-
Frontiers in Immunology 2021Periodontitis is an oral inflammatory disease in which the polymicrobial synergy and dysbiosis of the subgingival microbiota trigger a deregulated host immune response,... (Review)
Review
Humanized Mouse Models for the Study of Periodontitis: An Opportunity to Elucidate Unresolved Aspects of Its Immunopathogenesis and Analyze New Immunotherapeutic Strategies.
Periodontitis is an oral inflammatory disease in which the polymicrobial synergy and dysbiosis of the subgingival microbiota trigger a deregulated host immune response, that leads to the breakdown of tooth-supporting tissues and finally tooth loss. Periodontitis is characterized by the increased pathogenic activity of T helper type 17 (Th17) lymphocytes and defective immunoregulation mediated by phenotypically unstable T regulatory (Treg), lymphocytes, incapable of resolving the bone-resorbing inflammatory milieu. In this context, the complexity of the immune response orchestrated against the microbial challenge during periodontitis has made the study of its pathogenesis and therapy difficult and limited. Indeed, the ethical limitations that accompany human studies can lead to an insufficient etiopathogenic understanding of the disease and consequently, biased treatment decision-making. Alternatively, animal models allow us to manage these difficulties and give us the opportunity to partially emulate the etiopathogenesis of periodontitis by inoculating periodontopathogenic bacteria or by placing bacteria-accumulating ligatures around the teeth; however, these models still have limited translational application in humans. Accordingly, humanized animal models are able to emulate human-like complex networks of immune responses by engrafting human cells or tissues into specific strains of immunodeficient mice. Their characteristics enable a viable time window for the study of the establishment of a specific human immune response pattern in an setting and could be exploited for a wider study of the etiopathogenesis and/or treatment of periodontitis. For instance, the antigen-specific response of human dendritic cells against the periodontopathogen favoring the Th17/Treg response has already been tested in humanized mice models. Hypothetically, the proper emulation of periodontal dysbiosis in a humanized animal could give insights into the subtle molecular characteristics of a human-like local and systemic immune response during periodontitis and support the design of novel immunotherapeutic strategies. Therefore, the aims of this review are: To elucidate how the microbiota-elicited immunopathogenesis of periodontitis can be potentially emulated in humanized mouse models, to highlight their advantages and limitations in comparison with the already available experimental periodontitis non-humanized animal models, and to discuss the potential translational application of using these models for periodontitis immunotherapeutics.
Topics: Animals; Disease Management; Disease Models, Animal; Disease Susceptibility; Host Microbial Interactions; Humans; Immunocompromised Host; Lymphocyte Transfusion; Mice; Mice, Transgenic; Microbiota; Organ Transplantation; Periodontitis; Stem Cell Transplantation
PubMed: 34220811
DOI: 10.3389/fimmu.2021.663328 -
Haematologica Dec 2009Granulocyte transfusions were first used to treat infections in neutropenic patients in the early 1960s. The first donors were patients with chronic myeloid leukemia....
Granulocyte transfusions were first used to treat infections in neutropenic patients in the early 1960s. The first donors were patients with chronic myeloid leukemia. Forty years later the value of these transfusions remains unclear. In this perspective article Drs. Drewniak and Kuijpers discuss the relevant data. See related paper on page 1661.
Topics: Anemia, Aplastic; Bacterial Infections; Clinical Trials, Phase III as Topic; Granulocytes; Humans; Leukocyte Transfusion; Mycoses; Randomized Controlled Trials as Topic; Survival Analysis; Survival Rate
PubMed: 19996116
DOI: 10.3324/haematol.2009.013680 -
Blood Feb 2008Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used in healthy donors for collection of peripheral blood progenitor cells (PBPCs) for... (Review)
Review
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used in healthy donors for collection of peripheral blood progenitor cells (PBPCs) for allogeneic transplantation and granulocytes for transfusion. The spectrum of its biologic and molecular activities in healthy individuals is coming into sharper focus, creating a unique set of challenges and clarifying the need to monitor and safeguard donor safety. Accumulating evidence indicates that rhG-CSF effects are not limited to the myeloid cell lineage. This may reflect the presence of functional G-CSF receptors on other cell types and tissues, as well as rhG-CSF-induced modulation of cytokine networks. While most rhG-CSF-induced effects are transient and self-limiting, preliminary, provocative data have suggested the possibility of a more durable effect on the chromosomal integrity of lymphocytes. While these reports have not been validated and have been subject to criticism, they are prompting prospective studies and monitoring efforts to determine whether there is a significant risk of long-term adverse events (eg, hematologic malignancies) in healthy PBPC and granulocyte donors. Based on the totality of information that is currently available, the administration of rhG-CSF to healthy donors for the purpose of PBPC donation continues to have a favorable risk-benefit profile.
