In April 2016 Manchester eScholar was replaced by the University of Manchester’s new Research Information Management System, Pure. In the autumn the University’s research outputs will be available to search and browse via a new Research Portal. Until then the University’s full publication record can be accessed via a temporary portal and the old eScholar content is available to search and browse via this archive.

Immune responses in patients withLysosomal Storage Disorders treated with Enzyme Replacement Therapy and Haemopoietic Stem Cell Transplantation

Saif, Muhammad

[Thesis]. Manchester, UK: The University of Manchester; 2013.

Access to files

Abstract

Lysosomal storage disorders (LSDs) are caused by defective lysosomal degradation of macromolecules resulting in accumulation of substrates in various tissues. This gradually leads to organ dysfunction and the classical clinical presentation with multisystem involvement. Historically the management of LSDs was confined to symptomatic treatment only. More recently other therapies have become available. Treatment options include cellular therapy in the form of Haemopoietic Stem Cell Transplant (HSCT), Enzyme Replacement Therapy (ERT), Substrate Reduction Therapy (SRT), Chaperone Mediated Therapy (CMT) and gene therapy. Whilst HSCT and ERT are established strategies in clinical practice for some LSDs, others are still in the development phase. The easy accessibility of ERT in the developed world (despite a high cost burden of approximately £144,000 per patient per annum in the UK), fewer risks associated with its administration and good metabolic and clinical outcome, have made ERT the treatment of choice for a number of LSDs. In recent years immune response has been identified as a significant factor in attenuating or nullifying the response to ERT. Despite recognition of this problem, there is a lack of reliable diagnostic tools to test and evaluate the antibody responses in the centres delivering ERT and far too little attention has been focused on development, optimisation and standardization of immune assays.In this project, IgG ELISA and two different functional enzyme inhibition assays (catalytic inhibition and cellular uptake inhibition) were developed and optimized. The immune response to ERT was then studied in recipients of ERT in MPSI, MPSVI and Pome disease. Our practice of delivering ERT in recipients of allogeneic HSCT prior to transplant provided us with an opportunity to study the immune response in MPSIH patients during ERT and following HSCT. We demonstrated functionally active antibodies in long term recipients of ERT in MPSI and Pompe disease. Allo-immune response in MPSVI did not inhibit the delivered enzyme therapy. A high titre inhibitory immune response was detected in the majority of MPSIH patients after exposure to ERT. This immune response was abrogated by allogeneic HSCT rendering these patients tolerant to replaced enzyme, confirming HSCT as an effective immune tolerance induction mechanism.

Layman's Abstract

Infusion of Enzyme Replacement Therapy in lysosomal Storage Disorders can lead to generation of antibodies that can neutralize the efficacy of treatment. We studied the incidence and effect of these antibodies in patients who received enzyme therapy and those who received stem cell transplantation. Our result show that the antibodies can reduce the efficacy of infused therapy in MPSI and Pompe disease but not in MPSVI. Allogeneic stem cell transplantation can eradicate the antibodies produced in response to infused enzyme therapy.

Bibliographic metadata

Type of resource:
Content type:
Form of thesis:
Type of submission:
Degree programme:
MD Medicine (Human Development)
Publication date:
Location:
Manchester, UK
Total pages:
220
Abstract:
Lysosomal storage disorders (LSDs) are caused by defective lysosomal degradation of macromolecules resulting in accumulation of substrates in various tissues. This gradually leads to organ dysfunction and the classical clinical presentation with multisystem involvement. Historically the management of LSDs was confined to symptomatic treatment only. More recently other therapies have become available. Treatment options include cellular therapy in the form of Haemopoietic Stem Cell Transplant (HSCT), Enzyme Replacement Therapy (ERT), Substrate Reduction Therapy (SRT), Chaperone Mediated Therapy (CMT) and gene therapy. Whilst HSCT and ERT are established strategies in clinical practice for some LSDs, others are still in the development phase. The easy accessibility of ERT in the developed world (despite a high cost burden of approximately £144,000 per patient per annum in the UK), fewer risks associated with its administration and good metabolic and clinical outcome, have made ERT the treatment of choice for a number of LSDs. In recent years immune response has been identified as a significant factor in attenuating or nullifying the response to ERT. Despite recognition of this problem, there is a lack of reliable diagnostic tools to test and evaluate the antibody responses in the centres delivering ERT and far too little attention has been focused on development, optimisation and standardization of immune assays.In this project, IgG ELISA and two different functional enzyme inhibition assays (catalytic inhibition and cellular uptake inhibition) were developed and optimized. The immune response to ERT was then studied in recipients of ERT in MPSI, MPSVI and Pome disease. Our practice of delivering ERT in recipients of allogeneic HSCT prior to transplant provided us with an opportunity to study the immune response in MPSIH patients during ERT and following HSCT. We demonstrated functionally active antibodies in long term recipients of ERT in MPSI and Pompe disease. Allo-immune response in MPSVI did not inhibit the delivered enzyme therapy. A high titre inhibitory immune response was detected in the majority of MPSIH patients after exposure to ERT. This immune response was abrogated by allogeneic HSCT rendering these patients tolerant to replaced enzyme, confirming HSCT as an effective immune tolerance induction mechanism.
Layman's abstract:
Infusion of Enzyme Replacement Therapy in lysosomal Storage Disorders can lead to generation of antibodies that can neutralize the efficacy of treatment. We studied the incidence and effect of these antibodies in patients who received enzyme therapy and those who received stem cell transplantation. Our result show that the antibodies can reduce the efficacy of infused therapy in MPSI and Pompe disease but not in MPSVI. Allogeneic stem cell transplantation can eradicate the antibodies produced in response to infused enzyme therapy.
Thesis main supervisor(s):
Thesis co-supervisor(s):
Thesis advisor(s):
Language:
en

Institutional metadata

University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:190335
Created by:
Saif, Muhammad
Created:
25th March, 2013, 21:14:31
Last modified by:
Saif, Muhammad
Last modified:
3rd April, 2018, 11:47:48

Can we help?

The library chat service will be available from 11am-3pm Monday to Friday (excluding Bank Holidays). You can also email your enquiry to us.