Beverly Torok-Storb

Phenotype and engraftment potential of cytokine-mobilized peripheral blood mononuclear cells

Cytokine‐mobilized peripheral blood stem cell products are increasingly used for hematopoietic reconstitution after myeloablative therapy. Favorable engraftment kinetics, the ease of harvest, and the large number of CD34+ cells obtained that allow for graft manipulations (ie, tumor cell or T‐cell depletion) have made this stem cell source an attractive alternative to marrow. More recent data suggest that in addition to the increased number of CD34 cells, there may be also qualitative differences between leukapheresis products and marrow. In the allogeneic transplantation setting, the one log more T cells contained in granulocyte colony‐stimulating factor‐mobilized peripheral blood mononuclear cells compared with marrow has not translated into more severe graft‐versus‐host disease, indicating possible differences in T‐cell or accessory‐cell function. Whether such differences will compromise graft‐versus‐leukemia effects and disease‐free survival remains to be seen. Nevertheless, it is reasonable to speculate that cytokine‐mobilized peripheral blood products may eventually replace marrow as a source for hematopoietic stem cells. However, each new mobilization strategy needs to be evaluated carefully, as comparable increases in CD34 cell numbers may not necessarily affect the same, as yet undefined, qualitative changes that make this product so attractive.

Hematopoietic Stem Cells

The discovery of hematopoietic stem cells [5] (HSCs) provided a pioneering step in stem cell research. HSCs are a type of multipotent adult stem cell, characterized by their ability to selfrenew and differentiate into erythrocyte (red blood cell) and leukocyte (white blood cell) cell lineages. In terms of function, these cells are responsible for the continual renewal of the erythrocytes, leukocytes, and platelets in the body through a process called hematopoiesis. They also play an important role in the formation of vital organs such as the liver and spleen during fetal development. The early biological knowledge obtained from the studies of HSCs established the base of knowledge for understanding other stem cell systems. In addition, these cells have a vital role in furthering stem cell research for clinical applications. Regenerative medicine is a field of medicine that has applied HSCs to the treatment of bloodborne diseases such as leukemia and lymphoma and of cancer patients undergoing chemotherapy.

Associations between gastric dilatation-volvulus in Great Danes and specific alleles of the canine immune-system genes DLA88, DRB1, and TLR5

OBJECTIVE To determine whether specific alleles of candidate genes of the major histocompatibility complex (MHC) and innate immune system were associated with gastric dilatation-volvulus (GDV) in Great Danes. ANIMALS 42 healthy Great Danes (control group) and 39 Great Danes with ≥ 1 GDV episode. PROCEDURES Variable regions of the 2 most polymorphic MHC genes (DLA88 and DRB1) were amplified and sequenced from the dogs in each group. Similarly, regions of 3 genes associated with the innate immune system (TLR5, NOD2, and ATG16L1), which have been linked to inflammatory bowel disease, were amplified and sequenced. Alleles were evaluated for associations with GDV, controlling for age and dog family. RESULTS Specific alleles of genes DLA88, DRB1, and TLR5 were significantly associated with GDV. One allele of each gene had an OR > 2 in the unadjusted univariate analyses and retained a hazard ratio > 2 after controlling for temperament, age, and familial association in the multivariate analysis. CONCLUSIONS AND CLINICAL RELEVANCE The 3 GDV-associated alleles identified in this study may serve as diagnostic markers for identification of Great Danes at risk for GDV. Additional research is needed to determine whether other dog breeds have the same genetic associations. These findings also provided a new target for research into the etiology of, and potential treatments for, GDV in dogs.

Erratum: Long-term regulation of genetically modified primary hematopoietic cells in dogs (Molecular Therapy (2011) 19 (1287-1294) doi:10.1038/mt.2011.8)

Molecular Therapy (2011); 19: 1287–1294; doi:10.1038/mt.2011.8 Following the publication of this article, the authors noted that Beverly Torok-Storb should have been included as a co-author. Her affiliation is Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. The correct and complete author names are also above.

Corrigendum to “Long-term Regulation of Genetically Modified Primary Hematopoietic Cells in Dogs”

Molecular Therapy (2011); 19: 1287–1294; doi:10.1038/mt.2011.8 Following the publication of this article, the authors noted that Beverly Torok-Storb should have been included as a co-author. Her affiliation is Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. The correct and complete author names are also above.

Flow Cytofluorometric Analysis of Patient Mononuclear Cells and Clinical Response to Antithymocyte Globulin

The regulated production of blood cells requires that stem cells and progenitor cells interact with cells of the hematopoietic microenvironment in order to divide and produce blood elements. The microenvironment cells, or stromal cells, provide signals necessary for progenitor growth, maturation, and eventual release from the marrow. Stromal cells in turn are influenced by accessory cells consisting of lymphocytes and macrophages that are capable of circulating and infiltrating marrow spaces, where they are hypothesized to exert both positive and negative effects. Given the complexity of this system, and the fact that all components must be operating appropriately for steady-state hematopoiesis, it is easy to understand how a failure in blood cell production, otherwise known as aplastic anemia, could result from a number of distinct mechanisms. Aplasia could result if there was a primary defect in stem cells or a defect in the stromal elements, or an abnormality within the accessory cell population. Such defects could be acquired by infection or exposure to toxic elements, or possibly be genetically preprogrammed.

Lymphocyte/Marrow Co-Cultures as a Tool to Detect Transfusion-Induced Sensitization and Predict Marrow Graft Rejection in Dogs

Recent reports from several investigators make it reasonable to assume that lymphocytes, specifically T-cells, play a role in stimulating hemopoiesis (7,10,-11,13,26). In keeping with these observations, we have reported that peripheral blood lymphocytes (PBL) from normal dogs significantly increase the number of in vitro erythroid colonies (EC) grown from DLA-identical littermate marrow (22). The magnitude of stimulation observed depended upon the ratio of lymphocytes to EC precursors cultured, suggesting that lymphocytes might interact directly with erythroid colony-forming units in some capacity.