Abstract

The ideal therapy for the prevention of graft rejection would be one given short-term to achieve life-long tolerance without incurring side effects nor diminishing immunocompetence to infectious agents. Recent advances in the understanding of peripheral transplantation tolerance suggest that this may eventually be possible. The demonstration of regulatory cells with the ability to tame alloreactive clones may provide the framework for this advance. This review focuses on the challenging prospects of dominant tolerance and some of its characteristics, namely linked suppression and infectious tolerance.

Transplantation tolerance can be achieved therapeutically through two distinct approaches: inactivation of alloreactive clones and the induction of regulatory circuits. Although the approaches might seem incompatible, we here argue that most tolerance induction strategies involve, to a certain degree, both inactivation of alloreactive cells and the amplification of regulatory cells.

Current immunosupressive regimens target the whole immune system. However, an elective ablation of only the alloreactive clones, if feasible, offers a way of preventing graft rejection while sparing host's immunocompetence. One possible approach to achieving this involves the transfer of a high dose of bone marrow cells from the donor to establish mixed hemopoietic chimerism or macro-chi-merism.1-3 This permits for in vitro monitoring of the tolerant state by sampling lymphocytes from the host and testing their reactivity against donor-type cells. Such "functional" assays may be impracticable, inconvenient and not always reliable. Furthermore, it might prove difficult to deplete all alloreactive T-cell clones, and any expansion of residual cells might give rise to delayed transplant rejection.

The complementary strategy aims to control alloreactive cells in a different way. It is based on the induction of a dominant tolerance state and its hallmark is the emergence of regulatory CD4+ T cells.4 Unlike tolerance by deletion, here cells with the ability to react in vitro with donor type cells may still be demonstrated, but grafts are still accepted indefinitely. Furthermore, tolerance is very robust and resists the adoptive transfer of cells with the potential to mediate graft rejection -the reason why it is termed dominant.5,6 The regulatory cells can even do more

Receives G rait no therapy

Graf! reacted

Receives G rait no therapy

Graf! reacted

Receives G rait

Stiort-cou rse ani ¡tody the rapy

G rail accepted Receives fresh graft and third party graft

Graft accepted! Third-party graft rejected!

Receives G rait

Stiort-cou rse ani ¡tody the rapy

G rail accepted Receives fresh graft and third party graft

Graft accepted! Third-party graft rejected!

Figure E1.1. Demonstration of tolerance in antibody treated animals. Mice accept a second challenge with a graft of the same type, but readily reject third party grafts. Alloreactive cells, as demonstrated by proliferation assays, are present at any time point.

than just "suppress": if they are allowed to coexist with the naïve cells, they have the capacity to recruit new regulatory CD4+ T cells from that naïve pool. After this recruitment, the initial regulatory T cells can be removed experimentally and one observes that the new regulators can maintain tolerance themselves.7 This process can be repeated experimentally for several cell transfers, and has therefore been named infectious tolerance.8

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