Donor CD4 T Cells Trigger Costimulation Blockade-Resistant Donor Bone Marrow Rejection Through Bystander Activation Requiring IL-6

Hock, Karin; Pilat, Nina; Baranyi, Ulrike; Mahr, Benedikt; Gattringer, Martina; Klaus, Christoph; Wekerle, Thomas

doi:10.1111/ajt.12823

Cited by 10 publications

(9 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A). Accordingly, to improve graft MST, we added rapamycin (IL-2 cplx/rapa), lowered the dose of IL-2-0.5 μg per injection (LD IL-2; complexed with 2.5 μg JES6-1), and extended the length of treatment to 30 d (30 d LD IL-2 cplx/rapa); in addition, based on previous findings (21,27,28), we added a short-course (4 doses on days −1/1/4/6) of antiinflammatory treatment using anti-IL-6 mab [30 d LD IL-2 cplx/ rapa + anti-IL-6 (a-IL-6)]. For all of these regimens, no treatment was given after 30 d.…”

Section: Il-2/anti-il-2 Mab Complexes Synergize With Il-6 Blockade Tomentioning

confidence: 99%

Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat

Wiletel

Weijler

et al. 2019

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

View full text Add to dashboard Cite

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.

show abstract

Section: Il-2/anti-il-2 Mab Complexes Synergize With Il-6 Blockade Tomentioning

confidence: 99%

Treg-mediated prolonged survival of skin allografts without immunosuppression

Pilat

Wiletel

Weijler

et al. 2019

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

View full text Add to dashboard Cite

show abstract

“…Mixed lymphocyte reaction was performed as previously described (32,33). In brief unseparated splenocytes (4x10 5 ) were incubated in triplicates with 4x10 5 irradiated (30Gy) BALB/c (donor), C57BL/6 (recipient) stimulator cells or with medium for 72 hours.…”

Section: Mixed Lymphocyte Reactionmentioning

confidence: 99%

“…Mixed lymphocyte reaction was performed, as described previously (32,33). In brief, unseparated splenocytes (4 9 10 5 ) were incubated in triplicate with 4 9 10 5 irradiated (30 Gy) BALB/c (donor) cells, with C57BL/6 (recipient) stimulator cells or with medium for 72 h. Cells were pulsed with [3H]-thymidine (Amersham BioSciences, Little Chalfont, U.K.) for 18 h, and incorporated radioactivity was measured with a MicroBeta 1450 beta counter (Wallac; HVD Lifesciences, Vienna, Austria).…”

Section: Mixed Lymphocyte Reactionmentioning

confidence: 99%

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses

Schwarz

Unger

Mahr

et al. 2016

American Journal of Transplantation

Self Cite

View full text Add to dashboard Cite

B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

show abstract

“…Inhibition of the IL-6 signaling pathway reduces the severity of GvHD due to the augmentation of thymic-dependent and independent Treg reconstitution (32). Recently, we found that the co-transfer of high numbers of donor T cells triggers CB-resistant rejection of donor BM through IL-6-dependent bystander activation (33). Furthermore, disrupting the IL-6 signaling pathway with a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody (tocilizumab) is approved for clinical use in Castleman’s disease, rheumatoid and juvenile arthritis (34–36).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Donor CD4 T Cells Trigger Costimulation Blockade-Resistant Donor Bone Marrow Rejection Through Bystander Activation Requiring IL-6

Cited by 10 publications

References 55 publications

Treg-mediated prolonged survival of skin allografts without immunosuppression

Treg-mediated prolonged survival of skin allografts without immunosuppression

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses

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

Contact Info

Product

Resources

About