Characterization of very early circulating Natural Killer cells after hematopoietic stem cells transplantation
DOI:
https://doi.org/10.34119/bjhrv8n5-252Keywords:
natural killer cell, hematopoietic stem cell transplantation, immune reconstitution, cytokines, flow cytometryAbstract
Natural Killer cells are the first lymphocyte subpopulation to reconstitute after hematopoietic stem cell transplantation. Peripheral blood samples from thirteen patients who underwent allogeneic and autologous hematopoietic stem cell transplantation were analyzed at days 7, 14, 21 and 28 (± 2) after transplantation. Peripheral blood mononuclear cells were isolated using the Bulk Lysis™ EuroFlow standard operating protocol. They were stained for membrane markers with anti-CD45, anti-CD56, anti-CD16, anti-CD3, anti-CD14, anti-CD19, anti-CD2 and anti-CD7; and for intracellular cytokine detection with anti-IL-3, anti-GM-CSF and anti-TGF-1β. On day 7, the presence of Natural Killer cells was detected in 9 patients (mean: 11.6%, SD±: 6.3 of lymphocytes) as well as on day 14 (mean: 16.3%, SD±: 8.2), day 21 (mean: 31.6%, SD±: 9.5) and day 28 (mean: 22.7%, SD±: 6.1). An increase in CD56+16+ phenotype recovery was observed at days 21 (mean: 22%, SD±: 7.2 of lymphocytes, range: 8.0 – 36.1) and 28 (mean: 16%, SD±: 4.9, range: 6.6 – 25.7) when it was compared with CD56bright and CD56+16- (p<0.05). The production of cytokines IL-3, GM-CSF and TGF-β1 was observed during the recovery period of Natural Killer cells within 28 days after transplantation (p=0.04). These data suggest that Natural Killer cells have the ability to produce hematopoietic growth factors and related cytokines which may contribute to the reestablishment of hematopoiesis after transplantation, prevent graft-versus-host disease and enhance the engraftment.
References
ALLAN, David S. J. et al. TGF-β affects development and differentiation of human natural killer cell subsets. European journal of immunology, v. 40, n. 8, p. 2289–95, ago. 2010.
ALLAVENA, P. et al. Production of multiple cytokines by clones of human large granular lymphocytes. Cancer immunology, immunotherapy : CII, v. 19, n. 2, p. 121–6, 1985.
ASAI, O. et al. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. The Journal of clinical investigation, v. 101, n. 9, p. 1835–42, 1 maio 1998.
BARON, F. et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood, v. 104, n. 8, p. 2254–2262, 29 jun. 2004.
BRAHMI, Z. et al. NK cells recover early and mediate cytotoxicity via perforin/granzyme and Fas/FasL pathways in umbilical cord blood recipients. Human immunology, v. 62, n. 8, p. 782–90, ago. 2001.
CAMPBELL, Kerry S.; HASEGAWA, Jun. Natural killer cell biology: an update and future directions. The Journal of allergy and clinical immunology, v. 132, n. 3, p. 536–44, set. 2013.
COOPER, Megan a; FEHNIGER, Todd a; CALIGIURI, Michael a. The biology of human natural killer-cell subsets. Trends in Immunology, v. 22, n. 11, p. 633–640, nov. 2001.
COPELAN, Edward A. Hematopoietic Stem-Cell Transplantation. New England Journal of Medicine, v. 354, n. 17, p. 1813–1826, 27 abr. 2006.
CUTURI, M. C. et al. Production of hematopoietic colony-stimulating factors by human natural killer cells. The Journal of experimental medicine, v. 169, n. 2, p. 569–83, 1 fev. 1989.
EuroFlow Standard Operating Protocol (SOP) for Bulk Lysis for MRD panels (version 1.1 – 6 May 2014) by ESLHO and EuroFlow.
FRANCISCO-CRUZ, Alejandro et al. Granulocyte–macrophage colony-stimulating factor: not just another haematopoietic growth factor. Medical Oncology, v. 31, n. 1, p. 774, 22 jan. 2014.
GIEBEL, S. et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood, v. 102, n. 3, p. 814–819, 3 abr. 2003.
GOLDMAN, J. M. et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Annals of internal medicine, v. 108, n. 6, p. 806–14, jun. 1988.
HSU, Katharine C. et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood, v. 105, n. 12, p. 4878–4884, 2005.
IHLE, J. N. Interleukin-3 and hematopoiesis. Chemical immunology, v. 51, p. 65–106, 1992.
