IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 14. Immunological Tolerance

EXPERIMENTAL INDUCTION OF TOLERANCE

The advent of Transgenic Animals has provided new opportunities for studying tolerance to authentic self-Antigens

Until recently, artificially induced tolerance served as the sole experimental model. Animals were injected with antigens or foreign Cells, and The Fate of responding T or B cells was monitored under various conditions. However, it remained unclear to what extent this model accurately reflected natural tolerance to self-antigens.

Today, thanks to advances in transgenic technology, it is possible to study tolerance to self-antigens directly. These Methods allow researchers to introduce a specific Gene into mice of a defined genetic Background and analyze its impact on The Development of The Immune System. Furthermore, by linking the transgene to a tissue-specific promoter, Gene Expression can be restricted to specific Cell types. The immune system responds to the protein product of the transgene essentially as a true self-antigen (autoantigen), allowing all associated processes to be studied in vivo, free from the trauma and inflammatory responses that accompany the transplantation of foreign cells or Tissues. In addition, parental and transgenic mouse lines serve as ideal models for control experiments and lymphocyte transfer because they are congenic, differing at only a single locus. It is even possible to generate Transgenic Mice in which all T or B cells express a single antigen receptor. By dramatically increasing the frequency of antigen-specific precursor cells, this approach greatly facilitates the analysis of tolerance mechanisms. Finally, targeted mutagenesis allows immunologists to delete specific genes to investigate The Role of their products in inducing immunological tolerance.

There are three potential mechanisms by which autoreactive lymphocytes are prevented from responding to self-antigens:

✵ Clonal deletion: the physical removal of cells from the repertoire at a particular stage of their lifecycle.

✵ Clonal anergy: the functional inactivation of the Immune Response mechanism itself.

✵ Suppression: the downregulation of cellular activity resulting from interactions with other cells—such as cytokine-producing inhibitory cells or idiotype-specific lymphocytes that recognize the antigen-specific receptors of autoreactive cells.

Which of these mechanisms operates in a given situation depends on several factors: 1) the stage of Differentiation of the autoreactive lymphocytes, 2) the affinity of their receptors for the autoantigen, 3) The Nature of the antigen, 4) its concentration, 5) its tissue distribution, 6) the pattern of its expression, and 7) the presence or absence of costimulatory signals. As a general rule, in the absence of costimulation, the immune system is likely to ignore the antigen.