Bone marrow haematopoietic

Wilson A, Trumpp A (2006) Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6 93-106... 

Most cytokines act upon, or are produced by, leukocytes (white blood cells), which constitute the immune and inflammatory systems (Box 8.1). They thus play a central role in regulating both immune and inflammatory function and in related processes such as haematopoiesis (the production of blood cells from haematopoietic stem cells in the adult bone marrow), as well as in wound healing. Indeed, several immunosuppressive and anti-inflammatory drugs are now known to induce their biological effects by regulating production of several cytokines. 

The routine transduction of haematopoietic stem cells has, thus far, proven technically difficult. They are found only in low quantities in the bone marrow, and there is a lack of a suitable assay for stem cells. However, recent progress has been made in this regard, and routine transduction of such cells will likely be achievable within the next few years. 

Such cells are often classified on the basis of their original source as either embryonic or adult stem cells. As the name suggests, embryonic stem cells are derived from the early embryo, whereas adult stem cells are present in various tissues of the adult species. Much of the earlier work on embryonic stem cells was conducted using mouse embryos. Human embryonic stem cells were first isolated and cultured in the laboratory in 1998. Research on adult stem cells spans some four decades, with the discovery during the 1960s of haematopoietic stem cells in the bone marrow (Chapter 10). However, the exact distribution profile, role and ability to manipulate adult stem cells (particularly those outside of the bone marrow) are subjects of intense current research, and for which more questions remain than are answered. 

CLONAL DOMINANCE AFTER RECONSTITUTION OF THE HAEMATOPOIETIC SYSTEM WITH BONE MARROW CELLS RETROVIRALLY TRANSDUCED WITH MURINE CD34 VARIANTS... 

Viens P, Penault-Llorca F, Jacquemier J, et al. High-dose chemotherapy and haematopoietic stem cell transplantation for inflammatory breast cancer pathologic response and outcome. Bone Marrow Transplant 1998 21 249-254. 

The IL-3 receptor is found on a wide range of haematopoietic progenitor cells (see Chapter 6). They are also present on monocytes and B lymphocytes. Its major biological activity relates to stimulation of growth of various cell types derived from bone marrow cells and which represent the immature precursors to all blood cells (Chapter 6). IL-3 thus appears to play a central role in stimulating the eventual formation of various blood cell types, in particular monocytes, mast cells, neutrophils, basophils and eosinophils, from immature precursor cells in the bone marrow. Several other cytokines (including IL-2, -4, -5, -6, -7, -11, -15 and CSFs) also play important costimulatory roles in the maturation of the range of blood cells. 

Fig. 1. The immunodeficiency states. The ways in which the various defects are related can be appreciated by considering the evolution of lymph-haematopoietic lineages in the bone marrow.

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

In 14-week studies, male and female Fischer 344/N rats and BbCSF, mice were exposed to 100-1600 ppm [446-1780 mg/m ] bromoethane by inhalation for 6 h per day on five days per week. In rats, tremors, paresis, mineralization and degeneration in the brain, atrophy of the testes, haemosiderosis of the spleen and some depletion of haematopoietic cells in the bone marrow were observed. Involution of the ovary was observed in mice in the 800 and 1600 ppm dose groups (lARC, 1991). 

Rihova, B., Bilej, M., Vetvicka, V., et al. Biocompatibility of IV-(2-hydroxypropyl) methacrylamide copolymers containing adriamycin Immunogenicity, and effect on haematopoietic stem cells in bone marrow in vivo and mouse splenocytes and human peripheral blood lymphocytes in vitro. Biomaterials 10 335-342, 1989. 

Parietal cells also secrete intrinsic factor, which is necessary for the absorption of vitamin B12. Vitamin B12 is a cofactor of enzymes which synthesise tetrahydrofolic acid, which in turn is needed for the synthesis of DNA components. An impairment of DNA synthesis will affect rapidly dividing cell populations, among them the haematopoietic cells of the bone marrow, which may result in pernicious anaemia. This condition may result from a destruction of the gastric mucosa by, for example, autoimmune gastritis or the resection of large parts of the lower ileum, which is the main site of vitamin B12 absorption, or of the stomach. 

White blood cells, or leukocytes, are cells of the rmmune system (Table 15.1). Five different and diverse types of leukocytes exist, but they are all produced and derived from multipotent cells in the bone marrow known as haematopoietic stem cells. Leukocytes are found throughout the body, including the blood and lymphatic system. 

ACE INHIBITORS EPOETIN 1 haematopoietic effects of epoetin. 1 efficacy of ACE inhibitors Angiotensin II is believed to be responsible for sustaining secretion of eiythropoietin and for stimulating the bone marrow to produce erythrocytes. Epoetin has direct contractile effects on vessels (causing t BP) Watch for poor response to eiythropoietin and to ACE inhibitors. These effects may be delayed so monitor for the duration of co-administration... 

Steel factor haematopoietic stem cell bone-marrow cells, and many other cells Receptors... 

Fig. 15.3 The fusion protein has the annino-ternninal part of the Ber kinase and the carboxy-ternninal part of the Abl tyrosine kinase. The result is that the Abl kinase in the fused protein is hyperactive and drives proliferation of haematopoietic cells in the bone marrow. (See also Rgs 24-25 of ref. 31, reproduced with permission of Taylor and Francis, Inc.)...

The growth-inhibitory effects of these azides and their amine metabolites were also evaluated in comparison with AZT and AMT in vitro, using normal haematopoietic myeloid (CFU-GM) and erythroid (BFU-E) progenitor cells isolated from human bone marrow Table 3.6). Although... 

Burt RK, Marmont A, Arnold R, Heipi F, Firestein GS, Carrier E, Hahn B, Barr W, Oyama Y, Snowden J, Kalunian K, Traynor A (2003b) Development of a phase III trial of haematopoietic stem cell transplantation for systemic lupus erythmatosis. Bone Marrow Transplant Aug 23 (Suppl 1) S49-S51. 

Kramer MH, Kluin PM, Wijburg ER, Fibbe WE, Kluin-Nelemans HC. Differentiation of follicular lymphoma cells after autologous bone marrow transplantation and haematopoietic growth factor treatment. Lancet 1995 345(8948) 488-90. 

Bracket C, Azzi N, Demulder A, et al. Hydroxyurea treatment for sickle cell disease Impact on haematopoietic stem cell transplantation s outcome. Bone Marrow Transplant 2004 33 779-803. 

A treatment-associated bone marrow congestion was observed in female rats exposed to 1750 or 5000 ppm (7420 or 21 200mg/m ) ETBE for 3 months [82]. There was no accompanying effect on the haematopoietic cell population, and an increase in mean corpuscular volume was not considered clinically relevant. No similar effect was reported for male rats or for mice of either sex that had been treated in the same way. 

Zamir E, Geiger B, Cohen N, Kam Z, Katz B-Z. Resolving and classifying haematopoietic bone-marrow cell populations by multi-dimensional analysis of flow-cytometry data. Br J Haematol 2005 129(3) 420-431. 

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