ORCID Profile
0000-0001-7519-6720
Current Organisations
BIRDEM GENERAL HOSPITAL
,
University of Oxford
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Publisher: The American Association of Immunologists
Date: 07-2010
Abstract: Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing–remitting multiple sclerosis received an initial cycle of alemtuzumab (C ath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p & 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting “high-zone” tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.
Publisher: Elsevier BV
Date: 09-2004
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.SMIM.2006.01.010
Abstract: Our ability to harness tolerance mechanisms will have a major impact in organ transplantation. It should enable drug minimization, and eventually, the elimination of all immunosuppressive drugs. An improved understanding of the biology of regulatory T cells will make it possible to replace current induction regimens with those favouring the selective vaccination of T cells that prevent graft rejection. Once regulation is established, the continued supply of graft antigens should empower T cell regulation to become the dominant natural mechanism to prevent graft rejection.
Publisher: Oxford University Press (OUP)
Date: 15-03-1993
Publisher: Springer Science and Business Media LLC
Date: 2006
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1111/J.1600-6143.2008.02382.X
Abstract: CD40L antibodies have proven to be powerful immunosuppressive agents in nonhuman primates but unfortunately perturb blood coagulation. Neither the therapeutic nor the prothrombotic mechanism of anti-CD40L is defined sufficiently to determine whether these effects can be uncoupled. Recent evidence suggests that the Fc region of anti-CD40L antibodies interacting with Fc receptors plays an important role in stabilizing platelet aggregates. An Fc-disabled, aglycosylated anti-CD40L heavy chain variant was therefore created to determine whether it might still be useful in promoting transplantation tolerance. In a number of mouse models an engineered aglycosyl anti-CD40L recapitulated the effects of the intact anti-CD40L antibody in tolerance protocols involving transplantation of allogeneic bone marrow and skin. In contrast, another anti-CD40L variant with a conventional rat gamma2b heavy chain was less effective in ensuring long-term skin graft survival, possibly associated with its faster clearance from the circulation. These results show that short pulses of anti-CD40L antibody therapy may still be useful in tolerance protocols even when the Fc region is disabled.
Publisher: Wiley
Date: 14-09-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-08-2003
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.INTIMP.2004.09.005
Abstract: As arbitrators of the immune response, dendritic cells (DC) are uniquely placed to negotiate the balance between the opposing forces of tolerance and immunity, making them attractive candidates for clinical applications. Accordingly, DC have been used successfully in the treatment of cancer, enhancing immune responses to tumour-associated antigens (TAA) in experimental animal models and phase I clinical trials. A novel source of DC that has recently been described is the embryonic stem (ES) cell whose differentiation in vitro may be directed along multiple lineage pathways. Such pluripotency offers unparalleled opportunities for the treatment of chronic and degenerative disease states by the replacement of affected tissues, a vision which has inspired the emerging field of regenerative medicine. By sharing the genotype of therapeutic cell types, such as cardiomyocytes and dopaminergic neurons derived from the same ES cell line, so-called esDC may offer prospects for reprogramming the immune system to tolerate the grafted tissues. Here, we describe how the unique properties of esDC and the ES cells from which they derive, make them eminently suited to clinical applications, overcoming many of the issues that currently limit the effectiveness of DC-based immune intervention.
Publisher: The American Association of Immunologists
Date: 10-2009
Abstract: In the aftermath of thymic negative selection, natural and adaptive regulatory T cells (Tregs) must acknowledge peripheral, “danger-free” self-Ag to ensure their sustained activity. In this paper, we show that natural and adaptive Tregs or T cells transduced with cDNA for Foxp3, just like Th1 cells, express members of the MS4A family of transmembrane molecules. Naive T cells transduced with MS4A4B become able to respond to lower levels of Ag. Using two family members, MS4A4B and MS4A6B, as baits in a yeast split-ubiquitin Treg library screen, we demonstrate their interaction with each other and with GITR, Orai1, and other surface receptors. Interaction of 4B with GITR augments GITR signaling and T cell IL-2 production in response to triggering with GITR ligand or anti-GITR Abs. This interaction provides a mechanism whereby MS4A family members, through lateral coassociation with costimulatory molecules, may lify Ag signals. We propose that T cells preoccupied with immune defense use this MS4A family to enhance sensitivity to extrinsic Ag stimulation, ensuring its elimination, while Tregs use these adaptors to allow low level Ag signals to sustain regulatory function.
Publisher: Informa UK Limited
Date: 28-04-2021
DOI: 10.1080/21548331.2021.1906083
Abstract: Prevalence rates of patients with diabetes are growing across countries, and Bangladesh is no exception. Associated costs are also increasing, driven by costs associated with the complications of diabetes including hypoglycemia. Long-acting insulin analogues were developed to reduce hypoglycemia as well as improve patient comfort and adherence. However, they have been appreciably more expensive, reducing their affordability and use. Biosimilars offer a way forward. Consequently, there is a need to document current prescribing and dispensing rates for long-acting insulin analogues across Bangladesh, including current prices and differences, as a result of affordability and other issues. Mixed method approach including surveying prescribing practices in hospitals coupled with dispensing practices and prices among community pharmacies and drug stores across Bangladesh. This method was adopted since public hospitals only dispense insulins such as soluble insulins free-of-charge until funds run out and all long-acting insulin analogues have to be purchased from community stores. There has been growing prescribing and dispensing of long-acting insulins in Bangladesh in recent years, now accounting for over 80% of all insulins dispensed in a minority of stores. This increase has been helped by growing prescribing and dispensing of biosimilar insulin glargine at lower costs than the originator, with this trend likely to continue with envisaged growth in the number of patients. Consequently, Bangladesh can serve as an exemplar to other low- and middle-income countries struggling to fund long-acting insulin analogues for their patients. It was encouraging to see continued growth in the prescribing and dispensing of long-acting insulin analogues in Bangladesh via the increasing availability of biosimilars. This is likely to continue benefitting all key stakeholder groups.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-02-2001
Abstract: CD40 is a member of the tumor necrosis factor receptor superfamily. The interaction between CD40 and CD40 ligand (CD154) activates NF-κB, Jun N-terminal kinase, and Janus kinase/signal transducers and activators of transcription pathways and promotes B cell growth, differentiation, and survival as well as IL-12 production in macrophages and dendritic cells. We demonstrate here the existence of multiple isoforms of CD40 mRNA generated by alternative splicing and show that their expression is regulated differentially in activated macrophages and dendritic cells. Pre-CD40 RNA is spliced preferentially out to signal-transducible CD40 mRNA in the early stage of activation half of the CD40 mRNA is replaced by the signal-nontransducible CD40 mRNAs in the later stages (24 h). Using IL-12 p40 gene expression as a reporter for CD40 signaling, we show that three of the alternative isoforms can disable signaling through CD40. The major alternative isoform lacks the membrane-associated endodomain and seems to reduce the amount of the signal-transducible form available on the cell surface. It would seem, therefore, that CD40 expression is controlled by posttranscriptional and posttranslational regulation through alternative splicing. Modulation of isoform expression may provide a mechanism by which cells regulate their susceptibility to CD40L signaling.
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.1385/SCR:1:2:159
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Herman Waldmann.