Innate Immunity Post-Hematopoietic Stem Cell Transplantation: Focus on Epigenetics

Domingo-Gonzalez, Racquel; Moore, Bethany B.

doi:10.3233/nib-140079

Cited by 5 publications

(8 citation statements)

References 69 publications

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“…[75] Immune reconstitution following allogeneic HSC transplantation occurs in several phases. [76] An early phase of rapid myeloid cell reconstitution occurs within 20-30 days, while lymphoid cell reconstitution is delayed by up to a year. [77] Patients experience an "aplastic phase" of severe neutropenia until neutrophil progeny appear.…”

Section: Protocols Used In Human Hsc Transplantationmentioning

confidence: 99%

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Targeting the Spleen as an Alternative Site for Hematopoiesis

et al. 2019

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Bone marrow is the main site for hematopoiesis in adults. It acts as a niche for hematopoietic stem cells (HSCs) and contains non‐hematopoietic cells that contribute to stem cell dormancy, quiescence, self‐renewal, and differentiation. HSC also exist in resting spleen of several species, although their contribution to hematopoiesis under steady‐state conditions is unknown. The spleen can however undergo extramedullary hematopoiesis (EMH) triggered by physiological stress or disease. With the loss of bone marrow niches in aging and disease, the spleen as an alternative tissue site for hematopoiesis is an important consideration for future therapy, particularly during HSC transplantation. In terms of harnessing the spleen as a site for hematopoiesis, here the remarkable regenerative capacity of the spleen is considered with a view to forming additional or ectopic spleen tissue through cell engraftment. Studies in mice indicate the potential for such grafts to support the influx of hematopoietic cells leading to the development of normal spleen architecture. An important goal will be the formation of functional ectopic spleen tissue as an aid to hematopoietic recovery following clinical treatments that impact bone marrow. For example, expansion or replacement of niches could be considered where myeloablation ahead of HSC transplantation compromises treatment outcomes.

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Section: Protocols Used In Human Hsc Transplantationmentioning

confidence: 99%

“…Immune reconstitution following allogeneic HSC transplantation occurs in several phases . An early phase of rapid myeloid cell reconstitution occurs within 20–30 days, while lymphoid cell reconstitution is delayed by up to a year .…”

Section: Protocols Used In Human Hsc Transplantationmentioning

confidence: 99%

Targeting the Spleen as an Alternative Site for Hematopoiesis

et al. 2019

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“…There have been other studies that have also found a functional defect in monocytes after allogeneic HSCT, 31,32 and epigenetic changes in the regulation of the innate immune system have been suggested as a potential cause. 33 In our study, the infected HSCT patients did have a lower monocyte count than uninfected HSCT patients, which could have contributed to increased susceptibility to viral infections. However, our gene expression analysis used purified monocytes, which would have normalized the difference in monocyte count between infected and uninfected HSCT patients.…”

Section: Discussionmentioning

confidence: 52%

Characterization of innate immune viral sensors in patients following allogeneic hematopoietic stem cell transplantation

et al. 2018

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Viral infection is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplant (HSCT), with up to one in four deaths directly linked to viral disease. Whilst awaiting lymphocyte reconstitution post-HSCT, the innate antiviral immune response is the first line of defense against invading viruses. Several novel innate viral-sensing pathways have recently been characterized, but their physiological importance in humans is poorly understood. We analyzed a panel of innate viral-sensor genes in HSCT patients, and assessed whether differences in innate antiviral responses could account for variation in susceptibility to viral infections. Expression levels of innate viral sensors in HSCT patients with active viral infections, HSCT patients without active infections and healthy volunteers were highly homogenous. Although IFN-α expression was up-regulated in actively infected patients relative to controls, a corresponding up-regulation of innate viral sensor expression was not observed. IFN-α stimulation of patient PBMCs in vitro showed intact IFN-α signaling, but actively infected patients' PBMCs had reduced up-regulation of innate viral sensors. We show that the aberrant IFN-α responses in HSCT patients were not due to calcineurin inhibition. Our data therefore raises the possibility of an intrinsic defect in innate viral sensor up-regulation in HSCT patients following viral infection.

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“…Furthermore, we noted higher levels of IL-1β in BMDMs pre-treated with PGE 2 and infected with methicillin-resistant Staphylococcus aureus (MRSA) or Streptococcus pneumoniae compared to infected BMDMs not treated with PGE 2 ( Supplemental Fig.2B ). MRSA and S.pneumoniae are also main pathogens that infect immunosuppressed individuals 6 , 19 , 31 , 32 .…”

Section: Resultsmentioning

confidence: 99%

“…P. aeruginosa is an opportunistic pathogen which causes minimal pathogenicity in healthy individuals, but major mortality and morbidity in HSCT patients 2 , 6 , 19 , 31 , 37 , 38 . Susceptibility to this pathogen has been reported to occur even after immune reconstitution following HSCT 2 , 6 , 31 . HSCT patients have high levels of PGE 2 in the blood and BALF when compared to healthy individuals 18 - 20 .…”

Section: Discussionmentioning

confidence: 99%

Elevated prostaglandin E2 post–bone marrow transplant mediates interleukin-1β-related lung injury

et al. 2018

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Hematopoietic stem cell transplant (HSCT) treats or cures a variety of hematological and inherited disorders. Unfortunately, patients that undergo HSCT are susceptible to infections by a wide array of opportunistic pathogens. Pseudomonas aeruginosa bacteria can have life-threatening effects in HSCT patients by causing lung pathology that has been linked to high levels of the potent pro-inflammatory cytokine, interleukin-1β (IL-1β). Using a murine bone marrow transplant (BMT) model, we show overexpression of prostaglandin E2 (PGE2) post-BMT signals via EP2 or EP4 to induce cyclic adenosine monophosphate (cAMP) which activates protein kinase A (PKA) or the exchange protein activated by cAMP (Epac) to induce cAMP response element binding (CREB)-dependent transcription of IL-1β leading to exacerbated lung injury in BMT mice. Induction of IL-1β by PGE2 is time and dose dependent. Interestingly, IL-1β processing post-P. aeruginosa infection occurs via the enzymatic activity of either caspase-1 or caspase-8. Furthermore, PGE2 can limit autophagy-mediated killing of P. aeruginosa in alveolar macrophages, yet, autophagy doesn't play a role in PGE2-mediated up-regulation of IL-1β. Reducing PGE2 levels with indomethacin improved bacterial clearance and reduced IL-1β-mediated acute lung injury (ALI) in P. aeruginosa-infected BMT mice.

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Innate Immunity Post-Hematopoietic Stem Cell Transplantation: Focus on Epigenetics

Cited by 5 publications

References 69 publications

Targeting the Spleen as an Alternative Site for Hematopoiesis

Targeting the Spleen as an Alternative Site for Hematopoiesis

Characterization of innate immune viral sensors in patients following allogeneic hematopoietic stem cell transplantation

Elevated prostaglandin E2 post–bone marrow transplant mediates interleukin-1β-related lung injury

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