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Frontiers in Immunology 2017Donor-specific induced pluripotent stem cells (iPSCs) offer opportunities for personalized cell replacement therapeutic approaches due to their unlimited self-renewal... (Review)
Review
Donor-specific induced pluripotent stem cells (iPSCs) offer opportunities for personalized cell replacement therapeutic approaches due to their unlimited self-renewal potential and ability to differentiate into different somatic cells. A significant progress has been made toward generating iPSC lines that are free of integrating viral vectors, development of xeno-free culture conditions, and differentiation of pluripotent stem cells (PSCs) into functional somatic cell lineages. Since donor-specific iPSC lines are genetically identical to the individual, they are expected to be immunologically matched and these iPSC lines and their cellular derivatives are not expected to be immunologically rejected. However, studies in mouse models, utilizing rejection of teratomas as a model, have claimed that syngenic iPSC lines, especially the iPSC lines derived with integrating viral vectors, could be inherently immunogenic. This manuscript reviews current understanding of inherent immunogenicity of PSC lines, especially that of the human iPSC lines and their cellular derivatives, and strategies to overcome it.
PubMed: 28868053
DOI: 10.3389/fimmu.2017.00993 -
Journal of Translational Medicine Feb 2019Osteosarcoma (OS) is the most common cancer of bone. Jaw osteosarcoma (JOS) is rare and it differs from other OS in terms of the time of occurrence (two decades later)...
BACKGROUND
Osteosarcoma (OS) is the most common cancer of bone. Jaw osteosarcoma (JOS) is rare and it differs from other OS in terms of the time of occurrence (two decades later) and better survival. The aim of our work was to develop and characterize specific mouse models of JOS.
METHODS
Syngenic and xenogenic models of JOS were developed in mice using mouse (MOS-J) and human (HOS1544) osteosarcoma cell lines, respectively. An orthotopic patient-derived xenograft model (PDX) was also developed from a mandibular biopsy. These models were characterized at the histological and micro-CT imaging levels, as well as in terms of tumor growth and metastatic spread.
RESULTS
Homogeneous tumor growth was observed in both the HOS1544 and the MOS-J JOS models by injection of 0.25 × 10 and 0.50 × 10 tumor cells, respectively, at perimandibular sites. Histological characterization of the tumors revealed features consistent with high grade conventional osteosarcoma, and the micro-CT analysis revealed both osteogenic and osteolytic lesions. Early metastasis was encountered at day 14 in the xenogenic model, while there were no metastatic lesions in the syngenic model and in the PDX models.
CONCLUSION
We describe the first animal model of JOS and its potential use for therapeutic applications. This model needs to be compared with the usual long-bone osteosarcoma models to investigate potential differences in the bone microenvironment.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Female; Humans; Jaw Neoplasms; Lung Neoplasms; Mandible; Mice, Inbred C57BL; Mice, SCID; Osteosarcoma; Tumor Burden; X-Ray Microtomography; Xenograft Model Antitumor Assays
PubMed: 30813941
DOI: 10.1186/s12967-019-1807-5 -
Cancers Jan 2023Acute Myeloid Leukemia (AML) is a severe disease with a very high relapse rate. AML relapse may be attributable to leukemic stem cells (LSC). Notably, the "cancer stem...
Acute Myeloid Leukemia (AML) is a severe disease with a very high relapse rate. AML relapse may be attributable to leukemic stem cells (LSC). Notably, the "cancer stem cell" theory, which relates to LSCs, is controversial and criticized due to the technical peculiarities of the xenotransplant of human cells into mice. In this study, we searched for possible LSCs in an immunocompetent synergetic mice model. First, we found phenotypic heterogeneity in the ML23 leukemia line. We prospectively isolated a sub-population using the surface markers cKitCD9CD48Mac1, which have the potency to relapse the disease. Importantly, this sub-population can pass in syngeneic hosts and retrieve the heterogeneity of the parental ML23 leukemia line. The LSC sub-population resides in various organs. We present a unique gene expression signature of the LSC in the ML23 model compared to the other sub-populations. Interestingly, the ML23 LSC sub-population expresses therapeutic targeted genes such as CD47 and CD93. Taken together, we present the identification and molecular characterization of LSCs in a syngeneic murine model.
