Dataset Information

Long-term Persistence of Allosensitization After Islet Allograft Failure.

ABSTRACT:

Background

Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown.

Methods

We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured yearly for the duration of graft function within 1 y after graft failure at enrollment and yearly thereafter.

Results

In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 y postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow-up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7-15 y. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88%-98%) and DSA positivity persisted for 15 y in 75% (3/4) of subjects.

Conclusions

Allosensitization was minimal while subjects remained on immunosuppression, but after discontinuation of immunosuppressive therapy, the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 y. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting list times for identification of a suitable donor in the case of requiring a subsequent transplant.

SUBMITTER: Rios P

PROVIDER: S-EPMC8289921 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Long-term Persistence of Allosensitization After Islet Allograft Failure.

Rios Paola P Baidal David D Lemos Joana J Camhi Stephanie S SS Infante Marco M Padilla Nathalia N Alvarez Gil Ana M AM Fuenmayor Virginia V Ambut Jonathan J Qasmi Fatima A FA Mantero Alejandro M AM Cayetano Shari Messinger SM Ruiz Phillip P Ricordi Camillo C Alejandro Rodolfo R

Transplantation 20211101 11

<h4>Background</h4>Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown.<h4>Methods</h4>We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured year ...[more]

PMID: 33481552

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Project description:UnlabelledLong-term persistence with anti-osteoporosis drugs and determinants for discontinuation among fracture patients were examined. Persistence was 75.0 and 45.3 % after 1 and 5 years, respectively. Those aged ≥80 years were at increased risk of early discontinuation. Within 1 year after discontinuation, 24.3 % restarted therapy, yet 47.0 % persisted for 1 year.IntroductionThe risk of osteoporotic fracture can effectively be reduced with use of anti-osteoporosis drugs. However, little is known about persistence with these drugs after fracture where subsequent fracture risk is high. The aims were to determine long-term persistence with anti-osteoporosis drugs among fracture patients, including its determinants, and to describe restart and subsequent persistence.MethodsA cohort study was conducted within the Dutch PHARMO Database Network. Patients aged ≥50 years (n = 961) who received anti-osteoporosis drugs within 1 year after fracture, but not in the preceding year, were included (2002-2011). Persistence (defined as the proportion on treatment) and the proportion restarting after discontinuation were estimated using Kaplan-Meier analyses. Time-dependent Cox regression was used to identify determinants of non-persistence including age, sex, initial dosage regime, fracture type, comorbidities, and drug use.ResultsPersistence with anti-osteoporosis drugs was 75.0 % (95 % confidence interval (CI) 72.0-77.7) and 45.3 % (95 % CI 40.4-50.0) after 1 and 5 years, respectively. A significant determinant of non-persistence was age ≥80 years (reference 50-59 years: adjusted hazard ratio [adj. HR] 1.65; 95 % CI 1.15-2.38). This effect was not constant over time (≤360 days following initiation: adj. HR 2.07; 95 % CI 1.27-3.37; >360 days: adj. HR 1.08; 95 % CI 0.62-1.88). Within 1 year after discontinuation, 24.3 % (95 % CI 20.1-29.2) restarted therapy, yet 47.0 % persisted for 1 year.ConclusionsThis study identified suboptimal persistence with anti-osteoporosis drugs among fracture patients. Major target groups for measures aimed to improve persistence may be those aged >80 years and those restarting therapy.

Project description:Acute and chronic rejection continue to represent serious challenges in transplant medicine. Current medical regimens focus on suppressing T-cell responses, lack effectiveness for some patients and impose significant risks of infection and malignancy. Recent studies have suggested that inhibition of co-stimulation pathways between antigen presenting cells (dendritic cells, macrophages, B-cells) and T-cells may serve as an effective strategy to prevent rejection by promoting allograft tolerance as opposed to simply suppressing immune responses. This concept has garnered excitement across the transplant community and demonstrated promising results in human renal transplant studies. A commonly used approach is inhibition of B7-CD28 and CD40-CD40L costimulatory pathways. Blocking these pathways leads to prolonged allograft survival in fully HLA-mismatched mouse heart transplantation models and non-human primates. There are important gaps in knowledge pertaining to mechanisms by which co-stimulation blockade modulates the recipient immune responses and confers donor organ tolerance. The precise immune cell populations and mechanisms responsible for induction and maintenance of donor organ tolerance remain incompletely understood. We have leveraged single cell RNA sequencing to dissect how traditional immunosuppression (cyclosporine) and co-stimulation blockade (CTLA-4 Ig, anti-CD40L neutralizing antibodies) differentially impact the immune landscape of the transplanted heart using a fully HLA-mismatched mouse model (Balb/c donor heart à B6 recipient). Analysis of these datasets demonstrated striking differences between these treatment regimens. Mice that received co-stimulation blockade displayed a marked increase in the abundance of classical dendritic cells (cDC1s and cDC2s). Compared to the cyclosporine treated group, these cells expressed negative regulators of T-cell stimulation including PDL1. Using recipient mice that lack either cDC1s or cDC2s, we found that cDC1s are absolutely required for co-stimulation blockade to confer long-term allograft survival and prevent recipient immune responses against the transplanted donor heart.

Dataset Information

Long-term Persistence of Allosensitization After Islet Allograft Failure.

Background

Methods

Results

Conclusions

Publications

Long-term Persistence of Allosensitization After Islet Allograft Failure.

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