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Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

ABSTRACT: Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte-derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand-1 (PD-L1):CD86 ratios, high IL-10/no IL-12 productivity and poor ability to stimulate allogeneic T cell proliferation. Target DCreg doses (range 2.5-10 × 10⁶ cells/kg) were achieved in all but 1 of 15 recipients, with no infusion reactions. Following DCreg infusion, transiently elevated levels of donor HLA and immunoregulatory PD-L1, CD39, and CD73 were detected in circulating small extracellular vesicles. At the same time, flow and advanced image stream analysis revealed intact DCreg and "cross-dressing" of host DCs in blood and lymph nodes. PD-L1 co-localization with donor HLA was observed at higher levels than with recipient HLA. Between DCreg infusion and transplantation, T-bet^hi Eomes^hi memory CD8⁺ T cells decreased, whereas regulatory (CD25^hi CD127^- Foxp3⁺ ): T-bet^hi Eomes^hi CD8⁺ T cell ratios increased. Thus, donor-derived DCreg infusion may induce systemic changes in host antigen-presenting cells and T cells potentially conducive to modulated anti-donor immune reactivity at the time of transplant.

SUBMITTER: Macedo C

PROVIDER: S-EPMC8215622 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

Macedo Camila C Tran Lillian M LM Zahorchak Alan F AF Dai Helong H Gu Xinyan X Ravichandran Ranjithkumar R Mohanakumar Thalachallour T Elinoff Beth B Zeevi Adriana A Styn Mindi A MA Humar Abhinav A Lakkis Fadi G FG Metes Diana M DM Thomson Angus W AW

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20201223 7

Regulatory dendritic cells (DCreg) promote transplant tolerance following their adoptive transfer in experimental animals. We investigated the feasibility, safety, fate, and impact on host T cells of donor monocyte-derived DCreg infused into prospective, living donor liver transplant patients, 7 days before transplantation. The DCreg expressed a tolerogenic gene transcriptional profile, high cell surface programed death ligand-1 (PD-L1):CD86 ratios, high IL-10/no IL-12 productivity and poor abil ...[more]

PMID: 33171019

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Project description:Acute graft versus host disease (GVHD) remains a significant complication following hematopoietic stem cell transplant (HSCT), despite improved human leukocyte antigen (HLA) matching and advances in prophylactic treatment regimens. Previous studies have shown promising results for future regulatory dendritic cell (DCreg) therapies in the amelioration of GVHD. This study evaluates the effects of cryopreservation on the generation of DCreg, the generation of young and older DCreg in serum-free media, and the feasibility of generating DCreg from young and older HSCT patient monocytes. DCregs were generated in X-vivo 15 serum-free media from donor or patient monocytes. This study includes the use of monocytes from young and older healthy, donor, and HSCT patients with varying hematological diseases. Phenotypic differences in cell populations were assessed via flow cytometry while pro-inflammatory and anti-inflammatory cytokine production was evaluated in culture medium. The number of DCreg generated from cryopreserved monocytes of healthy donors was not significantly different from freshly isolated monocytes. DCreg generated from cryopreserved monocytes had comparable levels of co-stimulatory molecule expression, inhibitory molecule expression, and cytokine production as freshly isolated monocytes. Young and older healthy donor monocytes generated similar numbers of DCreg with similar cytokine production and phenotype. Although monocytes from older HSCT patients generated significantly fewer DCreg, DCreg from young and older HSCT patients had comparable phenotypes and cytokine production. Monocytes from young and older myelodysplastic syndrome (MDS) patients generated reduced numbers of DCreg compared to non-MDS-derived DCreg. We demonstrate that the cryopreservation of monocytes from HSCT patients of varying hematological diseases allows for the cost-effective generation of DCreg on an as-needed basis. Although the generation of DCreg from MDS patients requires further assessment, these data support the possibility of in vitro-generated DCreg as a therapy to reduce GVHD-associated morbidity and mortality in young and older HSCT recipients.

