Incomplete clonal deletion as prerequisite for tissue-specific minor antigen tolerization

Pilat, Nina; Mahr, Benedikt; Unger, Lukas; Hock, Karin; Schwarz, Christoph; Farkas, Andreas M.; Baranyi, Ulrike; Wrba, Fritz; Wekerle, Thomas

doi:10.1172/jci.insight.85911

Cited by 17 publications

(32 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Depleting T regs (α‐CD25) or blocking their effector molecules (α‐PD1, α‐CTLA4) suspended the cover of regulation leading to rapid rejection of the tolerized grafts. The infused T regs seemed to pass on their suppressive behaviour as they vanished over time . This observation was also made in a non‐myeloablative model based on T reg therapy in which the injected cells were required for the induction of tolerance, but not its maintenance .…”

Section: Mechanisms Preserving Tolerancementioning

confidence: 77%

Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Mahr

Wekerle

2017

Clinical and Experimental Immunology

View full text Add to dashboard Cite

Organ transplantation is the treatment of choice for patients with end-stage organ failure, but chronic immunosuppression is taking its toll in terms of morbidity and poor efficacy in preventing late graft loss. Therefore, a drugfree state would be desirable where the recipient permanently accepts a donor organ while remaining otherwise fully immunologically competent. Mouse studies unveiled mixed chimerism as an effective approach to induce such donor-specific tolerance deliberately and laid the foundation for a series of clinical pilot trials. Nevertheless, its widespread clinical implementation is currently prevented by cytotoxic conditioning and limited efficacy. Therefore, the use of mouse studies remains an indispensable tool for the development of novel concepts with potential for translation and for the delineation of underlying tolerance mechanisms. Recent innovations developed in mice include the use of pro-apoptotic drugs or regulatory T cell (T reg ) transfer for promoting bone marrow engraftment in the absence of myelosuppression and new insight gained in the role of innate immunity and the interplay between deletion and regulation in maintaining tolerance in chimeras. Here, we review these and other recent advances in murine studies inducing transplantation tolerance through mixed chimerism and discuss both the advances and roadblocks of this approach.

show abstract

Section: Mechanisms Preserving Tolerancementioning

confidence: 77%

Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Mahr

Wekerle

2017

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…Whether a difference exists in the effects of enforced proinsulin expression on CD8 + and CD4 + T cells remains unclear. However, in other settings some induction of Treg cells occurs when antigen-specific CD4 + T cells are present [39], although if deletion is highly effective [40] development/expansion of Treg cells is limited. Here, where proinsulin expression was enforced within MHC class II + APC, T-cell exhaustion appeared to play a key role in maintaining the unresponsive state of those G9 T cells that persisted after initial antigen encounter when the majority of cells are deleted.…”

Section: Discussionmentioning

confidence: 99%

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice

et al. 2017

View full text Add to dashboard Cite

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β cells. Therapies need to incorporate strategies to overcome the genetic defects that impair induction or maintenance of peripheral T-cell tolerance and contribute to disease development. We tested whether the enforced expression of an islet autoantigen in antigen-presenting cells (APC) counteracted peripheral T-cell tolerance defects in autoimmune-prone NOD mice. We observed that insulin-specific CD8 T cells transferred to mice in which proinsulin was transgenically expressed in APCs underwent several rounds of division and the majority were deleted. Residual insulin-specific CD8 T cells were rendered unresponsive and this was associated with TCR downregulation, loss of tetramer binding and expression of a range of co-inhibitory molecules. Notably, accumulation and effector differentiation of insulin-specific CD8 T cells in pancreatic lymph nodes was prominent in non-transgenic recipients but blocked by transgenic proinsulin expression. This shift from T-cell priming to T-cell tolerance exemplifies the tolerogenic capacity of autoantigen expression by APC and the capacity to overcome genetic tolerance defects.

show abstract

“…The use of “dirty” mice would be one step towards mimicking a highly experienced immune system which may interfere with tolerance induction [ 18 ••]. Also, the use of mouse strain combinations affects outcome as some are easier to tolerize than others [ 19 ], in particular if they lack minor antigen disparities, which is not realistic in the clinical setting and has been shown to euphemize long-term graft survival [ 20 ••, 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, neither regulation through Tregs nor classical anergy appear crucial several months after BMT for the maintenance of tolerance in established chimeras [ 30 ]. In sharp contrast, regulatory mechanisms have been shown to be critical even late after BMT in settings devoid of cytotoxic recipient conditioning [ 20 ••, 31 ]. Although the creation of “space” in distinct stem cell niches by myelosuppressive treatments enhances BM engraftment, it has been shown to be dispensable and can be overcome by very high doses of BM [ 32 , 33 ], modulation of the immune system by targeting apoptosis [ 34 ], or adoptive Treg transfer [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

“…Chimerism levels are generally lower in protocols without myelosuppression by irradiation or cytotoxic drugs; however, tolerance appears not linked to the degree of chimerism as long as it is stable and of multilineage nature. Interestingly, chimerism protocols relying on Tregs, and other regulatory mechanisms instead of deletional mechanisms only, have been shown to be superior in the prevention of chronic rejection [ 20 ••, 36 ] and could alleviate GVHD [ 37 •]. This raises the question whether protocols involving intense recipient pre-conditioning preclude or at least aggravate regulatory tolerance mechanisms or if regulatory mechanisms need to be actively induced via adoptive cell transfer or other forms of immunomodulation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combining Adoptive Treg Transfer with Bone Marrow Transplantation for Transplantation Tolerance

2017

Self Cite

View full text Add to dashboard Cite

Purpose of ReviewThe mixed chimerism approach is an exceptionally potent strategy for the induction of donor-specific tolerance in organ transplantation and so far the only one that was demonstrated to work in the clinical setting. Regulatory T cells (Tregs) have been shown to improve chimerism induction in experimental animal models. This review summarizes the development of innovative BMT protocols using therapeutic Treg transfer for tolerance induction.Recent FindingsTreg cell therapy promotes BM engraftment in reduced conditioning protocols in both, mice and non-human primates. In mice, transfer of polyclonal recipient Tregs was sufficient to substitute cytotoxic recipient conditioning. Treg therapy prevented chronic rejection of skin and heart allografts related to tissue-specific antigen disparities, in part by promoting intragraft Treg accumulation.SummaryAdoptive Treg transfer is remarkably effective in facilitating BM engraftment in reduced-intensity protocols in mice and non-human primates. Furthermore, it promotes regulatory mechanisms that prevent chronic rejection.

show abstract

Incomplete clonal deletion as prerequisite for tissue-specific minor antigen tolerization

Cited by 17 publications

References 46 publications

Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice

Combining Adoptive Treg Transfer with Bone Marrow Transplantation for Transplantation Tolerance

Contact Info

Product

Resources

About

Incomplete clonal deletion as prerequisite for tissue-specific minor antigen tolerization

Cited by 17 publications

References 46 publications

Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8+ T‐cell priming to tolerance in autoimmune‐prone NOD mice

Combining Adoptive Treg Transfer with Bone Marrow Transplantation for Transplantation Tolerance

Contact Info

Product

Resources

About

Antigen presenting cell‐targeted proinsulin expression converts insulin‐specific CD8⁺ T‐cell priming to tolerance in autoimmune‐prone NOD mice