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Brief Introduction to the Basic Scientific Principles of Hematopoietic Stem Cell Transplantation (HSCT)

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Hematopoietic Stem Cell Transplantation for the Pediatric Hematologist/Oncologist

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Abstract

The primary function of the immune system is to provide essential defense mechanisms against all foreign pathogens. The immune system has evolved in such a way that different immune responses are optimized to recognize and then eliminate or contain different types of foreign antigens which are expressed or secreted by foreign pathogens. It provides not only efficient and effective killing of microbes/pathogens via innate immunity but also specific long-lasting immunity against a particular microbe/pathogen to be triggered if the foreign microbe’s antigen is encountered in the future via adaptive immune responses. Immunologic mechanisms are intimately involved in engraftment, engraftment rejection, graft versus host disease, and graft versus malignancy effect. In addition, immunologic tolerance is key for allogeneic immune reconstitution post-hematopoietic stem cell transplantation (HSCT). Because of a better understanding of the immune system and its different immune properties and responses, physicians and researchers have been able to perform successfully and safely HSCT in humans. While many of the concepts of basic immunology and transplant biology are intertwined into other chapters of this book, this chapter focuses on providing the fundamental principles of basic immunology and transplant biology, including the development of the components of the immune system (i.e., hematopoiesis), the molecules, cells, tissues, and organs that make up the immune system as well as their structural and functional organization and the types of immune responses along with their cardinal features. Key concepts related to HSCT including antigen presentation, alloreactivity, and tolerance and how these processes relate to HSCT will be described in brief. Firstly, though, this chapter begins with the definitions of some key terms and concepts related to basic immunology and transplant biology in order to establish the “vocabulary” of the immune system.

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References

  1. Vira D, Basak SK, Veena MS, Wang MB, Batra RK, Srivatsan ES. Cancer stem cells, microRNAs, and therapeutic strategies including natural products. Cancer Metastasis Rev. 2012;31(3):733–51.

    Article  CAS  PubMed  Google Scholar 

  2. Allsopp RC, Cheshier S, Weissman IL. Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J Exp Med. 2001;193(8):917–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lavin Y, Mortha A, Rahman A, Merad M. Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol. 2015;15(12):731–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mbongue J, Nicholas D, Firek A, Langridge W. The role of dendritic cells in tissue-specific autoimmunity. J Immunol Res. 2014;2014:857143.

    Article  PubMed  PubMed Central  Google Scholar 

  5. den Haan JM, Arens R, van Zelm MC. The activation of the adaptive immune system: cross-talk between antigen-presenting cells, T cells and B cells. Immunol Lett. 2014;162(2 Pt B):103–12.

    Article  Google Scholar 

  6. Soudja Saïdi MH, Chandrabos C, Yakob E, Veenstra M, Palliser D, Lauvau G. Memory-T-cell-derived interferon-γ instructs potent innate cell activation for protective immunity. Immunity. 2014;40(6):974–88.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Brzostek J, Gascoigne NR, Rybakin V. Cell type-specific regulation of immunological synapse dynamics by B7 ligand recognition. Front Immunol. 2016;7:24.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dunn-Walters DK, Isaacson PG, Spencer J. Analysis of mutations in immunoglobulin heavy chain variable region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory B cells. J Exp Med. 1995;182(2):559–66.

    Article  CAS  PubMed  Google Scholar 

  9. Rothstein TL, Griffin DO, Holodick NE, Quach TD, Kaku H. Human B-1 cells take the stage. Ann N Y Acad Sci. 2013;1285:97–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Holtmeier W, Kabelitz D. gammadelta T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151–83.

    Article  CAS  PubMed  Google Scholar 

  11. Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011;12(1):21–7.

    Article  CAS  PubMed  Google Scholar 

  12. Halim TY, Steer CA, Matha L, Gold MJ, Martinez-Gonzalez I, McNagny KM, et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity. 2014;40(3):425–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464(7293):1367–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ryser J-E, Vassalli P. Mouse bone marrow lymphocytes and their differentiation. J Immunol. 1974;113(3):719–28.

    CAS  PubMed  Google Scholar 

  15. Hoggatt J, Scadden DT. The stem cell niche: tissue physiology at a single cell level. J Clin Invest. 2012;122(9):3029–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Discher DE, Mooney DJ, Zandstra PW. Growth factors, matrices, and forces combine and control stem cells. Science. 2009;324(5935):1673–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Goodman JW, Hodgson GS. Evidence for stem cells in the peripheral blood of mice. Blood. 1962;19:702–14.

    CAS  PubMed  Google Scholar 

  18. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106.

    Article  CAS  PubMed  Google Scholar 

  19. Mazo IB, Massberg S, von Andrian UH. Hematopoietic stem and progenitor cell trafficking. Trends Immunol. 2011;32(10):493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL. Physiological migration of hematopoietic stem and progenitor cells. Science. 2001;294(5548):1933–6.

