Chapter 99: Tolerance (Immunology – Basic Science)

INTRODUCTION

• The liver immunologic tolerance effect was first described in 1963 by Calne et al., who demonstrated that liver allografts may be accepted without immunosuppressive therapy.

• This chapter will provide:

  • Basic concepts of cellular and molecular mechanisms in liver tolerance

  • Strategies aimed at promoting stable, long-term immunologic tolerance in liver transplant recipients.

DEFINITION

• Tolerance is defined as a state of immune nonreactivity towards a specific set of antigens that is indefinitely maintained in the absence of ongoing immunosuppression.

INTRODUCTION TO CENTRAL, PERIPHERAL, AND LIVER TOLERANCE

• Central tolerance

  • Process that takes place in the primary lymphoid organs (the thymus and bone marrow) developing immune cells prior to export into the periphery.

  • Specific self-peptide-bound T lymphocytes to major histocompatibility complex (MHC) eliminated by clonal deletion.

  • T lymphocytes recognize antigenic fragments presented by MHC.

• Peripheral tolerance

  • Process generated after the cells reach the periphery by Treg (regulatory T cells)

  • Required for lymphocytes that have not been silenced in primary organs

  • Immune deviation: lymphocytes differentiate toward antigen-specific cells

  • Suppression of autoreactive cells by Tregs and the generation of anergy in lymphocytes that encounter the antigen in the absence of the costimulatory signals that accompany inflammation or in the presence of coinhibitory signals

• Liver tolerance

  • Unique immunologic microenvironment that supports the key immune surveillance functions exerted by the liver; responsible for clearing bloodborne pathogens without eliciting undesirable destructive immune responses against food-derived antigens and bacterial degradation products

CELL TYPES CONTRIBUTING TO LIVER IMMUNOLOGIC TOLERANCE IN THE PHYSIOLOGIC STEADY STATE

• Antigen-presenting cells (APCs) in the liver

  • Resident liver dendritic cells (DCs) (Fig. 99-1)

    • Type of APCs that does not enter the draining lymph node

    • Displays an immature phenotype that results in liver tolerogenic properties

    • Express in their surface low levels of MHC class I and costimulatory molecules such as CD40, CD80, and CD86

    • Induce cytokine production inhibition and proliferation of effector T cells via programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) responsible for tolerance induction in DCs.

    • Liver contains plasmacytoid DCs (PDC) and myeloid DC (MDC)

      • PDC: major source of interferon alpha (IFN-α).

      • MDC: secretes interleukin-2 (IL-12), modulates the activation of natural killer (NK) cells.

    • Development of immunogenic versus tolerogenic dendritic cells from immature MDCs is highly regulated and influenced greatly by external stimuli (Fig. 99-2).

      • IL-12 towards immunogenic

      • Tolerogenic signals such as IL-10 and CTLA4 induce MDC towards tolerogenic DC

  • Kupffer cells (KCs) (Figs. 99-3 and 99-4)

    • Tissue-resident macrophages.

    • Constitute 20% of nonparenchymal cells within the sinusoidal lumen in the periportal liver area.

    • Derived from bone marrow precursor and blood monocytes.

    • Largest group of tissue-resident macrophages in the body.

    • Participate in the endocytic uptake of antigens and macromolecules through a network of resident scavenger cell populations and a unique microanatomy.

    • Participate in the modulation of T-cell immune functions towards tolerogenic activity due ...