Dataset Information

A Phase I Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants.

ABSTRACT: There is considerable interest in therapeutic transfer of regulatory T cells (Tregs) for controlling aberrant immune responses. Initial clinical trials have shown the safety of Tregs in hematopoietic stem cell transplant recipients and subjects with juvenile diabetes. Our hypothesis is that infusion(s) of Tregs may induce transplant tolerance thus avoiding long-term use of toxic immunosuppressive agents that cause increased morbidity/mortality. Towards testing our hypothesis, we conducted a phase I dose escalation safety trial infusing billions of ex vivo expanded recipient polyclonal Tregs into living donor kidney transplant recipients. Despite variability in recipient's renal disease, our expansion protocol produced Tregs which met all release criteria, expressing >98% CD4⁺CD25⁺ with <1% CD8⁺ and CD19⁺ contamination. Our product displayed >80% FOXP3 expression with stable demethylation in the FOXP3 promoter. Functionally, expanded Tregs potently suppressed allogeneic responses and induced the generation of new Tregs in the recipient's allo-responders in vitro. Within recipients, expanded Tregs amplified circulating Treg levels in a sustained manner. Clinically, all doses of Treg therapy tested were safe with no adverse infusion related side effects, infections or rejection events up to two years post-transplant. This study provides the necessary safety data to advance Treg cell therapy to phase II efficacy trials.

SUBMITTER: Mathew JM

PROVIDER: S-EPMC5943280 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A Phase I Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants.

Mathew James M JM H-Voss Jessica J LeFever Ann A Konieczna Iwona I Stratton Cheryl C He Jie J Huang Xuemei X Gallon Lorenzo L Skaro Anton A Ansari Mohammed Javeed MJ Leventhal Joseph R JR

Scientific reports 20180509 1

There is considerable interest in therapeutic transfer of regulatory T cells (Tregs) for controlling aberrant immune responses. Initial clinical trials have shown the safety of Tregs in hematopoietic stem cell transplant recipients and subjects with juvenile diabetes. Our hypothesis is that infusion(s) of Tregs may induce transplant tolerance thus avoiding long-term use of toxic immunosuppressive agents that cause increased morbidity/mortality. Towards testing our hypothesis, we conducted a phas ...[more]

PMID: 29743501

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Project description:ImportanceThe proportion of living donor kidney transplants from donors unrelated to their recipients is increasing in the US.ObjectiveTo examine the association between donor-recipient biological relationship and allograft survival after living donor kidney transplant.Design, setting, and participantsThis retrospective cohort study used Organ Procurement and Transplantation Network data on US adult living donor kidney transplants (n = 86 154) performed from January 1, 2000, to December 31, 2014, excluding cases in which recipients previously received a kidney transplant (n = 10 342) or key data were missing (n = 2832). Last follow-up was March 20, 2020.ExposuresDonor-recipient biological relationship.Main outcomes and measuresThe primary outcome was death-censored allograft failure. Univariate and multivariable time-to-event analyses were performed for death-censored allograft failure for the overall cohort, then separately for recipients with and without primary diagnoses of cystic kidney disease and for transplants from African American and non-African American donors.ResultsAmong the 72 980 transplant donor and recipients included in the study (median donor age, 41 years; interquartile range [IQR], 32-50 years; 43 990 [60%] female; 50 014 [69%] White), 43 174 (59%) donors and recipients were biologically related and 29 806 (41%) were unrelated. Donors related to their recipients were younger (median [IQR] age, 39 [31-48] vs 44 [35-52] years) and less likely to be female (24 848 [58%] vs 19 142 [64%]) or White (26 933 [62%] vs 23 081 [77%]). Recipients related to their donors were younger (median [IQR] age, 48 [34-58] vs 50 [40-58] years), more likely to be female (18 035 [42%] vs 10 530 [35%]), and less likely to have cystic kidney disease (2530 [6%] vs 4600 [15%]). Related pairs had fewer HLA mismatches overall (median [IQR], 3 [2-3] vs 5 [4-5]). After adjustment for HLA mismatches, donor and recipient characteristics, and transplant era, donor-recipient biological relationship was associated with higher death-censored allograft failure (hazard ratio, 1.05; 95% CI, 1.01-1.10; P = .03). When stratified by primary disease, this association persisted only for recipients without cystic kidney disease. When stratified by donor race, this association persisted only for transplants from African American donors.Conclusions and relevanceIn this cohort study, living donor kidney transplants from donors biologically related to their recipients had higher rates of allograft failure than transplants from donors unrelated to their recipients after HLA matching was accounted for. Further study is needed to determine which genetic or socioenvironmental factors are associated with this finding.

