Chapter 44 : Induction of Immunological Tolerance as a Therapeutic Procedure

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A major goal of immunosuppressive therapy in management of chronic inflammatory diseases and allogeneic transplants has been to harness long-term tolerance processes from short-term treatments. This should limit morbidity from long-term undermining of immune mechanisms, which is the hallmark of current immunosuppression.

Citation: Waldmann H, Howie D, Cobbold S. 2017. Induction of Immunological Tolerance as a Therapeutic Procedure, p 771-785. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0019-2015
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Figure 1

Coreceptor blockade induces transplantation tolerance and linked suppression in adult mice. CBA/Ca mice would normally rapidly reject skin grafts from either B10.BR or BALB/k mice, as they differ in minor histocompatibility antigens. If the recipients are given a brief course of nondepleting MAbs that block the CD4 and CD8 coreceptors at the time of grafting, B10.BR skin grafts are, however, permanently accepted. Remarkably, such mice made tolerant of B10.BR skin can accept third-party grafts, even from “multiple minor” different BALB/k donors, if they share sufficient antigens in common with the tolerated graft, in a process known as linked suppression. Both the induction of tolerance and the process of linked suppression are blocked by antibodies that neutralize active TGF-β.

Citation: Waldmann H, Howie D, Cobbold S. 2017. Induction of Immunological Tolerance as a Therapeutic Procedure, p 771-785. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0019-2015
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Figure 2

Linked suppression depends on an interaction between regulatory T cells and antigen-presenting cells (APCs). The copresentation of tolerated (Ag1) and third-party (Ag2) antigen by the same APCs promotes an interaction between the Tregs maintaining tolerance and naive T cells that would otherwise have the potential to develop into effector cells against tissues expressing the target antigen. This “linking” of the two antigens by the APC allows the Treg to suppress the naive T cell (i.e., linked suppression) and, through the action of TGF-β (and other additional mechanisms, not shown), to also guide the naive T cell to differentiate into a second cohort of regulatory T cells, thereby further enforcing tolerance to the target antigen (i.e., infectious tolerance).

Citation: Waldmann H, Howie D, Cobbold S. 2017. Induction of Immunological Tolerance as a Therapeutic Procedure, p 771-785. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0019-2015
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Figure 3

Tolerance can be induced by pharmacological modulation of DCs. Female anti-male TCR transgenic mice would normally reject male skin grafts rapidly. If such mice are administered mature (lipopolysaccharide-activated), bone marrow-derived DCs from male mice, they are further primed for graft rejection. In contrast, pretreatment of the bone marrow-derived DCs by any one of a number of modulatory agents, such as VitD3, IL-10, or TGF-β (which suppress DC maturation), induces a state of tolerance to the male antigen. Such tolerant mice now accept male skin grafts indefinitely, and while this is not associated with deletion of male-specific T cells, it does lead to the systemic induction of Foxp3 anti-male Tregs.

Citation: Waldmann H, Howie D, Cobbold S. 2017. Induction of Immunological Tolerance as a Therapeutic Procedure, p 771-785. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0019-2015
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Figure 4

Regulatory T cells actively maintain tolerance within accepted skin grafts. Female anti-male TCR transgenic mice can be made tolerant of male skin grafts by a single injection of nondepleting anti-CD4 MAb. This is associated with the induction of Foxp3 Tregs, which are particularly concentrated in the tolerated skin but are often only at a low frequency systemically. This low frequency may not be sufficient to transfer tolerance with spleen cells (unless boosted by systemic antigen), but if the tolerated graft itself is adoptively transferred to empty mice, the grafts are accepted. This is not just passive acceptance by the mice that have no adaptive immune system of their own, because the administration of antibodies that block or deplete Tregs (e.g., antibodies to CD25, the hCD2. Foxp3 reporter when hCD2. Foxp3 reporter mice were the original graft recipients, or other functional blocking antibodies such as anti-CTLA4 or anti-TGF-β) all lead to rapid graft rejection. This demonstrates that Tregs are required to actively and continuously block the action of effector T cells that are also present in the grafted and tolerated skin.

