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. 2017 Dec;4(4):262-269.
doi: 10.1007/s40472-017-0166-5. Epub 2017 Oct 6.

Fifty Shades of Tolerance: Beyond a Binary Tolerant/Non-Tolerant Paradigm

Michelle L Miller  1 , Anita S Chong  2 , Maria-Luisa Alegre  1
Affiliations

Fifty Shades of Tolerance: Beyond a Binary Tolerant/Non-Tolerant Paradigm

Michelle L Miller et al. Curr Transplant Rep. 2017 Dec.

Abstract

Purpose of review: It has long been considered that tolerance in a transplant recipient is a binary all-or-none state: either the graft is accepted without immunosuppression identifying the recipient as tolerant, or the recipient rejects the graft and is not tolerant. This tolerance paradigm, however, does not accurately reflect data emerging from animal models and patients and requires revision.

Recent findings: It is becoming appreciated that there may be different gradations in the quality of tolerance based on underlying cellular mechanisms of immunological tolerance, and that individuals may enhance their tolerance by strengthening or combining different cellular mechanisms. Furthermore, evidence suggests that even if tolerance is lost, the loss may be only temporary, and in some circumstances tolerance can be restored.

Summary: Shifting our focus from an all-or-nothing tolerance paradigm to one with many shades may help us better understand how tolerance operates, and how this state may be tracked and enhanced for better patient outcomes.

Keywords: Erosion; Robustness; Tolerance; Transplantation.

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Figures

Figure 1:
Figure 1:. Threshold model of tolerance and mechanisms involved
Tolerance is not an all-or-none state but rather exists as a gradient of robust tolerance resulting from the number of combined mechanisms of T cell tolerance. If multiple mechanisms are simultaneously compromised this may result in dipping below the threshold necessary to prevent rejection (solid line). If individual mechanisms are disrupted, this may result in an erosion of tolerance (dashed line). Tolerance mechanisms may later recover resulting in a restoration of tolerance. Whether all tolerance mechanisms are fully restored or not will determine whether the restored tolerance state is as robust as the initial tolerance, or is potentially eroded. The example shown above lists different tolerance mechanisms examined and how their strength changes during a Listeria-triggered loss of tolerance and return of tolerance. Graft-specific Tregs are expanded or induced following tolerance induction, but these cells can be overwhelmed transiently by alloreactive conventional T cells (allo-Tconv) and Listeria-specific T cells in the graft. Tolerant mice maintain low numbers of allo-Tconv, similar to naïve mice, but these cells expand and stay elevated post-Listeria infection. Many tolerant T cells express the negative regulator PD-11, and in certain circumstances, such as post-infection, eroded tolerance becomes susceptible to PD-1/PD-L1 blockade. Naïve T cells have the potential for high alloreactivity but tolerance induction can result in their inhibition of cytokine production either extrinsically or intrinsically. Alloreactivity transiently increases during infection-mediated rejection, but approaches baseline levels during the restoration of tolerance.
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