Melvin Cohn and Rodney E. Langman

The Salk Institute, P.O. Box 85800, San Diego, California, 92186-5800

Received 8/15/96; Accepted 9/9/96; On-line 10/1/96

7. THINKING ABOUT THE IMMUNE SYSTEM

The guiding principle must be based on evolutionary considerations. There is a tug-of-war relationship between a mutationally derived increase in the immune protection against the pathogenic load and the mutational escape of the pathogen from destruction. This process reaches an apparent steady state when the level of protection is no longer limiting to the procreation of the species. The consequence of this limit is that no property is absolute or perfect. There is a limit to the degree of specificity of the receptors, the completeness of haplotype exclusion, the accuracy of signaling between cells, the black-and-whiteness of the Self-Nonself discrimination, the efficacy of effector function, and so on. In the end the immune system fails to protect for two reasons:

1) The response is too slow because the number of cells per ml that respond to the pathogen are too few.

2) The class of effector function that is induced is ineffective.

Vaccination and passive antibody treatments deal with the first problem by calling on specificities in the virtual or potential repertoire that are in too low frequency to be protective in a primary response. This is possible because the animal is being vaccinated or immunized under non-threatening conditions, thus allowing weeks and even months to pass while the response of low frequency specificities is being amplified. Passive antibody treatments can call upon antibodies isolated by hi-tech hybridoma and cloning methodologies or by combinatorial libraries. In this case, a mixture of antibodies can be used for treatment that are not only too rare to be induced by vaccination but may even be non-inducible yet functional as effector molecules (e.g., antibodies with mutations in the framework or with a DN region that creates a nonfunctional signaling antigen-receptor). Obviously these antibodies in the potential repertoire are available to us but unavailable to evolution.

Vaccination and passive antibody treatments require that the specificities involved be linked to effective effector functions. If there is no class or classes of response that would be effective in ridding the pathogen, then manipulation of the immune response would be useless. The effective class of response must be known if one is to design effective vaccines and antibody treatments. Clearly the treatments must be in the effective class.

The above interventions depend on understanding and knowledge. The more encompassing our understanding, the greater the probability that we will be able to creatively intervene.