Anti–IL6-receptor-alpha (tocilizumab) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses

Betts, Brian C.; Angelo, Erin T. St.; Kennedy, Michael G.; Young, James W.

doi:10.1182/blood-2011-06-363390

Cited by 36 publications

(33 citation statements)

References 27 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TG101348 additionally blocks other inflammatory cytokine signaling through the JAK2/pSTAT3 pathway, which simple inhibition of IL-6R-␣ by tocilizumab could not prevent. 13 JAK2 inhibitor treatment of moDCs interfered with their complete phenotypic maturation yet did not impair their potency as stimulators in allogeneic MLRs. Irrespective of any pretreatment effects on moDCs, however, achieving negative immunomodulatory effects on alloreactive T-cell responses required the presence of only 1M TG101348 during the initial interactions between alloantigen-specific T-cell responders and allogeneic moDC stimulators.…”

Section: Jak2 Induces Tolerance To Alloantigen 5335mentioning

confidence: 94%

“…[37][38][39] In fact, given that all conventional human DC subtypes secrete IL-23 (Romano and J.W.Y. unpublished data), this cytokine is a prime candidate to account for the lack of negative immunomodulation achieved by isolated blockade of IL-6R-␣ with tocilizumab, 13 in contrast to specific JAK2 inhibition, which can curtail signaling by both IL-6 and IL-23.…”

Section: Jak2 Induces Tolerance To Alloantigen 5335mentioning

confidence: 99%

“…12 Targeting IL-6 with mAb or knock-out strategies, however, has resulted in discordant effects on the Treg/Th17 axis in these mouse models. 10,11 We have attempted to replicate the immunosuppressive effect of IL-6 inhibition in mice by studying primary human DC:T-cell interactions in vitro with tocilizumab, 13 a mAb to the IL-6 receptor-alpha (IL-6R-␣) subunit. Tocilizumab achieved the intended on-target effect of blocking IL-6 signaling in both monocytederived dendritic cells (moDCs) and T cells.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen

Betts

Abdel-Wahab

Curran

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

IntroductionGVHD is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Broadly acting immunosuppressants curtail lymphocyte alloreactivity, but they increase infectious complications and can jeopardize the GVL or graft-versus-tumor benefit of the transplantation. An ideal approach to preventing and treating GVHD would limit alloantigen-specific reactivity while preserving immunity against pathogens and malignant cells.The systemic dysregulation of inflammatory cytokines mediates the pathophysiology of GVHD, especially the acute form. 1 Among these cytokines, IL-6 has recently received increased attention because it promotes inflammation by suppressing regulatory T-cell (Treg) development and promoting Th17 expansion. 2-7 IL-6 also supports the maturation and activation of human dendritic cells (DCs). 8,9 Mouse HSCT models of GVHD have shown that IL-6 induces direct cytopathic damage to the intestinal epithelium. Its neutralization reduces gut pathology and improves survival, 10,11 probably because of the primacy of the gastrointestinal tract in amplifying systemic GVHD. 12 Targeting IL-6 with mAb or knock-out strategies, however, has resulted in discordant effects on the Treg/Th17 axis in these mouse models. 10,11 We have attempted to replicate the immunosuppressive effect of IL-6 inhibition in mice by studying primary human DC:T-cell interactions in vitro with tocilizumab, 13 a mAb to the IL-6 receptor-alpha (IL-6R-␣) subunit. Tocilizumab achieved the intended on-target effect of blocking IL-6 signaling in both monocytederived dendritic cells (moDCs) and T cells. There were no functional consequences, however, for moDC maturation, alloreactive T-cell proliferation, Treg expansion, or allogeneic Th1/Th17 responses in vitro. Therefore, inhibition of IL-6 by isolated receptor blockade would not limit alloreactivity in a human system. We therefore focused on Janus kinase-2 (JAK2), which relays the signaling function not only of IL-6R-␣, but also of other inflammatory cytokine receptors with relevance for allogeneic graft-host interactions. 14 The JAKs comprise a family of nonreceptor protein tyrosine kinases, which include JAK1, JAK2, JAK3, and Tyk2. These kinases associate with the cytoplasmic domains of cytokine receptors. 14 Upon their own phosphorylation, the JAKs induce downstream phosphorylation of signal transducer and activator of transcription (pSTAT) proteins. 14 Activated pSTATs in turn function as transcription factors that mediate cellular differentiation and growth. 14 JAK2 mediates T-cell signaling in response to various proinflammatory cytokines, including IL-6, IL-12, and IL-23. 14 These cytokines are critical to the development and expansion ofTh1 cells, which use IL-12, and Th17 cells, which use IL-6 and IL-23. 2,15,16 Th1 and Th17 cells can in turn induce alloreactive end organ damage in GVHD. 17 JAK2 is therefore a principle gatekeeper of The online version of this article contains a data supplement.The publication costs of this article wer...

