Abstract:X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches ar… Show more
“…XIAP deficiency is an inborn error of immunity with a range of severe manifestations, and even when diagnosed early, provision of prophylactic therapies and close monitoring may not prevent fatal complications such as HLH. Outcomes following HSCT are significantly worse in patients with XIAP deficiency than those with other familial forms of HLH and even low grade GvHD is associated with disproportionate mortality [ 8 , 9 , 68 ]. Studies by Marsh et al [ 8 ] and Varghese et al [ 68 ] show high levels of toxicity following conventional myeloablative conditioning, likely due to loss of XIAP.…”
Section: Discussionmentioning
confidence: 99%
“…Studies by Marsh et al [ 8 ] and Varghese et al [ 68 ] show high levels of toxicity following conventional myeloablative conditioning, likely due to loss of XIAP. A high incidence of GvHD, mixed donor chimerism (< 95%) and relapsed HLH post-HSCT have been observed when using RIC-HSCT [ 9 ]. As such, development of autologous gene therapy strategies can offer patients lacking suitable donors an alternative clinical option which removes any risk of alloreactivity and allows the use of reduced toxicity conditioning.…”
Section: Discussionmentioning
confidence: 99%
“…More recent reports of reduced-intensity conditioning (RIC) regimens suggest these approaches are better tolerated with improved survival [ 8 – 10 ]. However, HSCT is associated with graft-versus-host disease (GvHD), which significantly increases the risk of mortality in patients with XIAP deficiency [ 9 ]. Autologous hematopoietic stem cell (HSC) gene therapy abrogates any risk of alloreactivity due to GvHD making it an extremely attractive potential therapy.…”
Background
X-linked inhibitor of apoptosis protein (XIAP) deficiency is a severe immunodeficiency with clinical features including hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) due to defective NOD2 responses. Management includes immunomodulatory therapies and hematopoietic stem cell transplant (HSCT). However, this cohort is particularly susceptible to the chemotherapeutic regimens and acutely affected by graft-vs-host disease (GvHD), driving poor long-term survival in transplanted patients. Autologous HSC gene therapy could offer an alternative treatment option and would abrogate the risks of alloreactivity.
Methods
Hematopoietic progenitor (Lin−ve) cells from XIAPy/− mice were transduced with a lentiviral vector encoding human XIAP cDNA before transplantation into irradiated XIAP y/− recipients. After 12 weeks animals were challenged with the dectin-1 ligand curdlan and recovery of innate immune function was evaluated though analysis of inflammatory cytokines, body weight, and splenomegaly. XIAP patient-derived CD14+ monocytes were transduced with the same vector and functional recovery was demonstrated using in vitro L18-MDP/NOD2 assays.
Results
In treated XIAPy/− mice, ~40% engraftment of gene-corrected Lin−ve cells led to significant recovery of weight loss, splenomegaly, and inflammatory cytokine responses to curdlan, comparable to wild-type mice. Serum IL-6, IL-10, MCP-1, and TNF were significantly reduced 2-h post-curdlan administration in non-corrected XIAPy/− mice compared to wild-type and gene-corrected animals. Appropriate reduction of inflammatory responses was observed in gene-corrected mice, whereas non-corrected mice developed an inflammatory profile 9 days post-curdlan challenge. In gene-corrected patient CD14+ monocytes, TNF responses were restored following NOD2 activation with L18-MDP.
Conclusion
Gene correction of HSCs recovers XIAP-dependent immune defects and could offer a treatment option for patients with XIAP deficiency.
