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Review
. 2017 Nov;38(11):829-843.
doi: 10.1016/j.it.2017.07.008. Epub 2017 Aug 18.

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Julien Zuber  1 , Megan Sykes  2
Affiliations
Review

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Julien Zuber et al. Trends Immunol. 2017 Nov.

Abstract

Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field, recently achieved in the clinic by combining bone marrow transplantation (BMT) with kidney transplantation following non-myeloablative conditioning. At high levels of chimerism such protocols can permit central deletional tolerance, but with a significant risk of graft-versus-host (GVH) disease (GVHD). By contrast, transient chimerism-based tolerance is devoid of GVHD risk and appears to initially depend on regulatory T cells (Tregs) followed by gradual, presumably peripheral, clonal deletion of donor-reactive T cells. Here we review recent mechanistic insights into tolerance and the development of more robust and safer protocols for tolerance induction that will be guided by innovative immune monitoring tools.

Keywords: clonal deletion; mixed chimerism; regulatory T cells; tolerance.

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Figures

Figure 1
Figure 1. Mechanisms involved in clinical chimerism-based regimens for inducing tolerance across HLA barriers
(A) Sustained full chimerism:, A large number of donor CD34+ HSCs (up to 17×106/kg) and donor T cells (3.8×106/kg) plus “facilitating cells” are administered to the recipients along with the kidney allograft after non-myeloablative conditioning (green lightning symbol). Graft-vs-Host-reactivity drives the expansion of donor T cells that destroy recipient T cells and hematopoietic cells, creating HSC niche space in bone marrow. The GVH response is partly attenuated by post-transplant cyclophosphamide treatment (yellow lightning). Durably engrafted donor HSCs supply the thymus with T-cell precursors and dendritic cells progenitors that induce central donor-specific tolerance. These conditions allow sustained full chimerism. Donor-derived T cells can mediate GVHD, yet fail to eliminate infectious organisms from recipient’s tissues, as post-transplant pathogen-specific immune responses are restricted to donor-MHC. (B) Transient mixed chimerism: Unfractionated bone marrow and kidney allograft are transplanted following non-myeloablative donor and recipient T cell-depleting induction (green lightning). Early Treg expansion, driven by lymphopenia and relative Treg sparing by the conditioning regimen combined with the presence of donor antigen, prevents the activation of HvG-reactive T cells and creates a microenvironmentthat supports peripheral deletion of donor-reactive T cells. In contrast to full chimeras, individuals with mixed or transient chimerism preserve efficient anti-infectious immune responses. Abbreviations: Cy, cyclophosphamide; GvH, Graft-vs-Host; HSC, hematopoietic stem cells; HvG, Host-vs-Graft; Tregs, regulatory T cells;
Figure 2
Figure 2. Approaches to inducing exhaustion and death of HvG-reactive T cells
A) Prolonged inefficient antigenic stimulation or anti-CD3 therapy results in altered balance between NFAT and AP-1, inducing an exhaustion program, as defined by the expression of several inhibitory cell surface receptors, including PD1, LAG3, TIM3, TIGIT and CTLA-4 and a hyporesponsive state. Both CsA and FK506 inhibit NFAT-dependent T-cell exhaustion. B) The two main apoptosis pathways, namely extrinsic (caspase 8-dependent) and intrinsic (caspase 9-dependent), involved in the peripheral deletion of HvG T cells following tolerance-inducing protocols are depicted. The complex crosstalk between autophagy and mitochondrial apoptosis is illustrated. Autophagy is initiated in response to metabolic cues (nutrient deprivation) and/or costimulatory blockade, both sensed by mTOR. If this process is insufficient, it triggers cytochrome c release and mitochondrial apoptosis. Furthermore, caspase activity hampers Beclin-1-dependent autophagy, fueling a positive amplification loop. Although both calcineurin inhibitors (CsA and FK506) block NFAT-dependent activation-cell death (extrinsic), CsA inhibits, unlike FK506, mitochondria depolarization and cytochrome c release. On the other hand, mitochondrial apoptosis is enhanced by mTOR and Bcl2/Bcl-xL (ABT-737) inhibition. Abbreviations: AP-1, activator protein 1; CsA, cyclosporin A; TCLA-4, cytotoxic T lymphocyte-associated protein 4; LAG3, lymphocyte-activation gene 3; mTORi, mammalian target of rapamycin inhibitor; NFAT, nuclear factor of activated T-cells; PD-1, programmed cell death protein 1; TCR, T cell receptor;
Figure 3
Figure 3. Pharmacological and biological agents with potential to tip the balance toward tolerance
Low-dose IL-2 selectively activates high-affinity IL2R-expressing Tregs, but has limited effect on Teffs. IL2R signaling relies mostly on the Jak3/STAT5 pathway in Tregs. In contrast, the PI3K/Akt/mTOR pathway is highly dispensable for the generation, expansion and survival of Tregs, yet not of Teff. Hence, mTORi favors Tregs over Teffs. Similarly, the critical role of anti-apoptotic Bcl2/Bcl-xL genes in hindering mitochondrial apoptosis in Teffs, but not Tregs, makes the former more vulnerable to Bcl2/Bcl-xL inhibition. Exposure of FOXP3+ Treg cells to pan-HDACi promotes the stability and function of Tregs, through acetylation of the FOXP3 gene. Tregs are unaffected by anti-CD40 antibody as they do not upregulate CD40L expression. Abbreviations: HA IL2R, high affinity IL-2 receptor; HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor; LA IL2R, low affinity IL-2 receptor; mTORi, mammalian target of rapamycin inhibitor; NFAT, nuclear factor of activated T-cells; PD-1, programmed cell death protein 1; PTEN, phosphatase and tensin homolog; TCR, T cell receptor; Teff, effector T cells; Treg, regulatory T cell; TSDR, Treg-specific demethylated region.
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