Tolerance and ways to break it.

The overall picture as regards cellular mechanisms in immunologic tolerance is thus clear. Thymic negative selection is an important and dominant mechanism for both CD4+ and CD8+ T cells for those antigens (and they may be very many indeed), the peptides of which get expressed within the thymus. The induction of anergy among peripheral T lymphocytes may represent an ancillary mechanism in some cases, but this is not as clear as it appeared 2 or 3 years ago. Evidently, in many cases, T cells simply ignore antigens present only within specialized organs, and these T cells, even if only of low affinity for the antigen in question, could be provoked into autoimmunity if sufficient help is provided, for example, through localized production of IL-2 or through provision of cross-reactive help. B-cell tolerance is also proven and involves deletional mechanisms (most likely maturation arrest) or functional inactivation (clonal anergy). The former phenomenon dominates for self-antigens that strongly cross-link the B cell's Ig receptors and the latter for weaker negative signals. Despite these two mechanisms, clonal ignorance prevails for many self-antigens. The secondary B-cell repertoire is also largely free of anti-self B cells, lack of T-cell help being a major factor in preventing the development of anti-self memory B cells. Therefore, to have the best chance of creating an immunogenic antitumor vaccine, a few simple and rather obvious rules must be followed. The antigen in question must be presented in such a way as to be palatable to "professional" antigen-presenting cells, particularly dendritic cells and macrophages. Immunotherapy protocols should avoid at all costs the widespread distribution of the antigen in question through the extracellular fluids. Indeed, it is possible that widespread circulation of a tumor-associated antigen through the serum and lymph because of large-scale shedding from the tumor cell may already have created a substantial degree of tolerance to the antigen in question in both T- and B-cell populations. If that has happened, it becomes particularly important to create a cancer vaccine capable of inducing help. This may well involve coupling of the most important epitopes to some highly immunogenic and foreign carrier. A wide choice of adjuvants is available for the designer of tumor vaccines, and in this regard the cancer immunotherapy community has much to learn from the rapidly developing field of infectious disease vaccinology using recombinant and other vaccines.(ABSTRACT TRUNCATED AT 400 WORDS)