KAUFMAN, Howard et al. Critical analysis of an oncolytic herpesvirus encoding granulocyte-macrophage colony stimulating factor for the treatment of malignant melanoma. Oncolytic Virotherapy, v. 3, p. 11, 15 jan. 2014.
KOLB, H. J. et al. Graft-versus-leukemia reactions in allogeneic chimeras. Blood, v. 103, n. 3, p. 767–776, 2 out. 2004.
LANIER, L. L. et al. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. Journal of immunology, v. 136, n. 12, p. 4480–6, 15 jun. 1986.
LIVNAT, S. et al. Analysis of cytotoxic effector cell function in patients with leukemia or aplastic anemia before and after marrow transplantation. Journal of immunology, v. 124, n. 1, p. 481–90, jan. 1980.
MILLER, J. S. et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT. Blood, v. 109, n. 11, p. 5058–5061, 1 jun. 2007.
MORETTA, A. et al. Analysis of immune reconstitution in children undergoing cord blood transplantation. Experimental hematology, v. 29, n. 3, p. 371–9, mar. 2001.
MURPHY, By William J. et al. Interleukin-2-Activated Natural Killer Cells Can Support Hematopoiesis In Vitro and Promote Marrow Engraftment In Vivo. Blood, v. 80, n. 3, p. 670–677, 1992.
NGUYEN, S. et al. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood, v. 105, n. 10, p. 4135–4142, 15 maio 2005.
NIEDERWIESER, D. et al. Rapid reappearance of large granular lymphocytes (LGL) with concomitant reconstitution of natural killer (NK) activity after human bone marrow transplantation (BMT). British journal of haematology, v. 65, n. 3, p. 301–5, mar. 1987.
NITSCHE, A. et al. Interleukin-3 Promotes Proliferation and Differentiation of Human Hematopoietic Stem Cells but Reduces Their Repopulation Potential in NOD/SCID Mice. Stem Cells, v. 21, n. 2, p. 236–244, 1 mar. 2003.
O’LEARY, H. A. et al. DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms. Leukemia, v. 31, n. 11, p. 2468–2478, 21 nov. 2017.
OLSON, Janelle A. et al. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood, v. 115, n. 21, p. 4293–301, 27 maio 2010.
OTTINGER, H. D. et al. Improved immune reconstitution after allotransplantation of peripheral blood stem cells instead of bone marrow. Blood, v. 88, n. 7, p. 2775–9, 1 out. 1996.
ROBERTSON, MJ; RITZ, J. Biology and clinical relevance of human natural killer cells. Blood, v. 76, n. 12, p. 2421–2438, 1990.
RUGGERI, Loredana et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science, v. 295, n. 5562, p. 2097–100, 15 mar. 2002.
SAVANI, B. N. et al. Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. Leukemia, v. 21, n. 10, p. 2145–52, out. 2007.
SHENOY, S. et al. Immune reconstitution following allogeneic peripheral blood stem cell transplants. Bone Marrow Transplantation, v. 23, p. 335–346, 1999.
SHILLING, H. G. et al. Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood, v. 101, n. 9, p. 3730–3740, 1 maio 2003.
URDAL, DAVID L. et al. Molecular Characterization of Colony- Stimulating Factors and Their Receptors: Human Interleukin-3. Annals of the New York Academy of Sciences, v. 554, p. 167–176, 1 maio 1989.
VAGO, Luca et al. Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation. Blood, v. 112, n. 8, p. 3488–99, 15 out. 2008.
VIEL, S. et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Science Signaling, v. 9, n. 415, p. ra19–ra19, 16 fev. 2016.
VIVIER, Eric; UGOLINI, Sophie. Natural killer cells: from basic research to treatments. Frontiers in immunology, v. 2, p. 18, 2011.
YAMASAKI, S. et al. Influence of transplanted dose of CD56+ cells on development of graft-versus-host disease in patients receiving G-CSF-mobilized peripheral blood progenitor cells from HLA-identical sibling donors. Bone Marrow Transplantation, v. 32, n. 5, p. 505–510, 27 set. 2003.
YU, Jianhua; FREUD, Aharon G.; CALIGIURI, Michael a. Location and cellular stages of natural killer cell development. Trends in immunology, v. 34, n. 12, p. 573–82, dez. 2013.
ZHAO, Xiang-Yu et al. Reconstitution of Natural Killer Cell Receptor Repertoires after Unmanipulated HLA-Mismatched/Haploidentical Blood and Marrow Transplantation: Analyses of CD94:NKG2A and Killer Immunoglobulin-Like Receptor Expression and Their Associations with Clinical O. Biology of Blood and Marrow Transplantation, v. 13, n. 6, p. 734–744, jun. 2007.
