Dataset Information

Zebrafish model for allogeneic hematopoietic cell transplantation not requiring preconditioning.

ABSTRACT: Recent work on vertebrate hematopoiesis has uncovered the presence of deeply rooted similarities between fish and mammals at molecular and cellular levels. Although small animal models such as zebrafish are ideally suited for genetic and chemical screens, the study of cellular aspects of hematopoietic development in lower vertebrates is severely hampered by the complex nature of their histocompatibility-determining genes. Hence, even when hosts are sublethally irradiated before hematopoietic cell transplantation, stable and long-term reconstitution by allogeneic stem cells often fails. Here, we describe the unexpected observation that transplantation and maintenance of allogeneic hematopoietic stem cells in zebrafish homozygous for the c-myb(t25127) allele, carrying a missense mutation (Ile181Asn) in the DNA binding domain can be achieved without prior conditioning. Using this model, we examined several critical parameters of zebrafish hematopoiesis in a near-physiological setting. Limiting dilution analysis suggests that the kidney marrow of adult zebrafish harbors about 10 transplantable hematopoietic stem cells; this tissue also contains thymus-settling precursors that colonize the thymic rudiment within days after transplantation and initiate robust T-cell development. We also demonstrate that c-myb mutants can be stably reconstituted with hematopoietic cells carrying specific genetic defects in lymphocyte development, exemplifying one of the many potential uses of this model in experimental hematology.

SUBMITTER: Hess I

PROVIDER: S-EPMC3600459 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Zebrafish model for allogeneic hematopoietic cell transplantation not requiring preconditioning.

Hess Isabell I Iwanami Norimasa N Schorpp Michael M Boehm Thomas T

Proceedings of the National Academy of Sciences of the United States of America 20130219 11

Recent work on vertebrate hematopoiesis has uncovered the presence of deeply rooted similarities between fish and mammals at molecular and cellular levels. Although small animal models such as zebrafish are ideally suited for genetic and chemical screens, the study of cellular aspects of hematopoietic development in lower vertebrates is severely hampered by the complex nature of their histocompatibility-determining genes. Hence, even when hosts are sublethally irradiated before hematopoietic cel ...[more]

PMID: 23431192

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Project description:Noninfectious pulmonary toxicity (NPT), a significant complication of allogeneic hematopoietic cell transplantation (alloHCT), includes idiopathic pneumonia syndrome (IPS), diffuse alveolar hemorrhage (DAH), and cryptogenic organizing pneumonia (COP), with an overall incidence ranging from 1% to 15% in different case series and a variable mortality rate. A registry study of the epidemiology and outcomes of NPT after alloHCT has not been conducted to date. The primary objective of the present study was to assess the incidence of and risk factors for IPS, DAH, and COP; the secondary objective was to assess overall survival (OS) in patients developing NPT. This retrospective study included adult patients who underwent alloHCT between 2008 and 2017 and reported to the Center for International Blood and Marrow Transplant Research. Multivariable Cox proportional hazards regression models were developed to identify the risk factors for development of NPT and for OS, by including pretransplantation clinical variables and time-dependent variables of neutrophil and platelet recovery, and acute graft-versus-host disease (GVHD) post-transplantation. This study included 21,574 adult patients, with a median age of 55 years. According to the HCT Comorbidity Index (HCT-CI), 24% of the patients had moderate pulmonary comorbidity and 15% had severe pulmonary comorbidity. The cumulative incidence of NPT at 1 year was 8.1% (95% confidence interval [CI], 7.7% to 8.5%). Individually, the 1-year cumulative incidences of IPS, DAH, and COP were 4.9% (95% CI, 4.7% to 5.2%), 2.1% (95% CI, 1.9% to 2.3%), and .7% (95% CI, .6% to .8%), respectively. Multivariable analysis showed that severe pulmonary comorbidity, grade II-IV acute GVHD, mismatched unrelated donor and cord blood transplantation, and HCT-CI score ≥1 significantly increased the risk of NPT. In contrast, alloHCT performed in 2014 or later, non-total body irradiation (TBI)- and TBI-based nonmyeloablative conditioning and platelet recovery were associated with a decreased risk. In a landmark analysis at day+100 post-transplantation, the risk of DAH was significantly lower in patients who had platelet recovery by day +100. Multivariable analysis for OS demonstrated that NPT significantly increased the mortality risk (hazard ratio, 4.2; P < .0001).

Dataset Information

Zebrafish model for allogeneic hematopoietic cell transplantation not requiring preconditioning.

Publications

Zebrafish model for allogeneic hematopoietic cell transplantation not requiring preconditioning.

Similar Datasets

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