Citation: Waldmann H, Howie D, Cobbold S. 2017. Induction of Immunological Tolerance as a Therapeutic Procedure, p 771-785. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0019-2015
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Figure 5

Interactions between regulatory T cells and myeloid cells maintain a tolerogenic microenvironment within tolerated tissues. Myeloid cells, including certain dendritic cells (Tol DC), type II macrophages (Mɸ), and mast cells can all express a range of enzymes, either intracellularly or secreted, that catabolize or utilize EAAs. In the context of an intact vasculature, this leads to the local depletion of amino acids, which represents one component of an immune-privileged or tolerogenic microenvironment. In addition, CD39 and CD73 coexpression on Tregs and other cell types, when enhanced by the local secretion of TGF-β, generates the anti-inflammatory mediator adenosine. Some Tregs also secrete IL-10, which further inhibits the ability of dendritic cells and Mɸ to present antigens for effector cell differentiation. Costimulatory ligands are also depleted from myeloid APCs by transendocytosis after capture by CTLA4 at the surface of Tregs. All these components of the tolerogenic microenvironment cooperate to limit the activity of naive and effector T cells while promoting Foxp3 expression and infectious tolerance. Graft rejection, on the other hand, is associated with leaking blood vessels and edema, which disrupts the tolerogenic niche, overwhelms the catabolic enzymes, and provides essential nutrients for T-cell activation and effector function.

Citation: Waldmann H, Howie D, Cobbold S. 2017. Induction of Immunological Tolerance as a Therapeutic Procedure, p 771-785. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0019-2015
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Figure 6

Nutrient and environmental sensing via mTOR regulates metabolism and Foxp3 expression. mTOR acts as an integrator of signals that arrive from a range of cell surface receptors and nutrient-sensing pathways and is critical in regulating cell metabolism and Foxp3 expression. The majority of these signals, including the TCR, growth factors, positive and negative costimulation (CD28 and PD-1), and the sphingosine 1-phosphate receptor (S1PR), converge on mTOR via the PI3K/AKT pathway, and are all dependent on recruiting phosphorylated Rheb to form the active TORC1 complex. The TORC1 complex can only be formed if there are sufficient EAAs to activate the regulator complex and the RAG proteins A to D. This means that a lack of amino acids effectively trumps all other signals via mTOR, inhibiting TORC1 activation, leading to enhanced oxidative phosphorylation (OxPhos), and allowing the Foxp3 gene to respond to TGF-β-mediated induction. Adenosine may also act indirectly on mTOR via cell surface receptors and/or adenosine transporters via AMP kinase (AMPK) signaling. It is interesting to note that at least three different classes of licensed drugs with immunomodulatory or metabolic activity (rapamycin, fingolimod, and metformin) target components of the mTOR signaling network.

Citation: Waldmann H, Howie D, Cobbold S. 2017. Induction of Immunological Tolerance as a Therapeutic Procedure, p 771-785. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0019-2015
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Figure 7

Tolerance or inflammation depends on the balance of Treg to T effector cell (Teff) and the response of mTOR to a range of microenvironmental factors. Whether the outcome of an immunological response is one of tolerance or inflammation is increasingly being considered as a balance between the number of Tregs and Teffs. This needs to be tempered by the influence of a number of other factors, particularly within the local microenvironment of the tolerated tissue, including the balance of adenosine to ATP, the effectiveness of amino acid depletion, and probably many other factors that may be associated with particular tissues and their state of health, such as inflammatory or anti-inflammatory cytokines, hypoxia, and reperfusion injury. Drugs that inhibit or activate mTOR might be able to adjust the balance point in favor of tolerance (for autoimmune disease and transplantation) or inflammation (for treatment of cancer) and provide a long-lasting therapeutic outcome from a short course of treatment.

Citation: Waldmann H, Howie D, Cobbold S. 2017. Induction of Immunological Tolerance as a Therapeutic Procedure, p 771-785. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0019-2015
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