On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity

The Role of Immune Checkpoints after Cellular Therapy

Cellular therapies utilize the powerful force of the human immune system to target malignant cells. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the most established cellular therapy, but chimeric antigen receptor (CAR) T cell therapies have gained attention in recent years. While in allo-HCT an entirely novel allogeneic immune system facilitates a so-called Graft-versus-tumor, respectively, Graft-versus-leukemia (GvT/GvL) effect against high-risk hematologic malignancies, in CAR T cell therapies genetically modified autologous T cells specifically attack target molecules on malignant cells. These therapies have achieved high success rates, offering potential cures in otherwise detrimental diseases. However, relapse after cellular therapy remains a serious clinical obstacle. Checkpoint Inhibition (CI), which was recently designated as breakthrough in cancer treatment and consequently awarded with the Nobel prize in 2018, is a different way to increase anti-tumor immunity. Here, inhibitory immune checkpoints are blocked on immune cells in order to restore the immunological force against malignant diseases. Disease relapse after CAR T cell therapy or allo-HCT has been linked to up-regulation of immune checkpoints that render cancer cells resistant to the cell-mediated anti-cancer immune effects. Thus, enhancing immune cell function after cellular therapies using CI is an important treatment option that might re-activate the anti-cancer effect upon cell therapy. In this review, we will summarize current data on this topic with the focus on immune checkpoints after cellular therapy for malignant diseases and balance efficacy versus potential side effects

Evaluation of factors associated with survival in allogeneic stem cell-transplanted patients admitted to the intensive care unit (ICU)

ABSTRACTIntroduction: There are conflicting results concerning the outcome of patients after an allogeneic hematopoietic stem cell transplantation (allo-HSCT) who required treatment in the intensive care unit (ICU). The aim of this study was to evaluate the outcome and prognostic parameters in terms of patient survival after allo-HSCT and admission to the ICU within the first 30 days after transplantation.Methods: Patients after allo-HSCT, who were ≥18 years and admitted to the ICU after the initiation of conditioning therapy and within the first 30 days after allo-HSCT at the University Hospital of Bonn between January 2017 and April 2021, were analysed retrospectively. Baseline data, laboratory parameters, established scoring systems, vital parameters, and outcome were collected.Results: 44 patients (median age of 63 years) were analysed. The 90-day survival rate was 50% (N = 22) and the 1-year survival rate was 27% (N = 12). The 90-day and 1-year survival rates of patients who required MV were 38% (N = 13) and 18% (N = 6). There was a significant correlation between increased mortality and an APACHE-Score ≥20 (p = 0.03), a SAPS-II-Score ≥60 (p = 0.04) and a SOFA-Score ≥9 (p = 0.03). Invasive mechanical ventilation (p = 0.05) and vasopressor support (p = 0.03) showed a negative correlation with the outcome.Conclusion: This study found several parameters (APACHE-II-Score, SAPS-II-Score, SOFA-Score, MV and vasopressor support) associated with increased mortality after allo-HSCT and admission to the ICU. The outcome of allo-HSCT patients admitted to the ICU is not as poor as previously reported. Even older patients under long-term ventilation may benefit from intensive care therapy

Preliminary Report for the Development of a Multiparameter Protocol for the Identification of Sinusoidal Obstruction Syndrome including Abdominal Ultrasound before and after Allogeneic Stem Cell Transplantation

Sinusoidal obstruction syndrome (SOS) is a rare complication after allogeneic hematopoietic stem cell transplantation (alloHSCT) caused by endothelial dysfunction. Previous definitions and diagnostic criteria for the presence of SOS include bilirubinemia, hepatomegaly and weight gain, but histological evaluation is still the only way to prove the diagnosis of SOS. However, biopsy remains an invasive technique and is therefore undesirable in the alloHSCT scenario. Hence, a non-invasive diagnostic strategy is critical. Besides thorough clinical assessment and laboratory values, ultrasound examination remains part of the diagnostic workflow in clinical routine. Previous studies defined sonographic abnormalities, which are associated with the occurrence of SOS, but a standardized protocol to perform reliable abdominal ultrasound has not been finally defined. In this study, we evaluated a multi-parameter protocol including laboratory values as well as ultrasound examination pre- and post-alloHSCT. The application of this protocol was feasible in clinical practice and achieved a high inter- and intra-rater reliability. In our population, no case of SOS was identifiable and, in line with previous studies, no changes known to be associated with SOS were detected by ultrasound examination in our cohort. Additionally, we investigated subgroups of patients partly fulfilling SOS diagnostic criteria analyzing correlations between the fulfilled criteria and aberrances in ultrasound measurements pre- and post-alloHSCT. Although statistical examination may be limited by a small sample size and missing SOS cases, hyperbilirubinemia, thrombocytopenia and weight gain showed only a coincidence with selected, enlarged liver dimensions in few patients. This may underline the fact that hepatomegaly occurs as an unspecific finding after alloHSCT. Our protocol, including the ultrasound examination pre- and post-alloHSCT and laboratory parameters, may help to rule out SOS early, but validation in a greater population and different transplantation centers is required to warrant broader appliance. Nevertheless, we aim to contribute to an elaborate and standardized work-flow in peri-alloHSCT patient care

Selective ABO immunoadsorption in hematopoietic stem cell transplantation with major ABO incompatibility

Objective ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA). Methods 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA. Results In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed. Conclusions Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed

The role of checkpoint blockade after allogeneic stem cell transplantation in diseases other than Hodgkin’s Lymphoma

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for many malignant high-risk hematological diseases. The Graft-vs.-Tumor (GvT) effect is the major hallmark of this treatment approach. However, disease relapse remains a major limitation. Boosting the GvT effect by checkpoint inhibitors (CI) is an attractive option in this desperate situation although potentially triggering Graft-vs.-Host Disease (GvHD). Early reports in patients with Hodgkin's lymphoma support the idea that CI therapy after HSCT is feasible and effective. We have retrospectively analyzed CI therapy for treatment of disease recurrence after allo-HSCT other than Hodgkin's lymphoma including 21 patients from eight German transplant centers. The median follow-up was 59 days. The overall response rate (ORR) was 43%. Patients receiving donor lymphocyte infusion (DLI) in combination with CI had superior response (ORR 80%). Severe acute GvHD grade III-IV and moderate to severe chronic GvHD were observed in 29% of all patients. Taken together, CI therapy in relapsed patients after HSCT, especially in combination with DLI, is effective but induces severe GvHD in a considerable proportion of patients. Thus, prospective trials or EBMT registry-based validation of different dosing and application schedules including immunosuppressive regimens in those patients are urgently needed