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Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

ABSTRACT: Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

PROVIDER: PRJNA757750 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15611524_1.fastq.gz	Fastqsanger.gz
	SRR15611524_2.fastq.gz	Fastqsanger.gz
	SRR15611525_1.fastq.gz	Fastqsanger.gz
	SRR15611525_2.fastq.gz	Fastqsanger.gz
	SRR15611526_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Project description:Oral rapamycin administration rapamycin is plagued by poor bioavailability and wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, numerous side effects and provides inadequate transplantation protection. Parental formulation was not possible due to rapamycin’s hydrophobicity (log P 4.3). Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)(PEG-b-PPS) polymersome (PS) nanocarriers modulates cellular biodistribution of rapamycin to change its immunosuppressive mechanism for enhanced efficacy while minimizing side effects. While oral rapamycin inhibits naïve T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) instead modulated Ly-6Clow monocytes and tolerogenic semi-mature dendritic cells, with immunosuppression mediated by CD8+ Tregs and rare CD4+ CD8+ double-positive T cells. As PEG-b-PPS PS are uniquely non-inflammatory, background immunostimulation from the vehicle was avoided, allowing immunomodulation to be primarily attributed to rapamycin’s cellular biodistribution. Repurposing mTOR inhibition significantly improved maintenance of normoglycemia in a clinically relevant, MHC-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of engineered nanocarriers to repurpose drugs for alternate routes of administration by rationally controlling cellular biodistribution.

2022-01-01 | GSE182776 | GEO

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability.

Project description:Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin's cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution.

| S-EPMC8934301 | biostudies-literature

Induction of regulatory M2 macrophage-like immunosuppressive cells from mouse ES cells that contribute to prolong allogeneic immune rejection

Project description:A promise of cell replacement therapy using pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) as donor source has been increased. However, particularly when ESCs were used, immune suppression should be required because the donor-recipient combination would be allogeneic. In this study, we examined a concept that some immunosuppressive cells could be induced from PSCs and those cells could prevent allogeneic immune rejection of the PSCs-based transplantation. In fact, we successfully induced immunosuppressive cells that resemble M2 macrophages in terms of cell surface molecule and gene expressions. They efficiently suppressed allogeneic T cell proliferative responses, at least partly, in nitric oxide dependent manner. We applied these cells to in vivoallogeneic transplantation and found that they substantially prolonged ESCs-derived graft survival. These results open a new insight for development of a practical immune-regulatory strategy in cell replacement therapy using PSCs. Difference of the gene expression between ESdSC and ESdDC was analyzed. Two independent experiment were performed.

2014-03-28 | E-GEOD-56302 | biostudies-arrayexpress

Induction of regulatory M2 macrophage-like immunosuppressive cells from mouse ES cells that contribute to prolong allogeneic immune rejection

2014-03-28 | GSE56302 | GEO

Defining TCF1+ progenitor allogeneic CD8 T cell subset in acute graft-versus-host disease

Project description:The goals of this study were to gain a better understanding of the heterogeneity and gene signatures of allogeneic PD-1+ CD8 T cells isolated from the spleen of GvHD B6 recipients of Balb/c T cells.

2022-10-14 | GSE215315 | GEO

Analysis of allogeneic and syngeneic CD8+ T cells reveals novel target genes and related pathway in acute graft-versus host disease

Project description:The goals of the study are to compare differenely expressed genes in allogeneic and syngeneic CD8+ T cells isolated from splenocytes of allogeneic (donor: C57BL/6, host: Balb/c) and syngeneic (donor: Balb/c, host: Balb/c) HSCT mice.

2022-12-16 | GSE212137 | GEO

Analysis of allogeneic and syngeneic CD4+ T cells reveals novel target genes and related pathway in acute graft-versus host disease

Project description:The goals of the study are to compare differently expressed genes in allogeneic and syngeneic CD4+ T cells isolated from splenocytes of allogeneic (donor: C57BL/6, host: Balb/c) and syngeneic (donor: Balb/c, host: Balb/c) HSCT mice.

2022-12-16 | GSE212135 | GEO

Analysis of allogeneic and syngeneic CD3+ T cells reveals novel target genes and related pathway in acute graft-versus host disease

Project description:The goals of the study are to compare differenely expressed genes in allogeneic and syngeneic CD3+ T cells isolated from splenocytes of allogeneic (donor: C57BL/6, host: Balb/c) and syngeneic (donor: Balb/c, host: Balb/c) HSCT mice.

2022-12-16 | GSE212129 | GEO

Allogeneic uterus transplantation in a rhesus model: A short-term graft viability study.

Project description:ObjectiveThis study examined the feasibility and safety of allogeneic uterus transplantation (UTx) from a living donor and assessed short-term graft viability in a rhesus model. This research is an important step towards further clinical application of UTx in humans.Materials and methodsFour female rhesus monkeys with regular menstrual cycles were used in this study, the animals were either donors or recipients depending on ABO blood type compatibility. Retrieval surgery was performed to connect the uterus and uterine arteries together with the ovarian uterine vein from the living donor, and the vagina of the recipient was excised. After the back table had been prepared, bilateral uterine arteries were anastomosed end-to-side with the iliac externa arteries, and bilateral ovarian uterine veins were anastomosed end-to-side with the iliac externa vena. The transplanted uterus was evaluated based on the conditions of arterial blood, and flow was evaluated by transabdominal ultrasonography one month post operation. The conditions of the transplanted uterus were examined by secondary laparotomy. The reproductive function of rhesus monkeys was evaluated on the basis of the menstrual cycle.ResultsAll 4 rhesus monkeys received the transplantation surgery without any surgical complications. No injury occurred in the other organs, and no vascular injury was observed in the allogeneic uterus. All recipients survived after the surgery with a 100% short-term survival rate. All recipients resumed normal menstruation within two months after surgery.ConclusionsOur short follow-up shows that allogeneic UTx surgery is a safe and feasible technology in the rhesus model. The arterial conditions and blood flow of the grafted uterus can be monitored by ultrasonography examination.

| S-EPMC7746281 | biostudies-literature

Tauroursodeoxycholic acid prevents acute graft-versus-host disease in mice by regulating intestinal apoptosis and inflammation

Project description:The effect of tauroursodeoxycholic acid on the development of acute graft-versus-host disease was tested in a murine allogeneic stem cell transplantation model. TUDCA was shown to reduce acute GVHD by reducing intestinal antigen presentation and following apoptosis and increasing the viability of intestinal epithelial cells.

2021-12-21 | GSE124426 | GEO

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