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

ABSTRACT: Transfer of recipient regulatory T cells (Tregs) induces mixed chimerism and tolerance in an irradiation-free bone marrow (BM) transplantation (BMT) model involving short-course co-stimulation blockade and mTOR inhibition. Boosting endogenous Tregs pharmacologically in vivo would be an attractive alternative avoiding the current limitations of performing adoptive cell therapy in the routine clinical setting. Interleukin-6 (IL-6) potently inhibits Treg differentiation and its blockade was shown to increase Treg numbers in vivo. Therefore, we investigated whether IL-6 blockade can replace adoptive Treg transfer in irradiation-free allogeneic BMT. Treatment with anti-IL-6 instead of Treg transfer led to multi-lineage chimerism (persisting for ~12 weeks) in recipients of fully mismatched BM and significantly prolonged donor skin (MST 58 days) and heart (MST > 100 days) graft survival. Endogenous Foxp3+ Tregs expanded in anti-IL-6-treated BMT recipients, while dendritic cell (DC) activation and memory CD8+ T cell development were inhibited. Adding anti-IL-17 to anti-IL-6 treatment increased Treg frequencies, but did not further prolong donor skin graft survival significantly. These results demonstrate that IL-6 blockade promotes BM engraftment and donor graft survival in non-irradiated recipients and might provide an alternative to Treg cell therapy in the clinical setting.

SUBMITTER: Granofszky N

PROVIDER: S-EPMC5515831 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:BackgroundAdvances in allogeneic hematopoietic stem cell transplant (HSCT) have increased patient survival, although substantial treatment-related toxicity remains, including chronic kidney disease (CKD). We assessed the association between CKD and survival and transplant-specific outcomes in HSCT recipients.MethodsWe conducted a retrospective study of all 408 adult patients with allogenic HSCT at Princess Margaret Cancer Centre (Toronto, Canada, 2015-18). We used logistic regression to identify risk factors for CKD at 1 year post-transplant. Associations between CKD at 1 year and overall survival, relapse-free survival, graft-versus-host-disease (GVHD)-free/relapse-free survival, relapse and transplant-related mortality were examined using extended time-varying Cox models. In a sensitivity analysis, we restricted the cohort to survivors at 1 year, using standard Cox proportional hazard models to examine associations between CKD and overall survival, relapse-free survival and GVHD-free/relapse-free survival, and Fine and Gray's competing risk models to determine associations between CKD and relapse/transplant-related mortality.ResultsThe prevalence of CKD at 1 year was 19% (46 patients) with median follow-up of 23 months. Multivariable regression identified age at transplant [adjusted OR (aOR) 1.09, 95% confidence interval (95% CI) = 1.05-1.14; P < 0.0001), female gender (aOR 2.83, 95% CI = 1.34-5.97; P = 0.006) and acute kidney injury during the first 100 days (aOR 3.86, 95% CI = 1.70-8.73; P = 0.001) as risk factors for CKD at 1 year. Patients with CKD at 1 year had significantly poorer overall survival than those without CKD, when adjusted for relevant covariates [adjusted HR (aHR) 1.93, 95% CI = 1.02-3.66; P = 0.04 in the time-varying Cox model, and aHR 2.06, 95% CI = 1.04-4.07; P = 0.04 using the standard Cox model]. CKD at 1 year was also associated with worse GVHD-free/relapse-free survival (aHR 1.65, 95% CI = 1.04-2.61; P = 0.03).ConclusionsCKD adversely affects the long-term prognosis for allogeneic HSCT recipients, with increased mortality risk and worse GVHD-free/relapse-free survival.

Project description:BackgroundCo-transplantation of bone marrow cells (BMCs) and mesenchymal stem cells (MSCs) is used as a strategy to improve the outcomes of bone marrow transplantation. Tonsil-derived MSCs (TMSCs) are a promising source of MSCs for co-transplantation. Previous studies have shown that TMSCs or conditioned media from TMSCs (TMSC-CM) enhance BMC engraftment. However, the factors in TMSCs that promote better engraftment have not yet been identified.MethodsMice were subjected to a myeloablative regimen of busulfan and cyclophosphamide, and the mRNA expression in the bone marrow was analyzed using an extracellular matrix (ECM) and adhesion molecule-targeted polymerase chain reaction (PCR) array. Nano-liquid chromatography with tandem mass spectrometry, real-time quantitative PCR, western blots, and enzyme-linked immunosorbent assays were used to compare the expression levels of metalloproteinase 3 (MMP3) in MSCs derived from various tissues, including the tonsils, bone marrow, adipose tissue, and umbilical cord. Recipient mice were conditioned with busulfan and cyclophosphamide, and BMCs, either as a sole population or with control or MMP3-knockdown TMSCs, were co-transplanted into these mice. The effects of TMSC-expressed MMP3 were investigated. Additionally, Enzchek collagenase and Transwell migration assays were used to confirm that the collagenase activity of TMSC-expressed MMP3 enhanced BMC migration.ResultsMice subjected to the myeloablative regimen exhibited increased mRNA expression of collagen type IV alpha 1/2 (Col4a1 and Col4a2). Among the various extracellular matrix-modulating proteins secreted by TMSCs, MMP3 was expressed at higher levels in TMSCs than in other MSCs. Mice co-transplanted with BMCs and control TMSCs exhibited a higher survival rate, weight recovery, and bone marrow cellularity compared with mice co-transplanted with BMCs and MMP3-knockdown TMSCs. Control TMSC-CM possessed higher collagenase activity against collagen IV than MMP3-knockdown TMSC-CM. TMSC-CM also accelerated BMC migration by degrading collagen IV in vitro.ConclusionsCollectively, these results indicate that TMSCs enhance BMC engraftment by the secretion of MMP3 for the modulation of the bone marrow extracellular matrix.

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

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