    Article  CAS  PubMed  Google Scholar 

  21. King KY, Goodell MA. Inflammatory modulation of hematopoietic stem cells: viewing the hematopoietic stem cell as a foundation for the immune response. Nat Rev Immunol. 2011;11(10):685–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, et al. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood. 2005;105(1):199–206.

    Article  CAS  PubMed  Google Scholar 

  23. Möbius-Winkler S, Hilberg T, Menzel K, Golla E, Burman A, Schuler G, et al. Time-dependent mobilization of circulating progenitor cells during strenuous exercise in healthy individuals. J Appl Physiol. 2009;107(6):1943–50.

    Article  PubMed  Google Scholar 

  24. Shah S, Ulm J, Sifri ZC, Mohr AM, Livingston DH. Mobilization of bone marrow cells to the site of injury is necessary for wound healing. J Trauma. 2009;67(2):315–21; discussion 21–2.

    Google Scholar 

  25. Levesque JP, Hendy J, Takamatsu Y, Williams B, Winkler IG, Simmons PJ. Mobilization by either cyclophosphamide or granulocyte colony-stimulating factor transforms the bone marrow into a highly proteolytic environment. Exp Hematol. 2002;30(5):440–9.

    Article  CAS  PubMed  Google Scholar 

  26. Lévesque J-P, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 2003;111(2):187–96.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3(7):687–94.

    Article  CAS  PubMed  Google Scholar 

  28. Uy GL, Rettig MP, Cashen AF. Plerixafor, a CXCR4 antagonist for the mobilization of hematopoietic stem cells. Expert Opin Biol Ther. 2008;8(11):1797–804.

    Article  CAS  PubMed  Google Scholar 

  29. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977–88.

    Article  CAS  PubMed  Google Scholar 

  30. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chow A, Lucas D, Hidalgo A, Mendez-Ferrer S, Hashimoto D, Scheiermann C, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med. 2011;208(2):261–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481(7382):457–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I, Barrick C, et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med. 2013;19(6):695–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P, He XC, et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med. 2014;20(11):1321–6.

    Article  CAS  PubMed  Google Scholar 

  35. Mercier FE, Ragu C, Scadden DT. The bone marrow at the crossroads of blood and immunity. Nat Rev Immunol. 2011;12(1):49–60.

    Google Scholar 

  36. Crane GM, Jeffery E, Morrison SJ. Adult haematopoietic stem cell niches. Nat Rev Immunol. 2017;17:573–590.

    Google Scholar 

  37. Jung Y, Wang J, Havens A, Sun Y, Wang J, Jin T, et al. Cell-to-cell contact is critical for the survival of hematopoietic progenitor cells on osteoblasts. Cytokine. 2005;32(3–4):155–62.

    Article  CAS  PubMed  Google Scholar 

  38. Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013;502(7473):637–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lucas D, Battista M, Shi PA, Isola L, Frenette PS. Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell. 2008;3(4):364–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mendez-Ferrer S, Lucas D, Battista M, Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 2008;452(7186):442–7.

    Article  CAS  PubMed  Google Scholar 

  41. Spiegel A, Shivtiel S, Kalinkovich A, Ludin A, Netzer N, Goichberg P, et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat Immunol. 2007;8(10):1123–31.

    Article  CAS  PubMed  Google Scholar 

  42. Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S, et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell. 2011;147(5):1146–58.

    Article  CAS  PubMed  Google Scholar 

  43. Kiel MJ, Acar M, Radice GL, Morrison SJ. Hematopoietic stem cells do not depend on N-cadherin to regulate their maintenance. Cell Stem Cell. 2009;4(2):170–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kiel MJ, Radice GL, Morrison SJ. Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell. 2007;1(2):204–17.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425(6960):836–41.

    Article  CAS  PubMed  Google Scholar 

  46. Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC, et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature. 2006;439(7076):599–603.

    Article  CAS  PubMed  Google Scholar 

  47. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–61.

    Article  CAS  PubMed  Google Scholar 

  48. Peled A, Kollet O, Ponomaryov T, Petit I, Franitza S, Grabovsky V, et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood. 2000;95(11):3289–96.

    CAS  PubMed  Google Scholar 

  49. Katayama Y, Hidalgo A, Peired A, Frenette PS. Integrin alpha4beta7 and its counterreceptor MAdCAM-1 contribute to hematopoietic progenitor recruitment into bone marrow following transplantation. Blood. 2004;104(7):2020–6.

    Article  CAS  PubMed  Google Scholar 

  50. Forde S, Tye BJ, Newey SE, Roubelakis M, Smythe J, McGuckin CP, et al. Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells. Blood. 2007;109(5):1825–33.

