Aging is a complex multifactorial process, a prominent component being the senescence of the immune system. Consequently, immune-related diseases develop, including atherosclerosis, cancer, and life-threatening infections, which impact on health and longevity. Rejuvenating the aged immune system could mitigate these diseases, thereby contributing to longevity and health. Currently, an appealing option for rejuvenating the immune system is heterochronous autologous hematopoietic stem cell transplantation (haHSCT), where healthy autologous bone marrow/peripheral blood stem cells are collected during the youth of an individual, cryopreserved, and re-infused when he or she has reached an older age. After infusion, young hematopoietic stem cells can reconstitute the compromised immune system and improve immune function. Several studies using animal models have achieved substantial extension of the life span of animals treated with haHSCT. Therefore, haHSCT could be regarded as a potential procedure for preventing age-related immune defects and extending healthy longevity. In this review, the pros, cons, and future feasibility of this approach are discussed.
COBISS.SI-ID: 33816281
Due to its extremely pleiotropic nature, the complex effects of IFN-[gamma] exerted both on immune and non-immune cell types still remain only partially understood. The longstanding view of IFN-[gamma] as being a predominantly inflammatory cytokine is constantly challenged by increasing demonstrations of its direct or indirect regulatory roles. Interferon-[gamma] can exert tolerogenic effects on both innate and adaptive immune cell types, promoting tolerance of various antigen-presenting cells, and augmenting function and differentiation of regulatory T cells, respectively. Its capacity to induce IDO-competence is not limited to immune cells but extends to other cell types such as mesenchymal stem cells, epithelial cells, and tumors. The pro-inflammatory role of IFN-[gamma] in tumor immune surveillance can backfire by directly inducing inhibitory molecule expression, such as PDL-1, on tumor cells. With increasing knowledge regarding the role of different helper T cell subsets in certain autoimmune diseases, the once contradictory observations of disease attenuation by IFN-[gamma] can now be explained by its opposing interplay with other effector cytokines, particularly IL-17. The paradoxically immunosuppressive role of IFN-[gamma] is also becoming evident in the transplantation setting, and graft-versus-host-disease. In the present review, we will discuss the latest findings that help to elucidate this dual role of IFN-[gamma] at a cellular level, and in various...
COBISS.SI-ID: 33729497
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 by 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.
COBISS.SI-ID: 33603289
The importance of microenvironment on dendritic cell (DC) function and development has been strongly established during the last two decades. Although DCs with general tolerogenic characteristics have been isolated and defined as a particular sub-population, it is predominantly their unequivocal biological plasticity, which allows for unparalleled responsiveness to environmental ques and shaping of their tolerogenic characteristics when interacting with tolerance-inducing biomolecules. Dendritic cells carry receptors for a great number of endogenous factors, which, after ligation, can importantly influence the development of their activation state. For this there is ample evidence merely by observation of DC characteristics isolated from various anatomical niches, e.g., the greater immunosuppressive potential of DCs isolated from intestine compared to conventional blood DCs. Endogenous biomolecules present in these environments most likely play a major role as a determinant of their phenotype and function. In this review, we will concisely summarize in what way various, tolerance-inducing endogenous factors influence DC biology, the development of their particular tolerogenic state and their subsequent actions in context of immune response inhibition and induction of regulatory T cells.
COBISS.SI-ID: 34026201
Inflammation plays a major role in progression of rheumatoid arthritis, a disease treated with antagonists of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta). New in vitro testing systems are needed to evaluate efficacies of new anti-inflammatory biological drugs, ideally in a patient-specific manner. To address this need, we studied microspheroids containing 10,000 human osteoarthritic primary chondrocytes (OACs) or chondrogenically differentiated mesenchymal stem cells (MSCs), obtained from three donors. Hypothesizing that this system can recapitulate clinically observed effects of anti-inflammatory drugs, spheroids were exposed to TNF-alpha, IL-1beta, or to supernatant containing secretome from activated macrophages (MCM). The anti-inflammatory efficacies of anti-TNF-alpha biologicals adalimumab, infliximab, and etanercept, and the anti-IL-1beta agent anakinra were assessed in short-term microspheroid and long-term macrospheroid cultures (100,000 OACs). While gene and protein expressions were evaluated in microspheroids, diameters, amounts of DNA, glycosaminoglycans, and hydroxiproline were measured in macrospheroids. The tested drugs significantly decreased the inflammation induced by TNF-alpha or IL-1beta. The differences in potency of anti-TNF-alpha biologicals at 24 h and 3 weeks after their addition to inflamed spheroids were comparable, showing high predictability of short-term cultures.
COBISS.SI-ID: 4669809