Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial

Viklický, Ondřej; Hrubá, Petra; Tomiuk, Stefan; Schmitz, Sarah; Gerstmayer, Bernhard; Sawitzki, Birgit; Miqueu, Patrick; Mrázová, Petra; Tycova, Irena; Svobodová, Eva; Honsová, Eva; Janßen, Uwe; Volk, Hans‐Dieter; Reinke, Petra

doi:10.1371/journal.pone.0169624

Cited by 11 publications

(6 citation statements)

References 48 publications

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“…In the field of transplantation, there is an emerging interest in enhancing the suppressor immune response as an alternative strategy to reach a clinical tolerogenic state and preserve long‐term graft function . The immunosuppressive action of rapamycin has been already described in different mouse models of transplantation and, in this study, we have characterized the immunomodulatory effects of PI‐103 and PKI‐587 in T‐cells in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 92%

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

et al. 2017

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The PI3K/mTOR signaling cascade is fundamental in T-cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T-cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T-cell activities. Substantial adverse effects in long-term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T-cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI-103 and PKI-587 inhibitors interfered IL-2-dependent responses in T-cells. However, in contrast to the inhibitory effects in non-Treg T-cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI-103, and PKI-587 targeted different signaling events and induced different metabolic patterns in primary T-cells. Similar to rapamycin, in vivo administration of PI-103 and PKI-587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T-cells and support their potential as a novel therapeutic option in transplantation.

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Section: Discussionmentioning

confidence: 92%

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

et al. 2017

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“…Beyond pilot analyses conveyed only in abstract form, the Berlin group performed a small trial to test the safety and efficacy of an immunosuppressive regimen that included alemtuzumab induction and day 2 post-transplant IFX to minimize immunosuppression. 41 The results suggested that the combined therapy permitted long-term graft survival in five patients treated with maintenance TAC monotherapy. Although intriguing, the small size and study design were insufficient to determine efficacy of the IFX therapy within the entire study regimen.…”

Section: Discussionmentioning

confidence: 93%

Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial

Hricik

Alhamad

Brennan

et al. 2022

JASN

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Background: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates tumor necrosis factor alpha (TNF) production that amplifies allograft inflammation and may negatively impact transplant outcomes. Methods: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase II clinical trial. Two-hundred twenty-five primary transplant recipients of deceased-donor kidneys (KTx) (38.2% Black/African-American, 44% White) were randomized to receive i.v. infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated prior to \ kidney reperfusion. All subjects received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary endpoint was the difference between groups in mean 24-month estimated glomerular filtration rate (eGFR). Results: There was no difference in the primary endpoint, 24-mo eGFR between IFX (52.45 ml/min/1.73m2, 95% CI 48.38-56.52) vs. PLBO (57.35 ml/min/1.73m2, 95% CI 53.18-61.52, p=0.099). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ and day 7 post-KTx plasma analyses showed ~10-fold lower TNF (p<0.001) in IFX vs. PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) vs. PLBO (13.4% p=0.004) with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) vs. PLBO (4.9%, p=0.06). Conclusions: IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peri-transplant inflammation as a strategy to improve KTx outcomes.

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“…described a patient who was diagnosed with acute rejection weeks after having stopped all his medication, despite favourable CTL results . Nevertheless, several longitudinal studies support the idea that the assessment of direct T cell responses by CTL‐derived or IFN‐γ ELISPOT methods might be a valuable tool in predicting limited uneventful drug tapering, either from steroids , anti‐metabolite or calcineurin inhibitors .…”

Section: Biomarkers: Somewhere Between Hope and Realitymentioning

confidence: 99%

Operational tolerance in kidney transplantation and associated biomarkers

Massart

Ghisdal

Abramowicz

et al. 2017

Clinical and Experimental Immunology

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SummaryIn the 1960s, our predecessors won a historical battle against acute rejection and ensured that transplantation became a common life-saving treatment. In parallel with this success, or perhaps because of it, we lost the battle for long-lived transplants, being overwhelmed with chronic immune insults and the toxicities of immunosuppression. It is likely that current powerful treatments block acute rejection, but at the same time condemn the few circulating donor cells that would have been able to elicit immunoregulatory host responses towards the allograft. Under these conditions, spontaneously tolerant kidney recipients -i.e. patients who maintain allograft function in the absence of immunosuppression -are merely accidents; they are scarce, mysterious and precious. Several teams pursue the goal of finding a biomarker that would guide us towards the 'just right' level of immunosuppression that avoids rejection while leaving some space for donor immune cells. Some cellular assays are attractive because they are antigen-specific, and provide a comprehensive view of immune responses toward the graft. These seem to closely follow patient regulatory capacities. However, these tests are cumbersome, and require abundant cellular material from both donor and recipient. The latest newcomers, nonantigen-specific recipient blood transcriptomic biomarkers, offer the promise that a practicable and simple signature may be found that overcomes the complexity of a system in which an infinite number of individual cell combinations can lead possibly to graft acceptance. Biomarker studies are as much an objective -identifying tolerant patients, enabling tolerance trials -as a means to deciphering the underlying mechanisms of one of the most important current issues in transplantation.

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Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial

Cited by 11 publications

References 48 publications

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial

Operational tolerance in kidney transplantation and associated biomarkers

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