An innovative immunosuppressant with a minimally invasive delivery system has emerged in the biomedical field. The application of biodegradable and biocompatible polymer forms, such as hydrogels, ...scaffolds, microspheres, and nanoparticles, in transplant recipients to control the release of immunosuppressants can minimize the risk of developing unfavorable conditions. In this review, we summarized several studies that have used implantable immunosuppressant delivery to release therapeutic agents to prolong allograft survival. We also compared their applications, efficacy, efficiency, and safety/side effects with conventional therapeutic-agent administration. Finally, challenges and the future prospective were discussed. Collectively, this review will help relevant readers understand the different approaches to prevent transplant rejection in a new era of therapeutic agent delivery.
Amino acid (AA) is a potent mitogen that controls growth and metabolism. Here we describe the identification of Rab1 as a conserved regulator of AA signaling to mTORC1. AA stimulates Rab1A GTP ...binding and interaction with mTORC1 and Rheb-mTORC1 interaction in the Golgi. Rab1A overexpression promotes mTORC1 signaling and oncogenic growth in an AA- and mTORC1-dependent manner. Conversely, Rab1A knockdown selectively attenuates oncogenic growth of Rab1-overexpressing cancer cells. Moreover, Rab1A is overexpressed in colorectal cancer (CRC), which is correlated with elevated mTORC1 signaling, tumor invasion, progression, and poor prognosis. Our results demonstrate that Rab1 is an mTORC1 activator and an oncogene and that hyperactive AA signaling through Rab1A overexpression drives oncogenesis and renders cancer cells prone to mTORC1-targeted therapy.
•Rab1A mediates amino acid signaling to activate mTORC1 independently of Rag•Rab1A regulates mTORC1-Rheb interaction on the Golgi apparatus•Rab1A is an oncogene that is frequently overexpressed in human cancer•Hyperactive amino acid signaling is a common driver for cancer
Thomas et al. show that Rab1 is a regulator of amino acid (AA) signaling to mTORC1, Rab1A overexpression promotes AA- and mTORC1-dependent oncogenic growth, and Rab1A overexpression in colorectal cancer correlates with increased mTORC1 activity, tumor progression, and poor patient prognosis.
Vascularized bone marrow (VBM) is essential in tolerance induction through chimerism. We hypothesized that the inclusion of VBM contributes to the induction of mystacial pad allotransplantation ...tolerance.
In this study, 19 VBM, nine mystacial pad, and six sequential VBM and mystacial pad allografts were transplanted from Brown Norway (BN) rats to Lewis (LEW) rats to test our hypothesis. The VBM recipients were divided into antilymphocyte serum (ALS) monotherapy group (two doses of ALS on day 3 pretransplantation and day 1 posttransplantation), immunosuppressant group a week of 2 mg/kg/day tacrolimus (Tac) and 3 weeks of 3 mg/kg/day rapamycin (RPM), and combined therapy group. The mystacial pad recipients were divided into VBM and non-VBM transplantation groups, and both groups were treated with an immunosuppression regimen that consists of ALS, Tac, and RPM. For the recipients of sequential VBM and mystacial pad allotransplantations, additional Tac was given 1 week after mystacial pad transplantation. Allograft survival, donor-specific tolerance, and chimerism level were evaluated.
With the administration of ALS and short-term Tac and RPM treatments, VBM recipients demonstrated long-term graft survival (>120 days) with persistent chimerism for 30 days. CD3
T cells from tolerant rats showed donor-specific hyporesponsiveness and tolerance to donor skin grafts but not to third-party counterparts. Furthermore, mystacial pad graft recipients with VBM transplantation exhibited a higher allograft survival rate than those without VBM transplantation median survival time (MST) >90 days vs. 70 days,
< 0.05.
This study demonstrated that VBM transplantation is an efficient strategy to induce and maintain donor-specific tolerance for an osseous-free allograft.
Solid organ and composite tissue allotransplanation have been widely applied to treat end-stage organ failure and massive tissue defects, respectively. Currently there are a lot of research endeavors ...focusing on induction of transplantation tolerance, to relieve the burden derived from long-term immunosuppressant uptake. The mesenchymal stromal cells (MSCs) have been demonstrated with potent immunomodulatory capacities and applied as promising cellular therapeutics to promote allograft survival and induce tolerance. As a rich source of adult MSCs, adipose tissue provides additional advantages of easy accessibility and good safety profile. In recent years, the stromal vascular fraction (SVF) isolated from adipose tissues following enzymatic or mechanical processing without
culture and expansion has demonstrated immunomodulatory and proangiogenic properties. Furthermore, the secretome of AD-MSCs has been utilized in transplantation field as a potential "cell-free" therapeutics. This article reviews recent studies that employ these adipose-derived therapeutics, including AD-MSCs, SVF, and secretome, in various aspects of organ and tissue allotransplantation. Most reports validate their efficacies in prolonging allograft survival. Specifically, the SVF and secretome have performed well for graft preservation and pretreatment, potentially through their proangiogenic and antioxidative capacities. In contrast, AD-MSCs were suitable for peri-transplantation immunosuppression. The proper combination of AD-MSCs, lymphodepletion and conventional immunosuppressants could consistently induce donor-specific tolerance to vascularized composite allotransplants (VCA). For each type of transplantation, optimizing the choice of therapeutics, timing, dose, and frequency of administration may be required. Future progress in the application of adipose-derived therapeutics to induce transplantation tolerance will be further benefited by continued research into their mechanisms of action and the development of standardized protocols for isolation methodologies, cell culture, and efficacy evaluation.
