Anti-Interleukin-6 Promotes Allogeneic Bone Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine Transplant Model

Granofszky, Nicolas; Farkas, Andreas M.; Muckenhuber, Moritz; Mahr, Benedikt; Unger, Lukas; Maschke, Svenja; Pilat, Nina; Holly, Raimund; Wiletel, Mario; Regele, Heinz; Wekerle, Thomas

doi:10.3389/fimmu.2017.00821

Cited by 15 publications

(19 citation statements)

References 68 publications

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“…In this respect, it is of interest that IL-6 blockade accentuated Treg expansion by IL-2 cplx and thereby may function by prolonging Treg function. This notion is in line with reports that IL-6 blockade in mice can stabilize Treg function (41) and also led to an increase in Treg numbers (20), both for thymic-derived and peripherally induced Tregs, and thereby reduces the severity of GVHD (42). Whether IL-6 blockade has similar effects on human Tregs is still unclear (43), although recent data have shown that anti-IL-6R mab (tocilizumab) therapy is beneficial for renal transplantation (44).…”

Section: Discussionsupporting

confidence: 91%

“…Since previous studies used only brief (3 d) treatment with IL-2 cplx, it was important to examine the effects of prolonged IL-2 cplx treatment. We also examined whether graft survival could be improved by IL-6 blockade (20,21). In this respect, histologic rejection of allografts is known to be associated with IL-6 expression, both in experimental models (22) and patients (23,24), and injection of anti-IL-6 mab can delay graft rejection (25).…”

Section: Significancementioning

confidence: 99%

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Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat

Wiletel

Weijler

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Injection of Interleukin-2 (IL-2) complexed with a particular anti–IL-2 monoclonal antibody (mab) JES6-1 has been shown to selectively expand CD4+Foxp3+ T regulatory T cells (Tregs) in vivo. Although the potency of this approach with regard to transplantation has already been proven in an islet transplantation model, skin graft survival could not be prolonged. Since the latter is relevant to human allograft survival, we sought to improve the efficiency of IL-2 complex (cplx) treatment for skin allograft survival in a stringent murine skin graft model. Here, we show that combining low doses of IL-2 cplxs with rapamycin and blockade of the inflammatory cytokine IL-6 leads to long-term (>75 d) survival of major histocompatibility complex-different skin allografts without the need for immunosuppression. Allograft survival was critically dependent on CD25+FoxP3+ Tregs and was not accompanied by impaired responsiveness toward donor alloantigens in vitro after IL-2 cplx treatment was stopped. Furthermore, second donor-type skin grafts were rejected and provoked rejection of the primary graft, suggesting that operational tolerance is not systemic but restricted to the graft. These findings plus the lack of donor-specific antibody formation imply that prolonged graft survival was largely a reflection of immunological ignorance. The results may represent a potentially clinically translatable strategy for the development of protocols for tolerance induction.

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Section: Discussionsupporting

confidence: 91%

Section: Significancementioning

confidence: 99%

Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat

Wiletel

Weijler

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…This plasticity in the secretory potential of MSCs represents limitations when cultured MSCs producing TGF-β are transferred into the inflammatory environment of the diseased retina. To prevent activation of pro-inflammatory cells, MSCs could be co-administrated with antibody anti-IL-6 or anti-IL-6 receptor, as this has been tested in patients with kidney allografts[76,77]. It has been shown that blocking of the IL-6 pathway can attenuate inflammation, support the activation of Tregs and enhance allograft survival.…”

Section: Resultsmentioning

confidence: 99%

Cytokine interplay among the diseased retina, inflammatory cells and mesenchymal stem cells - a clue to stem cell-based therapy

Holáň¹,

Heřmánková²,

Krulová³

et al. 2019

WJSC

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Retinal degenerative disorders, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration or glaucoma, represent the most common causes of loss of vision and blindness. In spite of intensive research, treatment options to prevent, stop or cure these diseases are limited. Newer therapeutic approaches are offered by stem cell-based therapy. To date, various types of stem cells have been evaluated in a range of models. Among them, mesenchymal stem/stromal cells (MSCs) derived from bone marrow or adipose tissue and used as autologous cells have been proposed to have the potential to attenuate the negative manifestations of retinal diseases. MSCs delivered to the vicinity of the diseased retina can exert local anti-inflammatory and repair-promoting/regenerative effects on retinal cells. However, MSCs also produce numerous factors that could have negative impacts on retinal regeneration. The secretory activity of MSCs is strongly influenced by the cytokine environment. Therefore, the interactions among the molecules produced by the diseased retina, cytokines secreted by inflammatory cells and factors produced by MSCs will decide the development and propagation of retinal diseases. Here we discuss the interactions among cytokines and other factors in the environment of the diseased retina treated by MSCs, and we present results supporting immunoregulatory and trophic roles of molecules secreted in the vicinity of the retina during MSC-based therapy.

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“…Coadministration of Tocilizumab to standard GvHD prophylaxis revealed promising potential in a phase I/II trial ( 32 ) and is also tested in several transplant trials ( 103 ). In the experimental setting, blocking IL-6 displayed a beneficial effect on the induction of chimerism and tolerance in non-human primates and mice ( 104 , 105 ).…”

Section: Future Prospectsmentioning

confidence: 99%

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

et al. 2017

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The perception that transplantation of hematopoietic stem cells can confer tolerance to any tissue or organ from the same donor is widely accepted but it has not yet become a treatment option in clinical routine. The reasons for this are multifaceted but can generally be classified into safety and efficacy concerns that also became evident from the results of the first clinical pilot trials. In comparison to standard immunosuppressive therapies, the infection risk associated with the cytotoxic pre-conditioning necessary to allow allogeneic bone marrow engraftment and the risk of developing graft-vs.-host disease (GVHD) constitute the most prohibitive hurdles. However, several approaches have recently been developed at the experimental level to reduce or even overcome the necessity for cytoreductive conditioning, such as costimulation blockade, pro-apoptotic drugs, or Treg therapy. But even in the absence of any hazardous pretreatment, the recipients are exposed to the risk of developing GVHD as long as non-tolerant donor T cells are present. Total lymphoid irradiation and enriching the stem cell graft with facilitating cells emerged as potential strategies to reduce this peril. On the other hand, the long-lasting survival of kidney allografts, seen with transient chimerism in some clinical series, questions the need for durable chimerism for robust tolerance. From a safety point of view, loss of chimerism would indeed be favorable as it eliminates the risk of GVHD, but also complicates the assessment of tolerance. Therefore, other biomarkers are warranted to monitor tolerance and to identify those patients who can safely be weaned off immunosuppression. In addition to these safety concerns, the limited efficacy of the current pilot trials with approximately 40–60% patients becoming tolerant remains an important issue that needs to be resolved. Overall, the road ahead to clinical routine may still be rocky but the first successful long-term patients and progress in pre-clinical research provide encouraging evidence that deliberately inducing tolerance through hematopoietic chimerism might eventually make it from dream to reality.

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Anti-Interleukin-6 Promotes Allogeneic Bone Marrow Engraftment and Prolonged Graft Survival in an Irradiation-Free Murine Transplant Model

Cited by 15 publications

References 68 publications

Treg-mediated prolonged survival of skin allografts without immunosuppression

Treg-mediated prolonged survival of skin allografts without immunosuppression

Cytokine interplay among the diseased retina, inflammatory cells and mesenchymal stem cells - a clue to stem cell-based therapy

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

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