Cell therapeutic approaches to immunosuppression after clinical kidney transplantation

Morath, Christian; Schmitt, Anita; Kälble, Florian; Zeier, Martin; Schmitt, Michael; Șandra-Petrescu, Flavius; Opelz, Gerhard; Terness, Peter; Schaier, Matthias; Kleist, Christian

doi:10.1007/s00467-017-3599-2

Cited by 14 publications

(14 citation statements)

References 98 publications

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“…Cellular therapies are gaining increasing attention as an alternative to conventional drug therapy for the control of allograft rejection (3). Effective rejection prophylaxis in the absence of immunosuppressive drugs has been achieved by establishing durable hematopoietic chimerism through combined or sequential hematopoietic stem cell application in kidney transplantation (4)(5)(6)(7).…”

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

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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.

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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

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“…Mehanizmi periferne tolerancije uključuju deleciju aloreaktivnih limfocita T, indukciju stanja energije funkcionalnom inaktivacijom limfocita T i regulacijom ili supresijom limfocita T pomoću drugih stanica ili čimbenika. Istražuje se više strategija, primjerice blokadu kostimulacije i primjenu regulacijskih limfocita (Treg) specifičnih za donorske antigene 12,33 .…”

Section: Tolerancijaunclassified

Imunobiologija transplantacije bubrega i mehanizmi djelovanja imunosupresivnih lijekova

Živčić-Ćosić

Trobonjača

2020

Med. Flum. (Online)

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Imunosni sustav obuhvaća imunost koju čini nespecifični (prirođeni) imunosni odgovor i specifičnu (stečenu) imunost koja se adaptivno razvija protiv stranih antigena. Presađivanje alogeničnog AB0-podudarnog bubrega prvenstveno stimulira specifičan imunosni odgovor usmjeren na peptidne antigene koji se predočavaju na donorskim stanicama u okviru molekula kodiranih glavnim sustavom tkivne podudarnosti MHC. Imunosni odgovor započinje prepoznavanjem antigena od strane limfocita T, pri čemu je neophodno međudjelovanje T-staničnog receptora s peptidnim antigenima predočenim od antigen-predočnih stanica i kostimulacijskog receptora s ligandom na antigen-predočnim stanicama. Oba signala su neophodna za ulazak limfocita T u stanični ciklus, a nakon toga se unutarstaničnim prijenosom signala aktiviraju geni za proizvodnju i lučenje citokina. Aktivirani limfociti T, koji migriraju do presatka gdje induciraju akutni upalni odgovor, djeluju izravno citotoksično i potpomažu proizvodnju protutijela od strane limfocita B te odgovore odgođenog tipa preosjetljivosti inducirane makrofagima. Čimbenici ovisni i neovisni o aloantigenu pridonose efektorskim mehanizmima koji uzrokuju reakciju odbacivanja presatka. Značajan napredak na područjima imunobiologije i imunogenetike omogućio je sigurnije i uspješnije liječenje transplantacijom organa. Izuzetno je važno rano otkrivanje i sprječavanje reakcije odbacivanja presatka. Uz primjenu suvremenih imunosupresivnih lijekova rijetko se javlja teška reakcija odbacivanja posredovana limfocitima T. Najčešći uzrok gubitka funkcije presatka je kronična reakcija odbacivanja posredovana protutijelima koja su usmjerena na HLA antigene darovatelja. U radu prikazujemo mehanizme nastanka reakcije odbacivanja presatka posredovane stanicama i protutijelima, mjesta djelovanja imunosupresivnih lijekova te razvoj novijih strategija liječenja s ciljem daljnjeg poboljšanja preživljenja pacijenata i presatka.

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“…Предполагается, что Т-регуляторные клетки играют ключевую роль в поддержании иммунологической толерантности в трансплантации [22,23]. Также известно, что фотоферез стимулирует образование Т-регуляторных клеток, что, по мнению ряда авторов, может объяснить толерогеннный эффект данной процедуры [23,25]. Поэтому мы проанализировали данную субпопуляцию по маркерам CD3+CD4+CD25+(hi)CD127-в отдаленном периоде и обнаружили их достоверное увеличение у пациентов основной группы.…”

Section: Types Of Infectious Complications After Kidney Transplantatiunclassified

Of Photopheresis in Kidney Transplantation

Faenko

Зулькарнаев

Чуксина

et al. 2018

RJTAO

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Aim– to perform a comparative study of the long-term results of the combined use of extracorporeal photochemotherapy (photopheresis) and drug immunosuppression and standard immunosuppressive therapy in patients after kidney transplantation.Materials and methods. An open cohort randomized study was conducted, including 60 patients with chronic kidney disease stage 5D. All patients underwent single-group cadaveric kidney transplantation. Patients were randomly divided into two groups. All transplants were paired, the fi rst kidney transplant was received by the patient of the main group, the second – by comparison group. 30 patients of the main group received standard protocol of immunosuppression and 10–15 sessions of photopheresis during the fi rst six months after transplantation. All patients of the comparison group received standard immunosuppressive therapy only. End points: primary – graft loss, surrogate – the number of acute rejection episodes and infectious complications, the dynamics of creatinine blood concentration, the glomerular fi ltration rate and daily proteinuria, the dynamics of tacrolimus C0 blood concentration. To study the mechanism of photopheresis action in the late postoperative period, we evaluated the immunological parameters: subpopulation of naive T-cells (CD3+CD4+CD45RO–CD28+), the level of CD28 molecule expression (MFI) on these cells and also – subpopulation of T-regulatory cells (CD3+CD4+CD25 (Hi)CD127–).Results.The use of photopheresis leads to the graft function improvement in the late postoperative period: the creatinine concentration (p = 0.017) in the blood and daily proteinuria (p = 0.011) were lower in patients of the main group, the glomerular fi ltration rate was higher (p = 0.027). The incidence rate ratio (IRR) of rejection in the main group was signifi cantly lower than in the comparison group: 0.2509 (95% CI 0.05386, 0.9167), p = 0.0358. The risk of graft loss was also lower in the main group: IRR 0.2782 (95% CI 0.07562, 0.8657), p = 0.026, as well as the risk of infectious complications: IRR 0.3888 (95% CI 0.2754; 0, 5445), p < 0.0001. Survival rate of transplants was higher in the main group (Log Rank p = 0.009; Breslow p = 0.005). The use of photopheresis made it possible to reduce the concentration of tacrolimus in the late postoperative period (p = 0.0017) without increasing the risk of graft rejection. The photopheresis tolerogenic effect in the late postoperative period may be due to an increase in the population of T-regulatory cells with the CD3+CD4+CD25(Hi)+CD127– phenotype compared to the patients which received only standard immunosuppressive therapy (p = 0.024).Conclusion.The preventive use of photopheresis contributes to improvement of the kidney transplantation long-term outcomes. Further studies are needed to study the mechanisms of photopheresis action and markers of partial immunological tolerance to the allograft.

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Cell therapeutic approaches to immunosuppression after clinical kidney transplantation

Cited by 14 publications

References 98 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

Imunobiologija transplantacije bubrega i mehanizmi djelovanja imunosupresivnih lijekova

Of Photopheresis in Kidney Transplantation

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