Expanded donor natural killer cell and IL‐2, IL‐15 treatment efficacy in allogeneic hematopoietic stem cell transplantation

Graft‐versus‐host disease (GVHD), leukemia relapse, and immune deficiency remain the major limitations of allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Donor natural killer cells (NK) and cytokines have good potential in GVHD prevention and immune reconstitution enhancement. Improved survival after allo‐HSCT therefore requires effective prophylaxis to reduce GVHD and strategy to mediate graft‐versus‐leukemia (GVL) effect. We studied the administration of expanded donor NK cell infusion and interleukin‐2 (IL‐2) and IL‐15 mixture treatment in a murine allo‐HSCT model for its effects on GVHD, immune reconstitution and leukemia relapse. In the GVHD model, recipient mice were reconstituted with bone marrow (BM) cells and splenocytes via vein. In the leukemia model, recipient mice were inoculated with EL9611 leukemia cells via vein 8 d prior to transplant. NK cell infusion mice group had lower clinical GVHD scores and suffered less severe GVHD‐associated weight loss than control mice group. 90% of control mice died of leukemia relapse within 52 d post‐transplant. NK cell infusion and IL‐2 and IL‐15 treatment recipient mice had improved survival compared with control mice. NK cell infusion and IL‐2 and IL‐15 treatment recipient mice had also accelerated lymphoid immune reconstitution compared with control mice group. Expanded donor NK cell infusion and IL‐2 and IL‐15 treatment could promote lymphoid immune reconstitution, mitigate GVHD, and reduce leukemia relapse in allo‐HSCT recipients. The findings may have important significance for complication prevention in clinical allo‐HSCT.

[1]  K. Rezvani,et al.  A clinical-scale selective allodepletion approach for the treatment of HLA-mismatched and matched donor-recipient pairs using expanded T lymphocytes as antigen-presenting cells and a TH9402-based photodepletion technique. , 2008, Blood.

[2]  Shaohua Chen,et al.  TRAV and TRBV repertoire, clonality and the proliferative history of umbilical cord blood T-cells. , 2007, Transplant immunology.

[3]  T. Waldmann.  The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design , 2006, Nature Reviews Immunology.

[4]  A. Moffett,et al.  Immunology of placentation in eutherian mammals , 2006, Nature Reviews Immunology.

[5]  N. Lee,et al.  Transplantation with higher dose of natural killer cells associated with better outcomes in terms of non‐relapse mortality and infectious events after allogeneic peripheral blood stem cell transplantation from HLA‐matched sibling donors , 2005, European journal of haematology.

[6]  C. Le,et al.  Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. , 2005, Blood.

[7]  J. D. Di Santo,et al.  Roles for Common Cytokine Receptor γ-Chain-Dependent Cytokines in the Generation, Differentiation, and Maturation of NK Cell Precursors and Peripheral NK Cells in Vivo1 , 2005, The Journal of Immunology.

[8]  M. V. D. van den Brink,et al.  Rhamm Expression and Isoform Balance Predicts Aggressive Disease and Poor Survival in Multiple Myeloma , 2022 .

[9]  S. Slavin,et al.  Allogeneic versus syngeneic killer splenocytes as effector cells for the induction of graft-versus-tumor effect. , 2004, Biology of Blood and Marrow Transplantation.

[10]  B. van der Holt,et al.  Interleukin-7 improves T-cell recovery after experimental T-cell-depleted bone marrow transplantation in T-cell-deficient mice by strong expansion of recent thymic emigrants. , 2003, Blood.

[11]  J. D. Di Santo,et al.  IL-15 is an essential mediator of peripheral NK-cell homeostasis. , 2003, Blood.

[12]  Daniel J Weisdorf,et al.  Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. , 2002, Blood.

[13]  M. Caligiuri,et al.  In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. , 2002, Blood.

[14]  D. Ho,et al.  Direct evidence for new T-cell generation by patients after either T-cell–depleted or unmodified allogeneic hematopoietic stem cell transplantationsPresented in part in abstract form at the 42nd Annual Meeting of the American Society of Hematology, San Francisco, CA, December 2000. , 2002 .

[15]  D. Ho,et al.  Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. , 2002, Blood.

[16]  H. Kirchner,et al.  Large-scale generation of natural killer lymphocytes for clinical application. , 2002, Journal of hematotherapy & stem cell research.

[17]  Katia Perruccio,et al.  Effectiveness of Donor Natural Killer Cell Alloreactivity in Mismatched Hematopoietic Transplants , 2002, Science.

[18]  D. Neuberg,et al.  Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults. , 2001, Blood.

[19]  R. Collins,et al.  Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. , 2001, Blood.

[20]  R. Collins,et al.  Assessment of thymic output in adults after haematopoietic stemcell transplantation and prediction of T-cell reconstitution , 2000, The Lancet.

[21]  M. Shlomchik,et al.  Prevention of graft versus host disease by inactivation of host antigen-presenting cells. , 1999, Science.

[22]  R. Hohl,et al.  Prophylactic reinfusion of T cells for T cell-depleted allogeneic bone marrow transplantation. , 1999, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[23]  J. Chu,et al.  [Establishment and biological characterization of a transplantable BALB/c mouse erythroblastic leukemia model]. , 1998, Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi.

[24]  Louis J. Picker,et al.  Changes in thymic function with age and during the treatment of HIV infection , 1998, Nature.

[25]  S L Morrison,et al.  Effect of C2-associated carbohydrate structure on Ig effector function: studies with chimeric mouse-human IgG1 antibodies in glycosylation mutants of Chinese hamster ovary cells. , 1998, Journal of immunology.

[26]  S. L. Johnston,et al.  Spectratyping of TCR expressed by CTL-infiltrating male antigen (HY)-disparate allografts. , 1998, Journal of immunology.

[27]  J. Crawford,et al.  An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. , 1996, Blood.

[28]  C. Mackall,et al.  Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. , 1996, Journal of immunology.

[29]  A. Rimm,et al.  Graft-versus-leukemia reactions after bone marrow transplantation. , 1990, Blood.