depletion of T cells.

Transplant related mortality and relapse after bmt have a negative influence on the outcome of patients transplanted for acute leukaemia in first remission. Transplant related mortality includes graft-versus-host disease, infections and graft failure. To prevent gvhd and associated infections without increased graft rejection, a protocol of combined in vivo/ex vivo T-cell depletion (Campath IgG 20 mg i.v. for 5 days and Campath IgM T-cell depleted graft) with no further immunosuppression was initiated. Up to now 22 adult patients (median age 39 years, range 21 to 51) have been transplanted. One graft failure most probably due to persistent leukaemia, three acute gvhd (grade I) and no chronic gvhd occurred. Two patients relapsed after bmt and died. Two further patients died due to idiopathic interstitial pneumonitis and acute liver failure, respectively. Eighteen patients are alive in complete remission. With a median follow up of 13 months (1-30) the probability of survival is 78%, disease free survival is 80% and transplant related mortality is 10%. We compared these results with 3 historical control groups with different regimens of gvhd prophylaxis. 1. MTX group (n = 15): With a median follow up of 135 (115-147) months after bmt the probability of survival is 40%, disease free survival is 40% and transplant related mortality is 60% (mainly gvhd and infection). 2. Campath group (only ex vivo T-cell depletion n = 25): With a median follow up of 86 (62-102) months probability of survival is 52%, disease free survival is 43% and transplant related mortality is 36% (mainly rejection and infection).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Matched unrelated donor bone marrow transplantation for chronic myeloid leukaemia in chronic phase: comparison of ex vivo and in vivo T-cell depletion.

Between January 1985 and March 1992, 48 patients with chronic phase CML underwent BMT from volunteer unrelated donors (MUD) serologically identical at HLA-A, B and DR loci. 19 patients received donor marrow ex vivo T-cell depleted (EX-TCD) with Campath monoclonal antibodies. 29 patients received unmanipulated donor marrow with CsA/MTX GVHD prophylaxis; 28 received additional intravenous antilymphocyte therapy from day +1 to +5 (IN-TCD). Overall 26 patients survive at median follow up of 362 days; actuarial survival at 3 years is 50%. 3 patients have sustained haematological relapse; actuarial leukaemia-free survival is 38%. There is no difference in overall survival between the EX-TCD and IN-TCD groups, but primary graft failure (n = 4) occurred only in the EX-TCD group, while GVHD (grade II or greater) occurred more frequently in the IN-TCD group (61% vs. 29%, p = 0.084). The optimum method for GVHD prophylaxis in MUD BMT remains uncertain.

Adolescent↗
PubMed1992

Gene structure of human CD59 and demonstration that discrete mRNAs are generated by alternative polyadenylation.

We have isolated the CD59 gene from human genomic libraries. The gene is distributed over more than 27 x 10(3) base-pairs and consists of one 5'-untranslated exon and three coding exons. The gene structure is similar to that of mouse Ly-6 with the exception of the larger size of CD59 introns. Northern blot analysis using six different probes located in the 3'-region of the gene shows that more than four different CD59 mRNA molecules are generated by alternative polyadenylation. Three of these polyadenylation sites were predicted from previously published cDNA sequences. We have isolated a fourth from Jurkat poly(A)+ RNA by the procedure of rapid amplification of cDNA ends. Alternative polyadenylation may be due to the RNA secondary structure around the typical polyadenylation signal, AAUAAA.

Antigens, CD↗
PubMed1992

Humanised monoclonal antibody therapy for rheumatoid arthritis.

Monoclonal antibodies that target T cells have shown some benefit in rheumatoid arthritis although responses have not been long lasting. This is partly due to insufficient therapy consequent upon antibody immunogenicity. Use of humanised antibodies, which are expected to be less foreign to man than conventional rodent antibodies, might overcome this problem. We therefore assessed in a phase 1 open study the potential of a "lymphocyte depleting" regimen of the humanised monoclonal antibody CAMPATH-1H in 8 patients with refractory rheumatoid arthritis. Apart from symptoms associated with first infusions of antibody, adverse effects were negligible. Significant clinical benefit was seen in 7 patients, lasting for eight months in 1. After one course of therapy, there was no measurable antiglobulin response, although 3 out of 4 patients have become sensitised on retreatment. Humanisation reduces the immunogenicity of rodent antibodies but anti-idiotype responses may still be seen on repeated therapy, even in patients sharing immunoglobulin allotype with the humanised antibody.

Adult↗
PubMed1992

Therapy with monoclonal antibodies. An in vivo model for the assessment of therapeutic potential.

A set of rat-human and rat-rat chimeric mAb has been created, all possessing V regions identical in their specificity for the mouse CD8 Ag. In vitro all antibodies were able to block cell-mediated lysis but varied greatly in their capacity to utilize rabbit complement. We examined the ability of these chimeric antibodies to deplete in vivo and established a clear hierarchy. Of the human IgG subclasses, only IgG1, 2, and 3 could fix complement in vitro, yet all (IgG1-4) were remarkably potent at depleting CD8+ PBL in vivo. In contrast, human IgA2 and IgE were ineffective at clearing CD8+ PBL. The vector system used to create these antibodies together with the small doses of antibodies required to deplete in vivo make this a simple and rapid system for testing the effects of different antibody isotypes and mutants. We have shown that a mutant of human IgG1, which is incapable of fixing complement, depletes perfectly well in vivo, whereas an aglycosyl IgG1 mutant is rendered inactive. Our model provides a unique opportunity to study effector functions and motifs that are used by mAb in vivo and will help in the design of improved antibodies for human therapy.