PubMed: 36765677
DOI: 10.3390/cancers15030720 -
Biomatter 2013Therapeutic monoclonal antibodies have revolutionized the treatment of cancer and other diseases. However, several limitations of antibody-based treatments, such as the... (Review)
Review
Therapeutic monoclonal antibodies have revolutionized the treatment of cancer and other diseases. However, several limitations of antibody-based treatments, such as the cost of therapy and the achievement of sustained plasma levels, should be still addressed for their widespread use as therapeutics. The use of cell and gene transfer methods offers additional benefits by producing a continuous release of the antibody with syngenic glycosylation patterns, which makes the antibody potentially less immunogenic. In vivo secretion of therapeutic antibodies by viral vector delivery or ex vivo gene modified long-lived autologous or allogeneic human mesenchymal stem cells may advantageously replace repeated injection of clinical-grade antibodies. Gene-modified autologous mesenchymal stem cells can be delivered subcutaneously embedded in a non-immunogenic synthetic extracellular matrix-based scaffold that guarantees the survival of the cell inoculum. The scaffold would keep cells at the implantation site, with the therapeutic protein acting at distance (immunotherapeutic organoid), and could be retrieved once the therapeutic effect is fulfilled. In the present review we highlight the practical importance of living cell factories for in vivo secretion of recombinant antibodies.
Topics: Antibodies, Monoclonal; Genetic Therapy; Humans; Immunotherapy; Injections, Subcutaneous; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Neoplasms; Organoids; Tissue Scaffolds
PubMed: 23507921
DOI: 10.4161/biom.23897 -
Journal of Orthopaedic Surgery and... Sep 2020Despite widespread use of femoral-sourced allografts in clinical spinal fusion procedures and the increasing interest in using femoral reamer-irrigator-aspirator (RIA)... (Comparative Study)
Comparative Study
BACKGROUND
Despite widespread use of femoral-sourced allografts in clinical spinal fusion procedures and the increasing interest in using femoral reamer-irrigator-aspirator (RIA) autograft in clinical bone grafting, few studies have examined the efficacy of femoral grafts compared to iliac crest grafts in spinal fusion. The objective of this study was to directly compare the use of autologous iliac crest with syngeneic femoral and iliac allograft bone in the rat model of lumbar spinal fusion.
METHODS
Single-level bilateral posterolateral intertransverse process lumbar spinal fusion surgery was performed on Lewis rats divided into three experimental groups: iliac crest autograft, syngeneic iliac crest allograft, and syngeneic femoral allograft bone. Eight weeks postoperatively, fusion was evaluated via microCT analysis, manual palpation, and histology. In vitro analysis of the colony-forming and osteogenic capacity of bone marrow cells derived from rat femurs and hips was also performed to determine whether there was a correlation with the fusion efficacy of these graft sources.
RESULTS
Although no differences were observed between groups in CT fusion mass volumes, iliac allografts displayed an increased number of radiographically fused fusion masses and a higher rate of bilateral fusion via manual palpation. Histologically, hip-derived grafts showed better integration with host bone than femur derived ones, likely associated with the higher concentration of osteogenic progenitor cells observed in hip-derived bone marrow.
CONCLUSIONS
This study demonstrates the feasibility of using syngeneic allograft bone in place of autograft bone within inbred rat fusion models and highlights the need for further study of femoral-derived grafts in fusion.
