Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease

Chen, Xiao; Das, Rupali; Komorowski, Richard; Beres, Amy; Hessner, Martin J.; Mihara, Masahiko; Drobyski, William R.

doi:10.1182/blood-2009-01-197178

Cited by 259 publications

(245 citation statements)

References 59 publications

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“…Notably, even in the very difficult model of allogeneic bone marrow grafting, blockade of IL-6 signalling using anti-IL-6 receptor augments Treg reconstitution and attenuates severity of graft versus host disease. 75 Thus not only can auto-antigen-driven inflammatory immune responses be reduced by IL-6 blockade, but auto-reactive Treg can be expanded: one means to enhance such induction of Treg would be delivery of LIF to the responding CD4 þ T cells. Indeed, in certain conditions LIF has added value, for example, being directly neuro-protective in EAE.…”

Section: Implications Of the Lif/il-6 Axismentioning

confidence: 99%

LIF in the regulation of T-cell fate and as a potential therapeutic

Metcalfe

2011

Genes Immun

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At the heart of lineage commitment within the adaptive immune response is the intrinsic genetic plasticity of the naive peripheral T lymphocyte (T cell). Primary activation by presentation of cognate antigen is coupled to rapid T-cell cycling and progressive epigenetic changes that guide the cell down distinct T-cell lineages, either effector (Th1, Th2, Th17) or tolerogenic (Treg). Fate choice is influenced both by strength of the priming activation signal and by cues from the micro-environment that are integrated with lineage-specific gene expression profiles, eventually becoming hard-wired in the fully differentiated cell. The micro-environmental cues include cytokines, and the discovery that leukaemia inhibitory factor (LIF) and interleukin (IL)-6 counter-regulate development of the Treg and Th17 lineages places LIF within the core regulatory circuitry of T cells. I first summarise current understanding of LIF and the LIF receptor in the context of T cells. Next, the central relevance of the LIF/IL-6 axis in immune-mediated disease is set in the context of (i) a new nano-therapeutic approach for targeted delivery of LIF and (ii) MARCH-7, a novel E3-ligase discovered to have a central mechanistic role in LIF-mediated T-cell biology, functioning as a rheostat-type regulator of endogenous LIF-signalling.

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Section: Implications Of the Lif/il-6 Axismentioning

confidence: 99%

LIF in the regulation of T-cell fate and as a potential therapeutic

Metcalfe

2011

Genes Immun

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“…IL6 increases circulating TH1 and TH17 T cell subsets and suppresses Tregs. In preclinical studies IL6 blockade has been associated marked responses in GVHD [161,162]. Tocilizumab when used for steroid-refractory GVHD has shown responses and prophylaxis with tocilizumab is associated with markedly reduced GVHD [163].…”

Section: Future Directionsmentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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owing to the advancement in reduced intensity conditioning (RIC) and in patients without HLA-matched donors due to the use of cord blood and haploidentical HSCT [4][5][6]. Although marked improvement has been made in supportive care, immunosuppressive therapy and DNA-based Human Leukocyte Antigen (HLA) typing, graft vs host disease (GVHD) remains a major cause of morbidity and non-relapse mortality among allogeneic HSCT recipients. It was first described by Billingham in 1966 as a syndrome where immunocompetent T cells from the donor recognize and damage the host tissue in an immunocompromised recipient. It presents with heterogeneous symptoms involving multiple organ systems including gastrointestinal tract, skin, mucosa, liver and lungs [7]. In the past clinical features occurring within 100 days after HSCT was called acute GVHD (aGVHD) and those happening after 100 days were labeled chronic GVHD (cGVHD) [8,9]. This definition was rather unsatisfactory thus National Institute of Health (NIH) consensus criteria were developed and have been revised. The criteria have added new categories such as late-onset aGVHD (acute GVHD occurring after 100 days) and overlap syndrome which includes features of both acute and chronic GVHD to the classification, and also have introduced new definitions for organ system involvement [10][11][12]. The categorization of acute vs chronic GVHD is based on the combination of clinical symptoms rather than the time of onset. Depending upon a number of variables associated with patients, donors, and types of transplant, the incidence of aGVHD varies with incidence of grade II-IV GVHD at 40 % in matched related donor (MRD) transplant to 50 % in MUD transplant. The main risk factors for aGVHD include degree of HLA mismatch, age of the patient, previous all immunization of the donor and the kind of GVHD prophylaxis used. About 30-70 % of allogeneic HSCT recipients alive after 100 days will Abstract Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

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“…15 The PAMPs, such as lipopolysaccharide (LPS), which is recognized by TLR-4, are released during the chemo-and radiotherapeutic conditioning regimens performed before the infusion of BMT donor cells. 16,17 In this way, the conditioning regimens amplify the secretion of proinflammatory cytokines such as IL-1, TNF-a, [17][18][19] IL-6 20 and other IFN family members in a process described as a 'cytokine storm'.…”

Section: Triggers For Induction Of Gvhdmentioning

confidence: 99%

New perspectives on the biology of acute GVHD

Paczesny

Hanauer

Sun

et al. 2009

Bone Marrow Transplant

158

126

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The use of allogeneic hematopoietic cell transplantation (HCT) has increased as new techniques have been developed for transplantation in patients who previously would not have been considered HCT candidates. However, its efficacy continued to be limited by the development of frequent and severe acute GVHD. The complex and intricate pathophysiology of acute GVHD is a consequence of interactions between the donor and host innate and adaptive immune responses. Multiple inflammatory molecules and cell types are implicated in the development of GVHD that can be categorized as:(1) triggers that initiate GVHD by therapy-induced tissue damage and the antigen disparities between host and graft tissue; (2) sensors that detect the triggers, that is, process and present alloantigens; (3) mediators such as T-cell subsets (naive, memory, regulatory, Th17 and natural killer T cells) and (4) the effectors and amplifiers that cause damage of the target organs. These multiple inflammatory molecules and cell types that are implicated in the development of GVHD have been described with models that use stepwise cascades. Herein, we provide a novel perspective on the immunobiology of acute GVHD and briefly discuss some of the outstanding questions and limitations of the model systems.

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Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease

Cited by 259 publications

References 59 publications

LIF in the regulation of T-cell fate and as a potential therapeutic

LIF in the regulation of T-cell fate and as a potential therapeutic

State-of-the-art acute and chronic GVHD treatment

New perspectives on the biology of acute GVHD

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