Abstract
Patients with treatment refractory Crohn’s disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD—Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT.
Highlights
Etiology, Epidemiology, and Management of Crohn’s Disease (CD)The intestinal inflammation associated with CD is caused by mucosal immune system reactivity to luminal antigen in genetically susceptible individuals
Given that reduced intensity mobilization and conditioning regimens are associated with lower morbidity in malignant and autoimmune diseases (ADs) [20, 55,56,57,58], the hypothesis that auto-HSCT using a reduced dose cyclophosphamide mobilization and low intensity conditioning (HSCTlite) will induce regression of ileocolonic ulceration in patients with refractory CD compared to standard of care will be tested via a soon-to-commence clinical trial (ASTIClite)
Based on clinical trials and EBMT registry data, auto-HSCT represents a promising therapy for patients with severe resistant
Summary
The intestinal inflammation associated with CD is caused by mucosal immune system reactivity to luminal antigen in genetically susceptible individuals. Failure of achieving durable treatment-free remissions in CD post-transplantation could indicate that aberrant adaptive autoimmune responses and formation of a pathogenic immunologic memory are not the driving force in disease pathogenesis, as confirmed for other systemic ADs. perturbations in the innate immune pathway resulting in compromised mucosal barrier functions may have a stronger implication in driving chronic autoimmune responses in CD, which may not be corrected by “resetting” the immune system with auto-HSCT. SjTRECs reflect developmental proximity to the thymus and the analysis of total sjTRECs levels and TCR beta variable region (TRBV) subfamily sjTRECs frequencies during immune reconstitution after HSCT is useful for more precisely determining thymic output function and T cell immune reconstitution [53] Such analyses have not yet been undertaken in the context of CD, the increased precision of this approach has the potential to provide a more robust insight into the relationship(s) between immune status, disease status, and therapeutic resistance after auto-HSCT
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