Animals↗
PubMed1992

Tolerance in the mouse to major histocompatibility complex-mismatched heart allografts, and to rat heart xenografts, using monoclonal antibodies to CD4 and CD8.

Mice given a single short course of anti-CD4 and anti-CD8 monoclonal antibodies (mAb) became tolerant of major histocompatibility complex (MHC)-incompatible vascularized heart allografts in a donor- and organ-specific manner. T cell depletion was not important, as blocking antibodies were equally effective. Anti-CD4 antibody therapy alone was sufficient to establish tolerance. Anti-CD8 mAb therapy alone was associated with poor recipient survival, although survivors were rendered tolerant. A second donor-type heart allograft to the neck was always accepted in recipients which had carried the first abdominal heart allograft for over 120 days, with the first heart also continuing to function. However, donor-type skin grafted at 100 days was sometimes rejected, albeit chronically. Those recipients that accepted the donor-type skin were able to reject third-party skin grafts mismatched at the MHC, or over multiple minor differences alone. Thus, the tolerance induced appeared to be donor and tissue specific, although spreading in some cases to tolerance of skin. Similarly donor-specific tolerance was found when xenogeneic PVG rat hearts were grafted into CBA/Ca mice using the same protocols of anti-CD4 plus anti-CD8 mAb. Resolution of the mechanisms underlying these forms of tolerance may permit the design of improved immunosuppressive protocols for human organ transplantation.

Animals↗
PubMed1992

The use of a non-depleting anti-CD4 monoclonal antibody to re-establish tolerance to beta cells in NOD mice.

The use of immunosuppressive drugs in the management of autoimmunity penalizes a large part of the immune system for the misdemeanors of a small minority of T cells. An ideal form of therapy would be one in which it were possible to render the immune system tolerant of the inciting antigens with minimal effects on other responses. We here show that it is possible to re-establish self tolerance in an animal model of insulin-dependent diabetes mellitus without prior deletion of CD4+ T cells using a short course of therapy with a non-lytic monoclonal antibody to the CD4 adhesion receptor on T cells. This tolerance can be achieved even when diabetogenic cells are already in the pancreas. Primary responses to antigens given after therapy has ceased are normal and secondary responses to antigens seen prior to, but not during, the period of antibody therapy can remain unaffected. This suggests that intervention with selected CD4 antibodies may have significant advantages over and above that provided not only by conventional immunosuppression but also over that provided by a depleting antibody.

Animals↗
PubMed1992

Classical transplantation tolerance in the adult: the interaction between myeloablation and immunosuppression.

Allogeneic bone marrow transplantation in the neonate is an effective way of inducing permanent tolerance to donor tissue. To do the same in the immunocompetent adult requires immunosuppression to counter host-versus-graft alloreactivity. Conditioning with monoclonal antibodies (mAb) to CD4 and CD8 has been sufficient where donor and recipient are mismatched at only multiple "minor" histocompatibility loci, or at major histocompatibility complex (MHC) class I plus "minor" loci, but not where the mismatch involves the entire MHC. Tolerance across the MHC barrier requires extra conditioning with agents that happen to be both immunosuppressive and myeloablative, so obscuring the assessment of which effect is important. By using dimethylmyleran as a selective "space"-creating myeloablative agent, and CD4 plus CD8 mAb as sole immunosuppressive agents, we have been able to dissect the relative requirements for immunosuppression and myeloablation. We show here that transplantation tolerance could only be achieved when both types of agent were combined together so as to guarantee sufficient donor-type hemopoietic chimerism. We argue that the donor marrow, given sufficient space, will engraft and provide a sustained source of tolerogen overriding any host resistance that antibodies cannot control.

Animals↗
PubMed1992

Immunomodulation of dog islets using a cocktail of monoclonal antibodies.

Islet allografts are particularly vulnerable to rejection, and current immunosuppressive agents are deleterious to their function. They are, however, highly suitable for 'immunomodulation', i.e., the removal or inactivation of passenger leukocytes to reduce their immunogenicity. For this purpose we have used 3 rat anti-dog monoclonal antibodies (Mabs) which are synergistic for leukocytolysis in the presence of autologous dog serum. Spleen cells or purified islets treated with these Mabs together with autologous serum were tested in mixed leukocyte and islet co-culture assays. The stimulatory properties of the Mab-pretreated splenocytes or islets were markedly reduced; moreover, the Mab cytolytic activity was shown to be confined to the leukocyte target cells and did not affect islet secretory function upon glucose stimulation. We conclude that this method of modifying the immunogenicity of dog islets could lead to successful islet grafting in vivo, allowing the reduction of conventional immunosuppression. Successful in vivo studies in this model, which are currently in progress, could have implications for clinical islet transplantation.

Animals↗
PubMed1992

Therapeutic immunosuppression of T cells.

Current immunosuppressive therapy carries a range of unwanted side effects, and tends to penalize the whole immune system. It is desirable to develop therapies that are more selective for antigen-reactive cells. As T lymphocytes use a wide range of surface receptors to interact with antigen-bearing cells and with each other, much interest is devoted to trying to develop agents that selectively block the interaction of these receptors with their ligands, and others that could be used to reprogram the immune system so that it might become tolerant to the antigens rather than attack them.

Animals↗