    Article  CAS  PubMed  Google Scholar 

  51. Grassinger J, Haylock DN, Storan MJ, Haines GO, Williams B, Whitty GA, et al. Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with alpha9beta1 and alpha4beta1 integrins. Blood. 2009;114(1):49–59.

    Article  CAS  PubMed  Google Scholar 

  52. Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ, Denhardt DT, et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood. 2005;106(4):1232–9.

    Article  CAS  PubMed  Google Scholar 

  53. Ponomaryov T, Peled A, Petit I, Taichman RS, Habler L, Sandbank J, et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest. 2000;106(11):1331–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sipkins DA, Wei X, Wu JW, Runnels JM, Cote D, Means TK, et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature. 2005;435(7044):969–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121(7):1109–21.

    Article  CAS  PubMed  Google Scholar 

  56. Taichman RS, Emerson SG. Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med. 1994;179(5):1677–82.

    Article  CAS  PubMed  Google Scholar 

  57. Taichman RS, Reilly MJ, Emerson SG. Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures. Blood. 1996;87(2):518–24.

    CAS  PubMed  Google Scholar 

  58. Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M, Sakano S, et al. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med. 2000;192(9):1365–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood. 2002;99(7):2369–78.

    Article  CAS  PubMed  Google Scholar 

  60. Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, et al. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell. 2008;2(4):356–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kiel MJ, Morrison SJ. Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol. 2008;8(4):290–301.

    Article  CAS  PubMed  Google Scholar 

  62. Yin T, Li L. The stem cell niches in bone. J Clin Invest. 2006;116(5):1195–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425(6960):841–6.

    Article  CAS  PubMed  Google Scholar 

  64. Passegué E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med. 2005;202(11):1599–611.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Nilsson SK, Dooner MS, Quesenberry PJ. Synchronized cell-cycle induction of engrafting long-term repopulating stem cells. Blood. 1997;90(11):4646–50.

    CAS  PubMed  Google Scholar 

  66. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014;9:47–71.

    Article  CAS  PubMed  Google Scholar 

  67. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391–402.

    Article  CAS  PubMed  Google Scholar 

  68. Eliasson P, Jönsson J-I. The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol. 2010;222(1):17–22.

    Article  CAS  PubMed  Google Scholar 

  69. Winkler IG, Barbier V, Wadley R, Zannettino AC, Williams S, Levesque JP. Positioning of bone marrow hematopoietic and stromal cells relative to blood flow in vivo: serially reconstituting hematopoietic stem cells reside in distinct nonperfused niches. Blood. 2010;116(3):375–85.

    Article  CAS  PubMed  Google Scholar 

  70. Vermi W, Lonardi S, Bosisio D, Uguccioni M, Danelon G, Pileri S, et al. Identification of CXCL13 as a new marker for follicular dendritic cell sarcoma. J Pathol. 2008;216(3):356–64.

    Article  CAS  PubMed  Google Scholar 

  71. Luther SA, Bidgol A, Hargreaves DC, Schmidt A, Xu Y, Paniyadi J, et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol. 2002;169(1):424–33.

    Article  CAS  PubMed  Google Scholar 

  72. von Behring E, Kitasato S. [The mechanism of diphtheria immunity and tetanus immunity in animals. 1890]. Mol Immunol. 1991;28(12):1317, 9–20.

    Google Scholar 

  73. Rangarajan H, Yassai M, Subramanian H, Komorowski R, Whitaker M, Gorski J, et al. Emergence of T cells that recognize nonpolymorphic antigens during graft-versus- host disease. Blood. 2012;119(26):6354–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP 3rd, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Matsuoka K, Kim HT, McDonough S, Bascug G, Warshauer B, Koreth J, et al. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2010;120(5):1479–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Nemazee D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol. 2006;6(10):728–40.

    Article  CAS  PubMed  Google Scholar 

  77. Mueller DL. Mechanisms maintaining peripheral tolerance. Nat Immunol. 2010;11(1):21–7.

    Article  CAS  PubMed  Google Scholar 

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  1. Division of Pediatric Oncology/Hematology, Penn State Health Children’s Hospital and Penn State Cancer Institute at the Penn State Milton S. Hershey Medical Center, 500 University Dr., P.O. Box 850, MC H085, Hershey, PA, 17033-0850, USA

    Valerie I. Brown MD, PhD

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  1. Division of Pediatric Oncology/Hematology, Penn State Health Children’s Hospital and Penn State Cancer Institute at the Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA

    Valerie I. Brown

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Brown, V.I. (2018). Brief Introduction to the Basic Scientific Principles of Hematopoietic Stem Cell Transplantation (HSCT). In: Brown, V. (eds) Hematopoietic Stem Cell Transplantation for the Pediatric Hematologist/Oncologist. Springer, Cham. https://doi.org/10.1007/978-3-319-63146-2_3

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