show abstract

Section: Jak2 Induces Tolerance To Alloantigen 5335mentioning

confidence: 94%

Section: Jak2 Induces Tolerance To Alloantigen 5335mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen

Betts

Abdel-Wahab

Curran

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

“…17 Cytokine concentrations and antagonist concentrations were chosen based on available prior reports. 18 Colony formations were enumerated daily for 2 weeks, in a manner identical to that described above, and the maximal numbers of colonies per well were used for analyses.…”

Section: Methodsmentioning

confidence: 99%

Peripheral Blood Cytokine Levels After Acute Myocardial Infarction

Shahrivari

Wise

Resende

et al. 2017

Circulation Research

View full text Add to dashboard Cite

Rationale Intracoronary infusion of bone marrow mononuclear cells (BM-MNCs) after acute myocardial infarction (AMI) has led to limited improvement in left ventricular (LV) function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans. Objective To test the hypothesis that peripheral blood (PB) cytokines predict bone marrow (BM) endothelial progenitor cell (EPC) colony outgrowth and cardiac function after AMI. Methods and Results BM and PB samples were collected from 87 participants 14–21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB IL-6 negatively correlated with endothelial colony forming cell (ECFC) colony maximum in the BM of AMI patients (estimate ± SE (ESE) −0.13±0.05, P=0.007). BM from healthy individuals showed a dose-dependent decrease in ECFC colony outgrowth in the presence of exogenous IL-1β or IL-6 (P <0.05). Blocking the IL-1R or IL-6R reversed cytokine impairment. In AMI study participants, the angiogenic cytokine platelet-derived growth factor BB glycoprotein (PDGF-BB) correlated positively with BM-derived CFU-EC colony maximum (ESE 0.01 ± 0.002, P<0.001), multipotent mesenchymal stromal cell (MSC) colony maximum (ESE 0.01±0.002, P=0.002) in BM, and MSC colony maximum in PB (ESE 0.02±0.005, P<0.001). Conclusions Two weeks after AMI, increased PB PDGF-BB was associated with increased BM function, while increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI. Clinical Trial Registrations clinicaltrials.gov Identifiers: NCT00684060

show abstract

“…Several IKK and NF-kB inhibitors are under development, as well as a number of natural products that can inhibit NF-kB activation when used at high doses [127]. Atlizumab, an IL-6-neutralizing monoclonal antibody MRA, could completely block IL-6 activity, is highly effective in the treatment of rheumatoid arthritis and Crohn's disease and is well tolerated with few reports of infection or toxicity [128]. Meanwhile, several studies in mouse models with STAT3 inhibitors, including AZD1480, cucurbitacin-I and cucurbitacin-B, showed that STAT3 is a promising target for redirecting inflammation in cancer therapy [129].…”

Section: Therapeutic Strategiesmentioning

confidence: 98%

Oncogene and Non-Oncogene Addiction in Inflammation-Associated Cancers

et al. 2013

View full text Add to dashboard Cite

Many cancers originate in tissues that are chronically inflamed, and the inflammatory microenvironment is considered to promote the progression of malignancy, including initiation, growth, angiogenesis, invasion and metastasis. The molecular mechanism of inflammation-induced progression of cancers has been widely discussed. Oncogene and non-oncogene addiction have been proposed as two distinct but complementary theories to explain the initiation and development of cancers. Furthermore, they also play a role in cancer-associated inflammation. A solid understanding of oncogene and non-oncogene addiction in cancer-associated inflammatory microenvironments will help to exploit cancer drug targets for cancer prevention and clinical treatment.

show abstract

Anti–IL6-receptor-alpha (tocilizumab) does not inhibit human monocyte-derived dendritic cell maturation or alloreactive T-cell responses

Cited by 36 publications

References 27 publications

Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen

Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen

Peripheral Blood Cytokine Levels After Acute Myocardial Infarction

Oncogene and Non-Oncogene Addiction in Inflammation-Associated Cancers

Contact Info

Product

Resources

About