The Impact of NLRP3 Activation on Hematopoietic Stem Cell Transplantation

NLR family pyrin domain-containing 3 (NLRP3) is an intracellular protein that after recognizing a broad spectrum of stressors, such as microbial motifs and endogenous danger signals, promotes the activation and release of the pro-inflammatory cytokines IL-1β and IL-18, thus playing an essential role in the innate immune response. Several blood cell types, including macrophages, dendritic cells, and hematopoietic stem and progenitor cells (HSPCs), express NLRP3, where it has been implicated in various physiological and pathological processes. For example, NLRP3 participates in the development and expansion of HSPCs, and their release from bone marrow into the peripheral blood has been implicated in certain hematological disorders including various types of leukemia. In addition, accumulating evidence indicates that activation of NLRP3 plays a pivotal role in the development of transplant complications in patients receiving hematopoietic stem cell transplantation (HSCT) including graft versus host disease, severe infections, and transplant-related mortality. The majority of these complications are triggered by the severe tissue damage derived from the conditioning regimens utilized in HSCT which, in turn, activates NLRP3 and, ultimately, promotes the release of proinflammatory cytokines such as IL-1β and IL-18. Here, we summarize the implications of NLRP3 in HSCT with an emphasis on the involvement of this inflammasome component in transplant complications.

Current Status of Cardiac Transplantation in the 21st Century

Advanced heart failure is an entity where irreversible structural heart disease is associated with persistent, refractory symptoms and quantitative decrease in cardiopulmonary capacity. Despite advanced and comprehensive medical therapy, patients are at high risk of death due to cardiogenic shock or cardiac arrest. Heart transplantation was developed as a surgical intervention to replace the failing recipient heart with a healthy heart from a recently deceased donor. In this article, we discuss the current state of cardiac transplantation, more than 5 decades after the first human cardiac transplantation was performed. Apart from an historical overview of the development of surgical techniques, we focus on appropriate patient selection, pretransplant evaluation, and recognition and treatment of post-transplant complications.

Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors: a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18–68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1–77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.

Pediatric Liver Transplantation as Enzyme Replacement Therapy for Rare Metabolic Diseases with No Structural Liver Damage

Objective: Very rare monogenic metabolic diseases without structural liver damage can be cured by liver transplantation. This process is a surgical enzyme replacement therapy, and defective enzymes may or may not be confined to the liver. The aims of this single center study of children with metabolic diseases showing structurally normal liver parenchyma were to analyze the indications and post-operative outcomes of liver transplantation, identification of developmental and metabolic benefits of the procedure with recognition of peri-operative difficulties to improve the success rate. Materials and Methods: Patients under the age of 19-year-old who underwent liver transplantation for metabolic disorders with no structural liver injury between January 2015 and June 2021 analyzed retrospectively. Patient and graft survivals, indications for transplantation, presence of extra-hepatic enzyme deficiency causing other organ damage, inclusion of simultaneous or sequential kidney transplantation, immunosuppressive protocols, post-transplant complications, and metabolic outcomes were identified. Results: Eight children with primary hyperoxaluria type 1 (n = 4), Maple syrup urine disease (n = 1), Crigler-Najjar syndrome type 1 (n=1), familial hypercholesterolemia (n=1) and propionic acidemia (n = 1) received left lobe (n=6) and left lateral segment (2) allografts from living donors. The median age of 4 girls and 4 boys at time of transplantation was 6.8 years (range 2.2-12.7 years). The median follow-up time was 3.3 years (range 1.5-5.7 years). The most common post-transplant complications were biliary system complications and infections and, two patients died because of sepsis. Six patients are alive with normal functioning allografts and metabolically stable on unrestricted diet. Conclusion: Liver transplantation is a lifesaving treatment and improves patient’s and parent’s life quality for metabolic disorders with no parenchymal injury despite strict dietary restrictions and medical therapies. Especially, living donor liver transplantation is very important for populations with very low organ donation rates.