Project description:BackgroundLong-term kidney transplant survival at the population level is consistently favorable, but this survival varies widely at an individual level due to both recipient and donor factors. The distinct contribution of recipient and donor factors to individual post kidney transplant outcome remains unclear. Comparing outcomes in deceased donor (DD) recipients with potential but non-actualized living donors (DD1) to those recipients with actualized living donors (LD), and to DD recipients without potential living donors (DD0) may provide transplant candidates with more information about their own post-transplant prognosis.MethodsWe conducted an observational retrospective cohort study of kidney transplant candidates presenting to our centre for evaluation between 01/01/06 and 31/12/18, and who also received a transplant during that time. Patients were followed to 31/08/2019. Candidates were classified as DD0, DD1, or LD based on whether they had an identified living donor at the time of initial pre-transplant assessment, and if the donor actualized or not. Primary outcome was 5-year death-censored graft survival, adjusted for common pre- and post-transplant donor and recipient risk factors. Secondary outcomes analyzed included patient survival and graft function.ResultsThere were 453 kidney transplant recipients (LD = 136, DD1 = 83, DD0 = 234) who received a transplant during the study period. DD0 and DD1 did not differ in key donor organ characteristics. The 5-year death censored graft survival of DD1 was similar to LD (p = 0.19). DD0 graft survival was inferior to LD (p = 0.005), but also trended inferior to DD1 (p = 0.052). By multivariate Cox regression analysis, LD demonstrated similar 5-year graft survival to DD1 (HR for graft loss 0.8 [95% CI 0.25-2.6], p = 0.72) but LD graft survival was superior to DD0 (HR 0.34 [0.16-0.72], p = 0.005). The 5-year patient survival in DD1 was similar to LD (p = 0.26) but was superior to DD0 (p = 0.01).ConclusionsDD recipients with potential but non-actualized living donors exhibit similar mid-term graft and patient survival compared to LD recipients. Having an identified living donor at the time of pre-transplant assessment portends a favorable prognosis for the recipient.

Project description:BackgroundThe optimal timing of dialysis access placement in individuals with stage 5 CKD is challenging to estimate. Preemptive living donor kidney transplant (LDKT) is the gold-standard treatment for ESKD due to superior graft survival and mortality, but dialysis initiation is often required. Among LDKT recipients, we sought to determine which clinical characteristics were associated with preemptive transplant. Among non-preemptive LDKT recipients, we sought to determine what dialysis access was used, and their duration of use before receipt of living donor transplant.MethodsWe retrospectively extracted data on 569 LDKT recipients, >18 years old, who were transplanted between January 2014 and July 2019 at UCSF, including dialysis access type (arteriovenous fistula [AVF], arteriovenous graft [AVG], peritoneal dialysis catheter [PD], and venous catheter), duration of dialysis, and clinical characteristics.ResultsPreemptive LDKT recipients constituted 30% of our cohort and were older, more likely to be White, more likely to have ESKD from polycystic kidney disease, and less likely to have ESKD from type 2 diabetes. Of the non-preemptive patients, 26% used AVF, 0.5% used AVG, 32% used peritoneal catheter, 11% used venous catheter, and 31% used more than one access type. Median (IQR) time on dialysis for AVF/AVG use was 1.86 (0.85-3.32) years; for PD catheters, 1.12 (0.55-1.92) years; for venous catheters, 0.66 (0.23-1.69) years; and for multimodal access, 2.15 (1.37-3.72) years.ConclusionsWe characterized the dialysis access landscape in LDKT recipients. Venous catheter and PD were the most popular modality in the first quartile of dialysis, and patients using these modalities had shorter times on dialysis compared with those with an AVF. Venous catheter or PD can be considered a viable bridge therapy in patients with living donor availability given their shorter waitlist times. Earlier referral of patients with living donor prospects might further minimize dialysis need.

Project description:Background: The induction of donor-specific immunological tolerance could improve outcome after kidney transplantation. However, no tolerance protocol is available for routine clinical use. Chimerism-based regimens hold promise, but their widespread application is impeded in part by unresolved safety issues. This study tests the hypothesis that therapy with polyclonal recipient regulatory T cells (Tregs) and anti-IL6R (tocilizumab) leads to transient chimerism and achieves pro-tolerogenic immunomodulation in kidney transplant recipients also receiving donor bone marrow (BM) without myelosuppressive conditioning of the recipient. Methods/design: A prospective, open-label, controlled, single-center, phase I/IIa academic study is performed in HLA-mismatched living donor kidney transplant recipients. Study group: Recipients of the study group receive in vitro expanded recipient Tregs and a donor bone marrow cell infusion within 3 days after transplantation and tocilizumab for the first 3 weeks post-transplant. In addition they are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Starting 6 months post-transplant, sirolimus and steroids are withdrawn in a step-wise manner in stable patients. Control group: Recipients of the control group are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Co-primary endpoints of safety (impaired graft function [eGFR <35 mL/min/1.73 m2], graft-vs.-host disease or patient death by 12 months) and efficacy (total leukocyte donor chimerism within 28 days post-transplant) are assessed. Secondary endpoints include frequency of biopsy-proven acute rejection episodes and subclinical rejection episodes on surveillance biopsies, assessment of kidney graft function, and the evaluation whether the study protocol leads to detectable changes in the immune system indicative of pro-tolerogenic immune modulation. Discussion: The results of this trial will provide evidence whether treatment with recipient Tregs and donor BM is feasible, safe and efficacious in leading to transient chimerism. If successful, this combination cell therapy has the potential to become a novel treatment option for immunomodulation in organ transplantation without the toxicities associated with myelosuppressive recipient conditioning. Trial registration: European Clinical Trials Database EudraCT Nr 2018-003142-16 and clinicaltrials.gov NCT03867617.

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Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

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Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients.

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