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  • 1
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    DataSheet_1.pdf
    Frontiers Media SA ; 2023
    In:  Frontiers in Immunology Vol. 14 ( 2023-7-11)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-7-11)
    Abstract: The administration of modified immune cells (MIC) before kidney transplantation led to specific immunosuppression against the allogeneic donor and a significant increase in regulatory B lymphocytes. We wondered how this approach affected the continued clinical course of these patients. Methods Ten patients from a phase I clinical trial who had received MIC infusions prior to kidney transplantation were retrospectively compared to 15 matched standard-risk recipients. Follow-up was until year five after surgery. Results The 10 MIC patients had an excellent clinical course with stable kidney graft function, no donor-specific human leukocyte antigen antibodies (DSA) or acute rejections, and no opportunistic infections. In comparison, a retrospectively matched control group receiving standard immunosuppressive therapy had a higher frequency of DSA (log rank P = 0.046) and more opportunistic infections (log rank P = 0.033). Importantly, MIC patients, and in particular the four patients who had received the highest cell number 7 days before surgery and received low immunosuppression during follow-up, continued to show a lack of anti-donor T lymphocyte reactivity in vitro and high CD19 + CD24 hi CD38 hi transitional and CD19 + CD24 hi CD27 + memory B lymphocytes until year five after surgery. Conclusions MIC infusions together with reduced conventional immunosuppression were associated with good graft function during five years of follow-up, no de novo DSA development and no opportunistic infections. In the future, MIC infusions might contribute to graft protection while reducing the side effects of immunosuppressive therapy. However, this approach needs further validation in direct comparison with prospective controls. Trial registration https://clinicaltrials.gov/ , identifier NCT02560220 (for the TOL-1 Study). EudraCT Number: 2014-002086-30.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2023.1089664
    DOI: 10.3389/fimmu.2023.1089664.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606827-8
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  • 2
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    Online Resource
    Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Society of Nephrology Vol. 34, No. 1 ( 2023-01), p. 160-174
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 1 ( 2023-01), p. 160-174
    Abstract: In previous work, the authors demonstrated that kidney transplant recipients developed donor-specific unresponsiveness when they were given a pretransplant infusion of modified donor-derived PBMCs. In this study, they provide evidence that the immunosuppressive properties of these cells persist and the donor-specific unresponsiveness is long-lasting. In the four patients who received the highest dose of the modified immune cells, administration of these cells was associated with a striking increase in IL-10–producing regulatory B lymphocytes and evidence of the consensus gene expression signature of operational tolerance. In vitro , donor-specific unresponsiveness was abolished after B lymphocyte depletion, suggesting a direct pathophysiologic role for regulatory B lymphocytes. These findings support the notion that modified donor-derived PBMCs may be useful in kidney transplantation, but this approach requires further validation and rigorous controlled randomized studies. Background We recently demonstrated that donor-derived modified immune cells (MICs)—PBMCs that acquire immunosuppressive properties after a brief treatment—induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls. Methods Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080. Results Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P 〈 0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness. Conclusions These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants. Clinical Trial registry name and registration number: MIC Cell Therapy for Individualized Immunosuppression in Living Donor Kidney Transplant Recipients (TOL-1), NCT02560220
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2022020210
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2029124-3
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  • 3
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    Phase I trial of donor-derived modified immune cell infusion in kidney transplantation
    American Society for Clinical Investigation ; 2020
    In:  Journal of Clinical Investigation Vol. 130, No. 5 ( 2020-4-6), p. 2364-2376
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 130, No. 5 ( 2020-4-6), p. 2364-2376
    Type of Medium: Online Resource
    ISSN: 0021-9738 , 1558-8238
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1172/JCI133595
    DOI: 10.1172/JCI133595DS1
    DOI: 10.1172/JCI133595DS2
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2020
    detail.hit.zdb_id: 2018375-6
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  • 4
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    Individualised immunosuppression with intravenously administered donor-derived modified immune cells compared with standard of care in living donor kidney transplantation (TOL-2 Study): protocol for a multicentre, open-label, phase II, randomised controlled trial
    BMJ ; 2022
    In:  BMJ Open Vol. 12, No. 11 ( 2022-11), p. e066128-
    Details
    In: BMJ Open, BMJ, Vol. 12, No. 11 ( 2022-11), p. e066128-
    Abstract: Donor-derived modified immune cells (MIC) induced long-term specific immunosuppression against the allogeneic donor in preclinical models of transplantation. In a phase I clinical trial (TOL-1 Study), MIC treatment resulted in a cellular phenotype that was directly and indirectly suppressive to the recipient’s immune system allowing for reduction of conventional immunosuppressive therapy. Here, we describe a protocol for a randomised controlled, multicentre phase-IIb clinical trial of individualised immunosuppression with intravenously administered donor MIC compared with standard-of-care (SoC) in living donor kidney transplantation (TOL-2 Study). Methods and analysis Sixty-three living donor kidney transplant recipients from six German transplant centres are randomised 2:1 to treatment with MIC (MIC group, N=42) or no treatment with MIC (control arm, N=21). MIC are manufactured from donor peripheral blood mononuclear cells under Good Manufacturing Practice conditions. The primary objective of this trial is to determine the efficacy of MIC treatment together with reduced conventional immunosuppressive therapy in terms of achieving an operational tolerance-like phenotype compared with SoC 12 months after MIC administration. Key secondary endpoints are the number of patient-relevant infections as well as a composite of biopsy-proven acute rejection, graft loss, graft dysfunction or death. Immunosuppressive therapy of MIC-treated patients is reduced during follow-up under an extended immunological monitoring including human leucocyte antigen-antibody testing, and determination of lymphocyte subsets, for example, regulatory B lymphocytes (Breg) and antidonor T cell response. A Data Safety Monitoring Board has been established to allow an independent assessment of safety and efficacy. Ethics and dissemination Ethical approval has been provided by the Ethics Committee of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (AFmu-580/2021, 17 March 2022) and from the Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institute, Langen, Germany (Vorlage-Nr. 4586/02, 21 March 2022). Written informed consent will be obtained from all patients and respective donors prior to enrolment in the study. The results from the TOL-2 Study will be published in peer-reviewed medical journals and will be presented at symposia and scientific meetings. Trial registration number NCT05365672 .
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1136/bmjopen-2022-066128
    DOI: 10.1136/bmjopen-2022-066128.supp1
    DOI: 10.1136/bmjopen-2022-066128.supp2
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2599832-8
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