Immunosuppressive properties of mitomycin C-incubated human myeloid blood cells (MIC) in vitro

Dittmar, Laura; Mohr, Elisabeth; Kleist, Christian; Ehser, Sandra; Demirdizen, Haydar; Șandra-Petrescu, Flavius; Hundemer, Michael; Opelz, Gerhard; Terness, Peter

doi:10.1016/j.humimm.2015.06.008

Cited by 10 publications

(12 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These patients also showed strong Breg induction with concomitant IL-10 production as well as evidence of an immune tolerance signature according to the definition of the Immune Tolerance Network. Taken together with the results obtained in our previous experimental studies, these data support the idea that donor-specific immunosuppression is induced by MIC treatment (10)(11)(12). It is interesting that common infections, like upper respiratory tract infection or UTI, triggered a transient donor-specific responsiveness that disappeared again after resolution of the infection.…”

Section: Resultssupporting

confidence: 87%

“…When monocytes were treated with the alkylating agent mitomycin C and then matured to DCs, the resulting cells showed the morphology and phenotype of early immature DCs and strongly suppressed the T cell response. FACS analysis revealed low expression of stimulatory molecules such as CD80, CD83, CD86, and HLA class II histocompatibility antigen γ chain (HLA-DR) (12). When injected into the prospective experimental graft recipient, donor-derived MICs preferentially accumulated in peripheral lymphoid organs and induced regulatory lymphocytes (10).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Morath¹,

Schmitt²,

Kleist³

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

BACKGROUND.Preclinical experiments have shown that donor blood cells, modified in vitro by an alkylating agent (modified immune cells [MICs]), induced long-term specific immunosuppression against the allogeneic donor. METHODS.In this phase I trial, patients received either 1.5 × 10 6 MICs per kg BW on day -2 (n = 3, group A), or 1.5 × 10 8 MICs per kg BW on day -2 (n = 3, group B) or day -7 (n = 4, group C) before living donor kidney transplantation in addition to posttransplantation immunosuppression. The primary outcome measure was the frequency of adverse events (AEs) until day 30 (study phase) with follow-up out to day 360. RESULTS. MIC infusions were extremely well tolerated. During the study phase, 10 treated patients experienced a total of 69 AEs that were unlikely to be related or not related to MIC infusion. No donor-specific human leukocyte antigen Abs or rejection episodes were noted, even though the patients received up to 1.3 × 10 10 donor mononuclear cells before transplantation. Group C patients with low immunosuppression during follow-up showed no in vitro reactivity against stimulatory donor blood cells on day 360, whereas reactivity against third-party cells was still preserved. Frequencies of CD19 + CD24 hi CD38 hi transitional B lymphocytes (Bregs) increased from a median of 6% before MIC infusion to 20% on day 180, which was 19-and 68-fold higher, respectively, than in 2 independent cohorts of transplanted controls. The majority of Bregs produced the immunosuppressive cytokine IL-10. MIC-treated patients showed the Immune Tolerance Network operational tolerance signature. CONCLUSION. MIC administration was safe and could be a future tool for the targeted induction of tolerogenic Bregs.

show abstract

Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Morath¹,

Schmitt²,

Kleist³

et al. 2020

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…Preclinical studies have demonstrated that monocytes, when treated with mitomycin C and matured into DCs, take on the morphology and phenotype of early immature DCs. This MIC population could strongly suppress T‐cell responses and induce donor‐specific immunosuppression in experimental models [87,88]. Kidney transplant recipients were infused with donor‐derived MIC pretransplant, and a control group retrospectively selected to match maintenance regimens.…”

Section: Introductionmentioning

confidence: 99%

Regulatory B cells in transplantation: roadmaps to clinic

et al. 2020

View full text Add to dashboard Cite

Over the last two decades, an additional and important role for B cells has been established in immune regulation. Preclinical studies demonstrate that regulatory B cells (Breg) can prolong allograft survival in animal models and induce regulatory T cells. Operationally tolerant human kidney transplant recipients demonstrate B-cell-associated gene signatures of immune tolerance, and novel therapeutic agents can induce Bregs in phase I clinical trials in transplantation. Our rapidly expanding appreciation of this novel B-cell subtype has made the road to clinical application a reality. Here, we outline several translational pathways by which Bregs could soon be introduced to the transplant clinic.

show abstract

“…MIC are donor-derived peripheral blood mononuclear cells (PBMC) that are treated ex vivo by an alkylating agent. This results in a cellular phenotype that is directly and indirectly suppressive to the immune system 5–10. Transferred in the living kidney transplantation model, PBMC are taken from the kidney donor by unstimulated leukapheresis 7 days before surgery.…”

Section: Introductionmentioning

confidence: 99%

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

Morath

Schmitt

et al. 2022

BMJ Open

Self Cite

View full text Add to dashboard Cite

IntroductionDonor-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 analysisSixty-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 disseminationEthical 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 numberNCT05365672.

show abstract

Immunosuppressive properties of mitomycin C-incubated human myeloid blood cells (MIC) in vitro

Cited by 10 publications

References 33 publications

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation

Regulatory B cells in transplantation: roadmaps to clinic

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

Contact Info

Product

Resources

About