“…XIAP deficiency is an inborn error of immunity with a range of severe manifestations, and even when diagnosed early, provision of prophylactic therapies and close monitoring may not prevent fatal complications such as HLH. Outcomes following HSCT are significantly worse in patients with XIAP deficiency than those with other familial forms of HLH and even low grade GvHD is associated with disproportionate mortality [ 8 , 9 , 68 ]. Studies by Marsh et al [ 8 ] and Varghese et al [ 68 ] show high levels of toxicity following conventional myeloablative conditioning, likely due to loss of XIAP.…”
Section: Discussionmentioning
confidence: 99%
“…Studies by Marsh et al [ 8 ] and Varghese et al [ 68 ] show high levels of toxicity following conventional myeloablative conditioning, likely due to loss of XIAP. A high incidence of GvHD, mixed donor chimerism (< 95%) and relapsed HLH post-HSCT have been observed when using RIC-HSCT [ 9 ]. As such, development of autologous gene therapy strategies can offer patients lacking suitable donors an alternative clinical option which removes any risk of alloreactivity and allows the use of reduced toxicity conditioning.…”
Section: Discussionmentioning
confidence: 99%
“…More recent reports of reduced-intensity conditioning (RIC) regimens suggest these approaches are better tolerated with improved survival [ 8 – 10 ]. However, HSCT is associated with graft-versus-host disease (GvHD), which significantly increases the risk of mortality in patients with XIAP deficiency [ 9 ]. Autologous hematopoietic stem cell (HSC) gene therapy abrogates any risk of alloreactivity due to GvHD making it an extremely attractive potential therapy.…”
Background
X-linked inhibitor of apoptosis protein (XIAP) deficiency is a severe immunodeficiency with clinical features including hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) due to defective NOD2 responses. Management includes immunomodulatory therapies and hematopoietic stem cell transplant (HSCT). However, this cohort is particularly susceptible to the chemotherapeutic regimens and acutely affected by graft-vs-host disease (GvHD), driving poor long-term survival in transplanted patients. Autologous HSC gene therapy could offer an alternative treatment option and would abrogate the risks of alloreactivity.
Methods
Hematopoietic progenitor (Lin−ve) cells from XIAPy/− mice were transduced with a lentiviral vector encoding human XIAP cDNA before transplantation into irradiated XIAP y/− recipients. After 12 weeks animals were challenged with the dectin-1 ligand curdlan and recovery of innate immune function was evaluated though analysis of inflammatory cytokines, body weight, and splenomegaly. XIAP patient-derived CD14+ monocytes were transduced with the same vector and functional recovery was demonstrated using in vitro L18-MDP/NOD2 assays.
Results
In treated XIAPy/− mice, ~40% engraftment of gene-corrected Lin−ve cells led to significant recovery of weight loss, splenomegaly, and inflammatory cytokine responses to curdlan, comparable to wild-type mice. Serum IL-6, IL-10, MCP-1, and TNF were significantly reduced 2-h post-curdlan administration in non-corrected XIAPy/− mice compared to wild-type and gene-corrected animals. Appropriate reduction of inflammatory responses was observed in gene-corrected mice, whereas non-corrected mice developed an inflammatory profile 9 days post-curdlan challenge. In gene-corrected patient CD14+ monocytes, TNF responses were restored following NOD2 activation with L18-MDP.
Conclusion
Gene correction of HSCs recovers XIAP-dependent immune defects and could offer a treatment option for patients with XIAP deficiency.
“…Forty children and young adults with a median age at HSCT of 6.5 years (0.45-27) reached an overall survival rate of 74% and a rate of event-free survival of 64% at two years post transplant, but the incidence of severe treatment-related toxicities like respiratory distress syndrome or life-threatening bleeding was high (25% and 23%, respectively). 108 In summary, further characterisation of genetic components of paediatric ADs will evolve our understanding, and direct appropriate treatment, including allogeneic HSCT, which is a standard of care according to EBMT guidelines. 118 'Standard' autologous HSCT is clearly ineffective in these patients as a means of long-term cure.…”
Section: Autoimmune Diseases With Genetic Featuresmentioning
confidence: 99%
“…A further recent study on children with XIAP deficiency, a rare genetic disease which causes severe autoimmunity such as treatment‐refractory IBD and life‐threatening sHLH, reports encouraging survival data after allogeneic HSCT following reduced‐intensity or reduced‐toxicity conditioning. Forty children and young adults with a median age at HSCT of 6.5 years (0.45–27) reached an overall survival rate of 74% and a rate of event‐free survival of 64% at two years post transplant, but the incidence of severe treatment‐related toxicities like respiratory distress syndrome or life‐threatening bleeding was high (25% and 23%, respectively) 108 …”
Section: Major Indications For Haematopoietic Stem Cell Transplantati...mentioning
Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations. K E Y W O R D S autoimmune diseases, haematopoietic stem cell transplantation, paediatric Selim Corbacioglu and Raffaella Greco contributed equally.
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