Dataset Information

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients.

ABSTRACT:

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.

SUBMITTER: Morath C

PROVIDER: S-EPMC10101591 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients.

Morath Christian C Schaier Matthias M Ibrahim Eman E Wang Lei L Kleist Christian C Opelz Gerhard G Süsal Caner C Ponath Gerald G Aly Mostafa M Alvarez Cristiam M CM Kälble Florian F Speer Claudius C Benning Louise L Nusshag Christian C Pego da Silva Luiza L Sommerer Claudia C Hückelhoven-Krauss Angela A Czock David D Mehrabi Arianeb A Schwab Constantin C Waldherr Rüdiger R Schnitzler Paul P Merle Uta U Tran Thuong Hien TH Scherer Sabine S Böhmig Georg A GA Müller-Tidow Carsten C Reiser Jochen J Zeier Martin M Schmitt Michael M Terness Peter P Schmitt Anita A Daniel Volker V

Journal of the American Society of Nephrology : JASN 20220922 1

<h4>Background</h4>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.<h4>Methods</h4>Ten patients from a phase 1 clinical trial who had received MIC infusions before kid ...[more]

PMID: 36137752

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Project description:Background: FoxP3+ follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue. Methods: To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in n = 211 kidney transplant recipients. At the time of measurement patients were 5-7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4-7 years). Age and gender matched healthy individuals served as controls. Results: While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients (p < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between cTfr and cTfh cells. This shifted balance was observed for both non-rejectors and rejectors. Previous pulse methylprednisolone or combined pulse methylprednisolone + intravenous immunoglobulin anti-rejection therapy led to a non-significant 30.6% (median) and 51.2% (median) drop in cTfr cells, respectively when compared to cTfr cell numbers in transplant patients who did not receive anti-rejection therapy. A history of alemtuzumab therapy did lead to a significant decrease in cTfr cells of 85.8% (median) compared with patients not treated with anti-rejection therapy (p < 0.0001). No association with tacrolimus or MMF pre-dose concentrations was found. Conclusion: This cross-sectional study reveals that anti-rejection therapy with alemtuzumab significantly lowers the number of cTfr cells in kidney transplant recipients. The observed profound effects by these agents might dysregulate cTfr functions.

Project description:Survival of solid organ grafts depends on life-long immunosuppression, which results in increased rates of infection and malignancy. Induction of tolerance to allografts would represent the optimal solution for controlling both chronic rejection (CR) and side effects of immunosuppression. Although spontaneous ‘‘operational tolerance’’ can occur in human kidney transplantation, the lack of noninvasive peripheral blood biological markers of this rare phenomenon precludes the identification of potentially tolerant patients in whom immunosuppression could be tapered as well as the development of new tolerance inducing strategies. Here, the potential of high throughput microarray technology to decipher complex pathologies allowed us to study the peripheral blood specific gene expression profile and corresponding EASE molecular pathways associated to operational tolerance in a cohort of human kidney graft recipients. In comparison with patients with CR, tolerant patients displayed a set of 343 differentially expressed genes, mainly immune and defense genes, in their peripheral blood mononuclear cells (PBMC), of which 223 were also different from healthy volunteers. Using the expression pattern of these 343 genes, we were able to classify correctly >80% of the patients in a cross-validation experiment and classified correctly all of the samples over time. Collectively, this study identifies a unique PBMC gene signature associated with human operational tolerance in kidney transplantation. 250 samples were analyzed, replicates included: some patients from the TOL and CR groups were sampled twice with an interval between the two different time points of at least 16 months (mean 25.8 months, range 16–31 months). All the samples were analyzed in duplicate or quadruplicate. 1. TOL (n = 21). patients with stable graft function (blood creatinemia<150 mmol/L, proteinuria<1 g/24 h) for at least 1 year (mean 6.4 years,range 1.6–17.2 years) after complete interruption of immunosuppressive therapy. 2. STA (n = 190). Patients with stable kidney graft function under immunosuppressive therapy. 3. CR (n = 31). Patients having a progressive degradation of their renal function (blood creatinemia ≥150 mmol/L, proteinuria ≥1 g/24 h). CR was diagnosed on a graft biopsy according to the updated Banff criteria. CR was defined by histological signs of chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell infiltration) and/or transplant glomerulopathy with glomerular double contours. 4. HV (n = 8). Subjects having normal blood formulae and no infectious or other concomitant pathology for at least 6 months before the study.

Dataset Information

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients.

Background

Methods

Results

Conclusions

Clinical trial registry name and registration number

Publications

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients.

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