Topics: Allografts; Animals; Autografts; Bone Marrow Cells; Bone Transplantation; Cells, Cultured; Disease Models, Animal; Feasibility Studies; Female; Femur; Ilium; Lumbar Vertebrae; Osteogenesis; Rats, Inbred Lew; Spinal Fusion; Stem Cells; Tomography, X-Ray Computed
PubMed: 32933551
DOI: 10.1186/s13018-020-01936-8 -
International Journal of Cell Cloning Mar 1989Graft-versus-host disease (GVHD) until recently was supposed to occur only when immunocompetent T lymphocytes are infused into immunoincompetent allogeneic hosts that... (Comparative Study)
Comparative Study Review
Graft-versus-host disease (GVHD) until recently was supposed to occur only when immunocompetent T lymphocytes are infused into immunoincompetent allogeneic hosts that possess histocompatibility antigens not possessed by the donor that could act as targets for cell-mediated cytotoxicity. A syndrome clinically and histologically identical to mild allogeneic GVHD occurs infrequently, following syngeneic or autologous bone marrow transplantation (BMT). This syndrome called syngeneic or autologous GVHD can be regularly produced with Cyclosporine (CsA) in animals undergoing syngeneic or autologous BMT. Animals with this syndrome develop T cells that are autocytotoxic to Ia antigen-bearing cells. The presence of an irradiated thymus and CsA administration is necessary to produce this disease. Operationally, this disease results from a disturbance of balance between a normally present autoregulatory cell and an autocytotoxic T cell. The study of mechanisms involved in the generation of this disease will add to our fundamental understanding of the cellular regulation of autocytotoxic T cell-medicated reactions and diseases. Most recently, we have been able to induce this disease in man with the aim of investigating its therapeutic effect in autologous BMT in patients with Ia-bearing tumors.
Topics: Animals; Graft vs Host Disease; Humans; Transplantation, Autologous; Transplantation, Isogeneic
PubMed: 2656886
DOI: 10.1002/stem.5530070203 -
Frontiers in Pharmacology 2021In recent, Botulinum Neurotoxin A1 (BoNT/A1) has been suggested as a potential anticancer agent due to neuronal innervation in tumor cells. Although potential BoNT/A1's...
In recent, Botulinum Neurotoxin A1 (BoNT/A1) has been suggested as a potential anticancer agent due to neuronal innervation in tumor cells. Although potential BoNT/A1's mechanism of action for the tumor suppression has been gradually revealed so far, there were no reports to figure out the exposure-response relationships because of the difficulty of its quantitation in the biological matrix. The main objectives of this study were to measure the anticancer effect of BoNT/A1 using a syngeneic mouse model transplanted with melanoma cells (B16-F10) and developed a kinetic-pharmacodynamic (K-PD) model for quantitative exposure-response evaluation. To overcome the lack of exposure information, the K-PD model was implemented by the virtual pharmacokinetic compartment link to the pharmacodynamic compartment of Simeoni's tumor growth inhibition model and evaluated using curve-fitting for the tumor growth-time profile after intratumoral injection of BoNT/A1. The final K-PD model was adequately explained for a pattern of tumor growth depending on represented exposure parameters and simulation studies were conducted to determine the optimal dose under various scenarios considering dose strength and frequency. The optimal dose range and regimen of ≥13.8 units kg once a week or once every 3 days was predicted using the final model in B16-F10 syngeneic model and it was demonstrated with an extra experiment. In conclusion, the K-PD model of BoNT/A1 was well developed to optimize the dosing regimen for evaluation of anticancer effect and this approach could be expandable to figure out quantitative interpretation of BoNT/A1's efficacy in various xenograft and/or syngeneic models.
PubMed: 35058777
DOI: 10.3389/fphar.2021.793349 -
BMC Genomics Jan 2020The clinical success of immune checkpoint inhibitors demonstrates that reactivation of the human immune system delivers durable responses for some patients and...
BACKGROUND
The clinical success of immune checkpoint inhibitors demonstrates that reactivation of the human immune system delivers durable responses for some patients and represents an exciting approach for cancer treatment. An important class of preclinical in vivo models for immuno-oncology is immunocompetent mice bearing mouse syngeneic tumors. To facilitate translation of preclinical studies into human, we characterized the genomic, transcriptomic, and protein expression of a panel of ten commonly used mouse tumor cell lines grown in vitro culture as well as in vivo tumors.