Topics: Granulocyte Colony-Stimulating Factor; Granulocytes; Humans; Leukocyte Transfusion; Monocytes; Neutrophils; Receptors, Granulocyte Colony-Stimulating Factor; Recombinant Proteins; Reference Values; Stem Cell Transplantation; Tissue and Organ Harvesting; Transplantation, Homologous
PubMed: 18057230
DOI: 10.1182/blood-2007-07-097543 -
Expert Review of Molecular Diagnostics Jan 2013“Tregs are highly promising agents for the prevention of graft-versus-host disease, induction of tolerance to transplanted antigens and the treatment of autoimmunity...
“Tregs are highly promising agents for the prevention of graft-versus-host disease, induction of tolerance to transplanted antigens and the treatment of autoimmunity in humans.”
Topics: Autoimmunity; Graft vs Host Disease; Humans; Immune Tolerance; Lymphocyte Activation; Lymphocyte Transfusion; T-Lymphocytes, Regulatory; Transplantation Immunology
PubMed: 23256698
DOI: 10.1586/erm.12.133 -
The Korean Journal of Internal Medicine Dec 2009Nonmyeloablative stem cell transplantation (NST) is increasingly used with beneficial effects because it can be applied to older patients with hematological malignancies... (Review)
Review
Nonmyeloablative stem cell transplantation (NST) is increasingly used with beneficial effects because it can be applied to older patients with hematological malignancies and those with various complications who are not suitable for conventional myeloablative stem cell transplantation (CST). Various conditioning regimens differ in their myeloablative and immunosuppressive intensity. Regardless of the type of conditioning regimen, graft-versus- host disease (GVHD) in NST occurs almost equally in CST, although a slightly delayed development of acute GVHD is observed in NST. Although graft-versus-hematological malignancy effects (i.e., graft-versus-leukemia effect, graft-versus-lymphoma effect, and graft-versus-myeloma effect) also occur in NST, completely eradicating residual malignant cells through allogeneic immune responses is insufficient in cases with rapidly growing disease or uncontrolled progressive disease. Donor lymphocyte infusion (DLI) is sometimes combined to support engraftment and to augment the graft-versus-hematological malignancy effect, such as the graft-versus-leukemia effect. DLI is especially effective for controlling relapse in the chronic phase of chronic myelogenous leukemia, but not so effective against other diseases. Indeed, NST is a beneficial procedure for expanding the opportunity of allogeneic hematopoietic stem cell transplantation to many patients with hematological malignancies. However, a more sophisticated improvement in separating graft-versus-hematological malignancy effects from GVHD is required in the future.
Topics: Antigen-Presenting Cells; Graft vs Host Disease; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Lymphocyte Transfusion; Lymphoma, Non-Hodgkin; Multiple Myeloma; Transplantation Conditioning
PubMed: 19949725
DOI: 10.3904/kjim.2009.24.4.287 -
Drug Delivery Nov 2017Cell-mediated drug delivery systems employ specific cells as drug vehicles to deliver drugs to targeted sites. Therapeutics or imaging agents are loaded into these cells... (Review)
Review
Cell-mediated drug delivery systems employ specific cells as drug vehicles to deliver drugs to targeted sites. Therapeutics or imaging agents are loaded into these cells and then released in diseased sites. These specific cells mainly include red blood cells, leukocytes, stem cells and so on. The cell acts as a Trojan horse to transfer the drug from circulating blood to the diseased tissue. In such a system, these cells keep their original properties, which allow them to mimic the migration behavior of specific cells to carry drug to the targeted site after in vivo administration. This strategy elegantly combines the advantages of both carriers, i.e. the adjustability of nanoparticles (NPs) and the natural functions of active cells, which therefore provides a new perspective to challenge current obstacles in drug delivery. This review will describe a fundamental understanding of these cell-based drug delivery systems, and discuss the great potential of combinational application of cell carrier and NPs.