Project description:BACKGROUND:It is not common for people to come across a living kidney donor, let alone consider whether they would ever donate a kidney themselves while they are alive. Narrative storytelling, the sharing of first-person narratives based on lived experience, may be an important way to improve education about living donor kidney transplants (LDKTs). Developing ways to easily standardize and disseminate diverse living donor stories using digital technology could inspire more people to consider becoming living donors and reduce the kidney shortage nationally. OBJECTIVE:This paper aimed to describe the development of the Living Donation Storytelling Project, a web-based digital library of living donation narratives from multiple audiences using video capture technology. Specifically, we aimed to describe the theoretical foundation and development of the library, a protocol to capture diverse storytellers, the characteristics and experiences of participating storytellers, and the frequency with which any ethical concerns about the content being shared emerged. METHODS:This study invited kidney transplant recipients who had received LDKTs, living donors, family members, and patients seeking LDKTs to record personal stories using video capture technology by answering a series of guided prompts on their computer or smartphone and answering questions about their filming experience. The digital software automatically spliced responses to open-ended prompts, creating a seamless story available for uploading to a web-based library and posting to social media. Each story was reviewed by a transplant professional for the disclosure of protected health information (PHI), pressuring others to donate, and medical inaccuracies. Disclosures were edited. RESULTS:This study recruited diverse storytellers through social media, support groups, churches, and transplant programs. Of the 137 storytellers who completed the postsurvey, 105/137 (76.6%) were white and 99/137 (72.2%) were female. They spent 62.5 min, on average, recording their story, with a final median story length of 10 min (00:46 seconds to 32:16 min). A total of 94.8% (130/137) of storytellers were motivated by a desire to educate the public; 78.1% (107/137) were motivated to help more people become living donors; and 75.9% (104/137) were motivated to dispel myths. The ease of using the technology and telling their story varied, with the fear of being on film, emotional difficulty talking about their experiences, and some technological barriers being reported. PHI, most commonly surnames and transplant center names, was present in 62.9% (85/135) of stories and was edited out. CONCLUSIONS:With appropriate sensitivity to ensure diverse recruitment, ethical review of content, and support for storytellers, web-based storytelling platforms may be a cost-effective and convenient way to further engage patients and increase the curiosity of the public in learning more about the possibility of becoming living donors.

Project description:Background and objectivesMany donors and recipients report an improved bond posttransplantation; however, unexpected conflicts and tension may also occur. Insights into the lived experiences of the donor-recipient relationship can inform strategies for interventions and support. We aimed to describe donor and recipient expectations and experiences of their relationship before and after living kidney donor transplantation.Design, setting and participantsSemistructured interviews were conducted with 16 donor-recipient pairs before the transplant and 11-14 months post-transplant. Transcripts were analysed thematically.ResultsWe identified seven themes (with respective subthemes): donation as enacting familial responsibility for care; analytical decision making to mitigate regret (avoiding anticipated regret and maintaining control, removing emotional impulsivity); strengthened interpersonal ties (gaining a deeper appreciation among family members, stronger empathy for each other, improving social participation); instability of relational impacts (anger and aggression threatening dynamics, unanticipated stress and emotional lability, triggering familial tension); renegotiating social roles (unexpected continuation of caregiving responsibilities, inability to relinquish the caregiving role, disappointment with unfulfilled renewal of intimacy, dissatisfaction over discrepant energy levels); guilt over unmet expectations and inevitability of the gift relationship (vague and transient indebtedness, expectation of reciprocity, transferring kidney ownership).ConclusionsDonor-recipient relationships may be improved through increased empathy, appreciation, and ability to participate in life together; however, unfulfilled expectations and behavioural and emotional changes in recipients (a side effect related to immunosuppression) remain unresolved consequences of living kidney donor transplantation. Education and counselling to help donors and recipients adjust to potential changes in relationship dynamics may help protect and foster relational stability postdonation.

Dataset Information

A Phase I Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants.

Publications

A Phase I Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants.

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