RESULTS
Our studies identified a number of genetic and cellular phenotypic differences that distinguish commonly used mouse syngeneic models in our study from human cancers. Only a fraction of the somatic single nucleotide variants (SNVs) in these common mouse cell lines directly match SNVs in human actionable cancer genes. Some models derived from epithelial tumors have a more mesenchymal phenotype with relatively low T-lymphocyte infiltration compared to the corresponding human cancers. CT26, a colon tumor model, had the highest immunogenicity and was the model most responsive to CTLA4 inhibitor treatment, by contrast to the relatively low immunogenicity and response rate to checkpoint inhibitor therapies in human colon cancers.
CONCLUSIONS
The relative immunogenicity of these ten syngeneic tumors does not resemble typical human tumors derived from the same tissue of origin. By characterizing the mouse syngeneic models and comparing with their human tumor counterparts, this study contributes to a framework that may help investigators select the model most relevant to study a particular immune-oncology mechanism, and may rationalize some of the challenges associated with translating preclinical findings to clinical studies.
Topics: Animals; CTLA-4 Antigen; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genomics; Humans; Mice; T-Lymphocytes
PubMed: 31898484
DOI: 10.1186/s12864-019-6344-3 -
International Journal of Molecular... Apr 2020Due to their multifactorial aspects, mesenchymal stem cells (MSCs) have been widely established as an attractive and potential candidate for the treatment of a multitude... (Comparative Study)
Comparative Study
Due to their multifactorial aspects, mesenchymal stem cells (MSCs) have been widely established as an attractive and potential candidate for the treatment of a multitude of diseases. A substantial number of studies advocate that MSCs are poorly immunogenic. In several studies, however, immune responses were observed following injections of xenogeneic donor MSCs. In this study, the aim was to examine differences in immune responses exerted based on transplantations of xenogeneic, syngeneic, and allogeneic MSCs in the wild-type mouse brain. Xenogeneic, allogeneic, and syngeneic MSCs were intracerebrally injected into C57BL/6 mice. Mice were sacrificed one week following transplantation. Based on immunohistochemical (IHC) analysis, leukocytes and neutrophils were expressed at the injection sites in the following order (highest to lowest) xenogeneic, allogeneic, and syngeneic. In contrast, microglia and macrophages were expressed in the following order (highest to lowest): syngeneic, allogeneic, and xenogeneic. Residual human MSCs in the mouse brain were barely detected after seven days. Although the discrepancy between leukocytes versus macrophages/microglia infiltration should be resolved, our results overall argue against the previous notions that MSCs are poorly immunogenic and that modulation of immune responses is a prerequisite for preclinical and clinical studies in MSC therapy of central nervous system diseases.
Topics: Animals; Cells, Cultured; Female; Humans; Immunity; Leukocytes; Macrophages; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Microglia; Neutrophils; Transplantation, Heterologous; Transplantation, Homologous; Transplantation, Isogeneic
PubMed: 32357509
DOI: 10.3390/ijms21093052 -
Molecular Therapy. Methods & Clinical... Mar 2017Adeno-associated virus (AAV) vectors have emerged as a safe and efficient gene therapy platform. One complication is that a significant amount of empty particles have...
Adeno-associated virus (AAV) vectors have emerged as a safe and efficient gene therapy platform. One complication is that a significant amount of empty particles have always been generated as impurities during AAV vector production. However, the effects of such particles on AAV vector performance remain unclear. Here we systemically evaluated the biological properties of three types of "empty" AAV particles: syngeneic pseudo-vectors with partial AAV genomes derived from DNA of the corresponding full particles, allogeneic pseudo-vectors with partial genomes different from the corresponding full particles, and null pseudo-vectors with no DNA inside the capsids. The syngeneic particles in excess increased the corresponding full AAV vector transgene expression both in vivo and in vitro. However, such effects were not observed with null or allogeneic particles. The observed differences among these pseudo-AAV particles may be ascribed to the syngeneic pseudo-vector DNA facilitating the complementary DNA synthesis of the corresponding full AAV particles. Our study suggests that the DNA content in the pseudo-vectors plays a key role in dictating their effects on AAV transduction. The effects of residual "empty" particles should be adequately assessed when comparing AAV vector performance. The syngeneic AAV pseudo-vectors may be used to enhance the efficacy of gene therapy.
PubMed: 28345000
DOI: 10.1016/j.omtm.2016.12.004