Topics: Animals; Drug Carriers; Drug Compounding; Drug Delivery Systems; Erythrocyte Transfusion; Erythrocytes; Humans; Leukocyte Transfusion; Leukocytes; Nanomedicine; Nanoparticles; Pharmaceutical Preparations; Stem Cell Transplantation; Stem Cells; Technology, Pharmaceutical; Time Factors; Tissue Distribution
PubMed: 28155538
DOI: 10.1080/10717544.2016.1230903 -
Bone Marrow Transplantation Feb 2022We report on 318 patients with acute leukemia, receiving donor lymphocyte infusion (DLI) in complete hematologic remission (CHR) after allogeneic stem cell...
We report on 318 patients with acute leukemia, receiving donor lymphocyte infusion (DLI) in complete hematologic remission (CHR) after allogeneic stem cell transplantation (alloSCT). DLI were applied preemptively (preDLI) for minimal residual disease (MRD, n = 23) or mixed chimerism (MC, n = 169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n = 126). Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II-IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age ≥60 years (p = 0.046), advanced stage at transplantation (p = 0.003), shorter interval from transplantation (p = 0.018), and prior aGvHD ≥II° (p = 0.036) were risk factors for DLI-induced GvHD. GvHD did not influence CRI, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders. The study describes response and outcome of DLI in CHR and helps to identify candidates without increased risk of severe GvHD.
Topics: Acute Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Lymphocyte Transfusion; Lymphocytes; Middle Aged; Neoplasm, Residual; Recurrence; Retrospective Studies; Transplantation Conditioning
PubMed: 34750562
DOI: 10.1038/s41409-021-01515-3 -
Human Gene Therapy Jul 2011Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with...
Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34(+) cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission.
Topics: Adult; Chimerism; Female; Fusion Proteins, bcr-abl; Genetic Vectors; Graft vs Host Disease; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukocyte Transfusion; Male; Middle Aged; Proteomics; Receptors, Antigen, T-Cell, alpha-beta; Remission Induction; Retroviridae; Thymidine Kinase; Tissue Donors; Transduction, Genetic; Transgenes
PubMed: 21091264
DOI: 10.1089/hum.2010.162 -
BMJ (Clinical Research Ed.) Aug 2000
Review
Topics: Bone Marrow Diseases; Fetal Blood; Forecasting; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Leukocyte Transfusion; Patient Selection; Tissue Donors
PubMed: 10938056
DOI: 10.1136/bmj.321.7258.433 -
PloS One 2020Animal models are vital to the study of transfusion and development of new blood products. Post-transfusion recovery of human blood components can be studied in mice,...
Animal models are vital to the study of transfusion and development of new blood products. Post-transfusion recovery of human blood components can be studied in mice, however, there is a need to identify strains that can best tolerate xenogeneic transfusions, as well as to optimize such protocols. Specifically, the importance of using immunodeficient mice, such as NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice, to study human transfusion has been questioned. In this study, strains of wild-type and NSG mice were compared as hosts for human transfusions with outcomes quantified by flow cytometric analyses of CD235a+ erythrocytes, CD45+ leukocytes, and CD41+CD42b+ platelets. Complete blood counts were evaluated as well as serum cytokines by multiplexing methods. Circulating human blood cells were maintained better in NSG than in wild-type mice. Lethargy and hemoglobinuria were observed in the first hours in wild-type mice along with increased pro-inflammatory cytokines/chemokines such as monocyte chemoattractant protein-1, tumor necrosis factor α, keratinocyte-derived chemokine (KC or CXCL1), and interleukin-6, whereas NSG mice were less severely affected. Whole blood transfusion resulted in rapid sequestration and then release of human cells back into the circulation within several hours. This rebound effect diminished when only erythrocytes were transfused. Nonetheless, human erythrocytes were found in excess of mouse erythrocytes in the liver and lungs and had a shorter half-life in circulation. Variables affecting the outcomes of transfused erythrocytes were cell dose and mouse weight; recipient sex did not affect outcomes. The sensitivity and utility of this xenogeneic model were shown by measuring the effects of erythrocyte damage due to exposure to the oxidizer diamide on post-transfusion recovery. Overall, immunodeficient mice are superior models for xenotransfusion as they maintain improved post-transfusion recovery with negligible immune-associated side effects.
Topics: Animals; Blood Component Transfusion; Erythrocyte Transfusion; Heterografts; Humans; Leukocyte Transfusion; Mice; Mice, Inbred NOD; Mice, SCID; Models, Animal; Platelet Transfusion
PubMed: 32735605
DOI: 10.1371/journal.pone.0237106