The road to purified hematopoietic stem cell transplants is paved with antibodies

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States.
Current opinion in immunology (Impact Factor: 7.87). 08/2012; 24(5):640-8. DOI: 10.1016/j.coi.2012.08.002
Source: PubMed

ABSTRACT Hematopoietic progenitor cell replacement therapy remains a surprisingly unrefined process. In general, unmanipulated bone marrow or mobilized peripheral blood (MPB) grafts which carry potentially harmful passenger cells are administered after treating recipients with high-dose chemotherapy and/or radiotherapy to eradicate malignant disease, eliminate immunologic barriers to allogeneic cell engraftment, and to 'make space' for rare donor stem cells within the stem cell niche. The sequalae of such treatments are substantial, including direct organ toxicity and nonspecific inflammation that contribute to the development of graft-versus-host disease (GVHD) and poor immune reconstitution. Passenger tumor cells that contaminate autologous hematopoietic grafts may contribute to relapse post-transplant. Use of antibodies to rid grafts of unwanted cell populations, and to eliminate or minimize the need for nonspecifically cytotoxic therapies used to condition transplant recipients, will dramatically improve the safety profile of allogeneic and gene-modified autologous hematopoietic stem cell therapies.

Download full-text


Available from: Aaron Logan, Jun 17, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hematopoietic stem cells (HSC) self-renewal takes place in the same microenvironment in which massive hematopoietic progenitor proliferation, commitment, and differentiation will occur. This is only made possible if the bone marrow microenvironment comprises different specific niches, composed by different stromal cells that work in harmony to regulate all the steps of the hematopoiesis cascade. Histological and functional assays indicated that HSC and multipotent progenitors preferentially colonize the endosteal and subendosteal regions, in close association with the bone surface. Conversely, committed progenitors and differentiated cells are distributed in the central and perisinusoidal regions, respectively. Over the last decade, many investigative teams sought to define which cell types regulate the HSC niche, how they are organized, and to what extent they interface with each other. System dynamics requires different stromal cells to operate distinct functions over similar HSC pools rather than a single stromal cell type controlling everything. Therefore, our focus herein is to depict the players in the endosteal and subendosteal regions, named the endosteal niche, a necessary step to better understand the interactions of the HSC within the niche and to identify potential targets to manipulate and/or modulate normal and malignant HSC behavior. J. Cell. Biochem. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 01/2015; 116(1). DOI:10.1002/jcb.24952 · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Regenerative therapies that use allogeneic cells are likely to encounter immunological barriers similar to those that occur with transplantation of solid organs and allogeneic hematopoietic stem cells (HSCs). Decades of experience in clinical transplantation hold valuable lessons for regenerative medicine, offering approaches for developing tolerance-induction treatments relevant to cell therapies. Outside the field of solid-organ and allogeneic HSC transplantation, new strategies are emerging for controlling the immune response, such as methods based on biomaterials or mimicry of antigen-specific peripheral tolerance. Novel biomaterials can alter the behavior of cells in tissue-engineered constructs and can blunt host immune responses to cells and biomaterial scaffolds. Approaches to suppress autoreactive immune cells may also be useful in regenerative medicine. The most innovative solutions will be developed through closer collaboration among stem cell biologists, transplantation immunologists and materials scientists.
    Nature Biotechnology 08/2014; DOI:10.1038/nbt.2960 · 39.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence of intratumor heterogeneity and its augmentation due to selective pressure of microenvironment and recent achievements in cancer therapeutics lead to the need to investigate and track the tumor subclonal structure. Cell sorting of heterogeneous subpopulations of tumor and tumor-associated cells has been a long established strategy in cancer research. Advancement in lasers, computer technology and optics has led to a new generation of flow cytometers and cell sorters capable of high-speed processing of single cell suspensions. Over the last several years cell sorting was used in combination with molecular biological methods, imaging and proteomics to characterize primary and metastatic cancer cell populations, minimal residual disease and single tumor cells. It was the principal method for identification and characterization of cancer stem cells. Analysis of single cancer cells may improve early detection of tumors, monitoring of circulating tumor cells, evaluation of intratumor heterogeneity and chemotherapeutic treatments. The aim of this review is to provide an overview of major cell sorting applications and approaches with new prospective developments such as microfluidics and microchip technologies.
    Biochimica et Biophysica Acta 02/2013; DOI:10.1016/j.bbcan.2013.02.004 · 4.66 Impact Factor