Obesity is referred to as a condition in which excess body fat has accumulated to an extent that it causes negative impacts on health. The formation of body fat is regulated by complicated networks ...in relation to energy metabolism, and gut microbiota have been regarded as a key player. Studies have shown that supplements of probiotics provide benefits to health, including an improvement in metabolic syndrome and the control of body weight. In the present study, three probiotic strains, AP-32, bv-77, and CP-9, stood out from nine candidates using a lipid consumption assay, and were subsequently introduced to further animal tests. A rodent model of obesity was induced by a high-fat diet (HFD) in Sprague-Dawley (SD) rats, and three probiotic strains were administered either separately or in a mixture. A low dose (5 × 10
CFU/kg/day) and a high dose (2.5 × 10
CFU/kg/day) of probiotics were orally provided to obese rats. The bioeffects of the probiotic supplements were evaluated based on five aspects: (1) the body weight and growth rate; (2) ketone bodies, non-esterified fatty acids (NEFAs), and feed efficiency; (3) blood biochemistry; (4) fat content; and (5) gut microbiota composition. Our results demonstrated that the supplement of AP-32, CP-9, and bv-77 alleviated the increasing rate of body weight and prevented the elevation of NEFAs and ketone bodies in obese rats. Although the effect on fat content showed a minor improvement, the supplement of probiotics displayed significant improvements in HFD-induced poor blood biochemical characteristics, such as alanine aminotransferase (ALT), aspartate Transaminase (AST), and uric acid, within 4 weeks. Furthermore, the combined supplement of three strains significantly increased
as compared with three individual strains, while its enrichment was negatively correlated with NEFAs and energy metabolism. In general, a mixture of three probiotic strains delivered a better outcome than a single strain, and the high dose of supplements provided a more profound benefit than the low dose. In conclusion, three probiotic strains, AP-32, bv-77, and CP-9, can alleviate body fat formation in obese rats. Furthermore, a combined supplement of these three probiotic strains may have potential in treating or controlling metabolic disorders.
A series of LiFe1–x V x PO4/C samples have been successfully prepared using a two-step solid-state reaction route. The effect of vanadium incorporation on the performance of LiFePO4 has ...systematically been investigated with X-ray diffraction, Raman spectroscopy, charge/discharge measurements, and cyclic voltammetry tests. It is found that V incorporation significantly enhances the electrochemical performance of LiFePO4. Particularly, the LiFePO4/C sample with 5 at. % vanadium doping exhibits the best performance with a specific discharge capacity of 129 mAh g–1 at 5.0 C after 50 cycles; the capacity retention ratio is higher than 97.5% at all C rates from 0.1 to 5.0 C. X-ray absorption spectroscopy results show that the valence of V in LiFe0.95V0.05PO4/C is between +3 and +4. It is confirmed that the samples with x ≤ 0.03 are in single phase, whereas the samples with 0.05 ≤ x < 1.00 contain two impurity phases: Li3V2(PO4)3 and LiVOPO4. A clear feature of vanadium incorporation in LiFePO4 has been specified.
•TiO2 film was deposited on surface of Ni50Ti50 substrate using atomic layer deposition techniques.•TiO2 film thickness, surface roughness, corrosion resistance and biocompatibility were ...investigated.•TiO2 film thickness is directly proportional with number of ALD cycles.•The maximum corrosion resistance, excellent surface morphology and Cell proliferation was achieved after 200 ALD cycles.
NiTi shape memory alloys (SMAs) have been widely applied in biomedical fields due to their excellent shape memory effect, super-elasticity, and biocompatibility. In this study, the plasma- enhanced atomic layer deposition was applied to deposit TiO2 film on the surface of Ni50Ti50 substrate. The characterization and surface properties of TiO2 film, bending strain test, corrosion resistance, nickel release and in vitro biocompatibility were studied to evaluate the performance of ALD-TiO2 film. The results show that the ALD-TiO2 film is uniform and exhibits an amorphous structure. The ALD-TiO2 films are less hydrophilic than the Ni50Ti50 substrate. As the deposition cycle increases, the water contact angle of ALD-TiO2 film only changes slightly. The ALD-TiO2 film exhibits an adequate adhesion to the Ni50Ti50 substrate and can withstand proper bending strain. ALD-TiO2 film can effectively inhibit the release of nickel ions. After being immersed in the simulated body fluid for 30 days, the amount of nickel ions released decreases from 60 ppb for Ni50Ti50 substrate to 20–20 ppb for Ni50Ti50 with 200-cycle ALD-TiO2 film. Meanwhile, Ni50Ti50 with ALD-TiO2 films have better corrosion resistance than the Ni50Ti50 substrate. In vitro biocompatibility reveals that the ALD-TiO2 film can enhance cell adhesion, promote cell proliferation and reduce cytotoxicity. After 5 days of culture, the 200-cycle ALD-TiO2 film can enhance the cell proliferation by 2.7 times and reduce the cytotoxicity from 48% for Ni50Ti50 substrate to 37% for Ni50Ti50 with 200-cycle ALD-TiO2 film. These results indicate that the TiO2 films deposited by PE-ALD technique can effectively improve the biocompatibility of NiTi SMAs.
