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IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients [GIL]

ABSTRACT: IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients [GIL]

PROVIDER: PRJNA1008239 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25735583.fastq.gz	Fastqsanger.gz
	SRR25735584.fastq.gz	Fastqsanger.gz
	SRR25735585.fastq.gz	Fastqsanger.gz
	SRR25735586.fastq.gz	Fastqsanger.gz
	SRR25735587.fastq.gz	Fastqsanger.gz

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IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients [GIL]

Project description:The efficacy of costimulation blockade (CTLA4Ig/belatacept) in transplantation is reduced by an increased incidence of T cell-mediated rejection, which also persists after induction therapy with anti-thymocyte globulin (ATG). Herein, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between Tregs and effector T cells in the peripheral compartment, it had no such effect within cardiac allografts, which showed signs of inflammation. Neutralizing IL-6 alleviated inflammation, increased intragraft Treg frequencies long-term, and enhanced intragraft IL-10 and Th2 cytokine expression. IL-6 blockade together with ATG led to long-term, rejection-free heart graft survival under CTLA4Ig therapy. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.

2024-04-21 | GSE241471 | GEO

IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients [FFPE]

2024-04-21 | GSE241470 | GEO

IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients

Project description:IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients

| PRJNA1008227 | ENA

IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients [FFPE]

Project description:IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients [FFPE]

| PRJNA1008236 | ENA

IL-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation in T cell-depleted recipients

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-04-21 | GSE241472 | GEO

Myeloid Niches Sustain Antitumor T Cells and License PD-1 Blockade via CD28 Costimulation

Project description:The local mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TILs) and responsiveness to PD-1 blockade remain partly elucidated. In human ovarian cancer we show that tumor-reactive intraepithelial (ie)CD8+ TILs engaged by antigen are polyfunctional and upregulate PD-1, which restrains their effectiveness. PD-1+ TILs exhibit a continuum of TCR-engaged/exhausted states with variable effector fitness related to CD28 costimulation, which they receive in intraepithelial niches involving myeloid antigen-presenting cells (mAPC). Following PD-1 blockade, activation of TILs requires CD28 costimulation mediated in situ by tumor mAPCs, which is locally enhanced by CTLA-4 blockade. CD40 ligand also amplifies TIL responses in situ, especially in tumors in which mAPCs are not activated. Thus, dysfunctional and exhausted TILs, in a state of TCR engagement but without proper CD28 costimulation by mAPCs in situ, are unlikely to fully benefit from PD-1 blockade.

2021-10-12 | GSE178245 | GEO

Costimulation Blockade in Kidney Transplant Recipients.

Project description:Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.

| S-EPMC6978297 | biostudies-literature

Interruption of OX40L signaling prevents costimulation blockade-resistant allograft rejection.

Project description:The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade-resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target. We next sought to improve the clinical efficacy of traditional costimulation blockade using belatacept by coupling it with anti-OX40L. Using a murine transplant model, we demonstrate that combined blockade enhances the suppression of alloreactive T cell proliferation and effector functions including both cytokine release and cytotoxic degranulation. We also show that anti-OX40L may be particularly useful in targeting alloreactive memory T cell responses that are relatively unaffected by traditional costimulation blockade regimens. Finally, we translated this therapy to a clinically relevant nonhuman primate renal transplant model, validating the efficacy of this regimen in a potentially novel steroid- and calcineurin inhibitor-free immunosuppression regimen.

| S-EPMC5333968 | biostudies-literature

Dominant intragraft plasma cells targeting bilirubin implicate local heme catabolism in human cardiac allograft vasculopathy

Project description:Cardiac allograft vasculopathy (CAV) is invariably associated with immune infiltrates around affected coronary arteries, including antibody-producing plasma cells (PC). We used single-cell-RNA-sequencing and IGHV profiling to characterize these infiltrating PC. We then generated 37 recombinant monoclonal antibodies (mAb) using rearranged immunoglobulin gene sequences from dominant intragraft PC clones as well as 24 control mab from peripheral blood PC. Unexpectedly, a majority (21/37) of mAb derived from intragraft PC, but none of the control mAb derived from blood PC, reacted to bilirubin, a by-product of heme degradation. Furthermore, we observed the deposition of bilirubin within lymphocytic aggregates of cardiac grafts with CAV but not in healthy heart tissue. Bilirubin also accumulated in the cytoplasm and the nuclei of smooth muscle cells in the tunica media of coronary arteries with CAV lesions. Lastly, expression of heme-oxygenase-1 and biliverdin reductases in graft-infiltrating macrophages as well as presence of Fe2+ ion in the media of arteries with hyperplasia further supported the implication of heme catabolism in CAV. Collectively, our findings suggest a key role for bilirubin in CAV. The enrichment of PC clones reactive to this metabolite within graft infiltrates indicates that it acts as a prominent target of local antibody responses.

2025-10-26 | GSE293483 | GEO

Panicum hallii cultivar:GIL.13.G

Project description:Panicum hallii GIL.13.G Transcriptome - GIL.13.G3.L_Illumina

| PRJNA1362271 | ENA