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1.
Biomolecules ; 12(4)2022 04 18.
Article in English | MEDLINE | ID: mdl-35454183

ABSTRACT

The stem cell theory of aging postulates that stem cells become inefficient at maintaining the original functions of the tissues. We, therefore, hypothesized that transplanting young bone marrow (BM) to old recipients would lead to rejuvenating effects on immunity, followed by improved general health, decreased frailty, and possibly life span extension. We developed a murine model of non-myeloablative heterochronic BM transplantation in which old female BALB/c mice at 14, 16, and 18(19) months of age received altogether 125.1 ± 15.6 million nucleated BM cells from young male donors aged 7-13 weeks. At 21 months, donor chimerism was determined, and the immune system's innate and adaptive arms were analyzed. Mice were then observed for general health and frailty until spontaneous death, when their lifespan, post-mortem examinations, and histopathological changes were recorded. The results showed that the old mice developed on average 18.7 ± 9.6% donor chimerism in the BM and showed certain improvements in their innate and adaptive arms of the immune system, such as favorable counts of neutrophils in the spleen and BM, central memory Th cells, effector/effector memory Th and Tc cells in the spleen, and B1a and B1b cells in the peritoneal cavity. Borderline enhanced lymphocyte proliferation capacity was also seen. The frailty parameters, pathomorphological results, and life spans did not differ significantly in the transplanted vs. control group of mice. In conclusion, although several favorable effects are obtained in our heterochronic non-myeloablative transplantation model, additional optimization is needed for better rejuvenation effects.


Subject(s)
Bone Marrow Transplantation , Frailty , Animals , Bone Marrow Transplantation/methods , Female , Longevity , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Spleen
2.
Eur J Haematol ; 100(4): 372-382, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29315822

ABSTRACT

OBJECTIVE: Hematopoietic stem and progenitor cells (HSPCs) can be used as a vector for gene therapies. In order to predict the number of HSPCs cells necessary to achieve the target level of chimerism in an autologous setting, syngeneic male bone marrow (BM) cells were transplanted into 35 non-conditioned female BALB/c mice. METHOD: The resulting chimerism was determined at 6-53 weeks using qPCR, cell subpopulation sorting, and colony-forming units (CFU) analysis. RESULTS: After the transplantation of 125.8 ± 2.5 million nucleated BM cells, the BM of recipients contained 20.0 ± 2.8% donor cells, representing a chimerism of 0.16 ± 0.02% per one million transplanted nucleated BM cells. Chimerism levels in the BM, neutrophils, and B cells were comparable, whereas in T cells it was lower, and in CFU was approximately twice greater than in BM. CONCLUSION: By extrapolating our murine data, and data from some previous studies to a human non-conditioned autologous CD34+ HSPC transplantation setting, we conclude that approximately 44 million CD34+ HSPCs would be needed to achieve 20% donor chimerism in a 70-kg human, which could serve as a starting point for the future use of HSCPs in gene and cell therapy.


Subject(s)
Bone Marrow Transplantation , Chimerism , Genetic Therapy , Transplantation Chimera , Animals , Biomarkers , Cell Differentiation , Cell Lineage , Cell Separation , Female , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Immunophenotyping , Male , Mice , Models, Animal , Tissue Donors
3.
Vaccine ; 30(40): 5856-63, 2012 Aug 31.
Article in English | MEDLINE | ID: mdl-22819990

ABSTRACT

Helicobacter pylori infection can cause gastritis, peptic ulcer and can lead to gastric cancer. Lengthy antibiotic therapy does not protect the host against reinfection. H. pylori evolved to evade the recognition of the immune response by modifying several of its components whose orthologous proteins from other bacteria activate the innate immune response. Flagella are essential for the H. pylori effective colonization of human duodenum and stomach. TLR5, a member of the Toll-like receptor family, recognizes flagellin of most bacteria, such as Escherichia coli, but does not recognize the flagellin FlaA of H. pylori. We restored the ability of FlaA for the recognition by TLR5 by engineering a chimeric flagellin, in which both terminal segments of H. pylori flagellin were replaced by the corresponding segments from TLR5-activating E. coli flagellin. Recombinant chimeric flagellin folded correctly and was able to activate TLR5. Significantly increased serum IgG and IgA antibody responses were determined in mice vaccinated with chimeric flagellin in comparison to mice vaccinated with a control protein (FlaA) or negative control. Antibody titers remained high even 8 months after the last immunization. Antibodies were able to bind native flagellin from H. pylori lysate. Vaccination with chimeric flagellin provided mice with significant protection against H. pylori. The approach of chimeric flagellin can therefore generate effective immunogens that enable activation of innate and adaptive immune response and can be used to construct efficient vaccines against H. pylori or other flagellated bacteria that evade TLR5 recognition.


Subject(s)
Antigens, Bacterial/immunology , Bacterial Vaccines/immunology , Flagellin/immunology , Helicobacter Infections/immunology , Helicobacter pylori/immunology , Adaptive Immunity , Animals , Antibodies, Bacterial/blood , Escherichia coli/immunology , HEK293 Cells , Helicobacter Infections/prevention & control , Humans , Immunity, Innate , Immunodominant Epitopes/immunology , Immunoglobulin A/blood , Immunoglobulin G/blood , Mice , Mice, Inbred BALB C , Recombinant Fusion Proteins/immunology , Toll-Like Receptor 5/immunology
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