Allograft rejection is one of the obstacles in achieving a successful vascularized composite allotransplantation (VCA). Treatments of graft rejection with lifelong immunosuppression (IS) subject the ...recipients to a lifelong risk of cancer development and opportunistic infections. Cell therapy has recently emerged as a promising strategy to modulate the immune system, minimize immunosuppressant drug dosages, and induce allograft tolerance. In this review, the recent works regarding the use of cell therapy to improve allograft outcomes are discussed. The current data supports the safety of cell therapy. The suitable type of cell therapy in allotransplantation is clinically dependent. Bone marrow cell therapy is more suitable for the induction phase, while other cell therapies are more feasible in either the induction or maintenance phase, or for salvage of allograft rejection. Immune cell therapy focuses on modulating the immune response, whereas stem cells may have an additional role in promoting structural regenerations, such as nerve regeneration. Source, frequency, dosage, and route of cell therapy delivery are also dependent on the specific need in the clinical setting.
The role of the vascularized bone marrow component as a continuous source of donor-derived hematopoietic stem cells that facilitate tolerance induction of vascularized composite allografts is not ...completely understood. In this study, vascularized composite tissue allograft transplantation outcomes between recipients receiving either conventional bone marrow transplantation (CBMT) or vascularized bone marrow (VBM) transplantation from Balb/c (H2d) to C57BL/6 (H2b) mice were compared. Either high- or low-dose CBMT (1.5 × 10
or 3 × 10
bone marrow cells, respectively) was applied. In addition, recipients were treated with costimulation blockade (1 mg anti-CD154 and 0.5 mg CTLA4Ig on postoperative days 0 and 2, respectively) and short-term rapamycin (3 mg/kg/day for the first posttransplant week and then every other day for another 3 weeks). Similar to high-dose conventional bone marrow transplantation, 5/6 animals in the vascularized bone marrow group demonstrated long-term allograft survival (>120 days). In contrast, significantly shorter median survival was noted in the low-dose CBMT group (~64 days). Consistently high chimerism levels were observed in the VBM transplantation group. Notably, low levels of circulating CD4
and CD8
T cells and a higher ratio of Treg to Teff cells were maintained in VBM transplantation and high-dose CBMT recipients (>30 days) but not in low-dose VBM transplant recipients. Donor-specific hyporesponsiveness was shown in tolerant recipients in vitro. Removal of the vascularized bone marrow component after secondary donor-specific skin transplantation did not affect either primary allograft or secondary skin graft survival.
Tipping the balance toward regulatory T cells (Tregs) through adoptive cell therapy has shown promise to induce transplantation tolerance. Although such strategy has been explored in many mice organ ...transplantation studies, less knowledge was available in rat systems. Furthermore, the behaviors of the transferred cells have not been well studied in real-time fashion.
Tregs from naïve LEW rats were purified in two steps with the autoMACS system. Immunosuppression potential of these cells was examined with mixed lymphocyte reaction. Following stimulation by the alloantigen in vitro, the purified Tregs were infused into the recipients of vascularized composite allotransplantation (VCA). Secondary allogeneic skin grafting challenge was performed on the recipients with long-term survived VCA. Live optical imaging was performed to track luciferase-expressing Tregs following infusion to the VCA recipients. Expression of relevant molecules was studied by flow cytometry or quantitative RT-PCR.
Rat Tregs were enriched following two-step cell sorting and showed immunosuppressive capacity. Upon infusion into the VCA recipients that have been treated with antilymphocyte serum and short-term Cyclosporin A, the antigen-stimulated Tregs significantly prolonged VCA survival and induced donor-specific tolerance. Tracking of the infused bioluminescent Tregs showed their specific homing to lymph nodes, and then to the VCAs. Following secondary skin grafting, Tregs specifically gathered at the donor-derived skin that was not rejected by the recipient. The in vivo migratory pattern coincided with the altered expression of cell surface molecules of CD62L, CD103, CD134, and CD278, following donor-antigen stimulation. Elevated expression of CCR4 and CCL22 in allograft may also participate in recruiting Tregs for maintenance of VCA survival and promoting donor-specific tolerance.
Sorted Tregs induced donor-specific tolerance to VCA in rats. Live cell tracking demonstrated that activated CD4+CD25+FoxP3+ Tregs targeted primarily to the lymph nodes and VCA. The Tregs migrated to the secondary grafted donor skin and contributed to the maintenance of donor-specific tolerance. These behaviors were associated with phenotypic changes induced by donor antigen stimulation. Increased expression of CCR4 and CCL22 in VCA skin may also be relevant.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
