Genetics of immunological tolerance: I. Bidirectional selective breeding of mice for oral tolerance.

The polygenic nature of oral tolerance regulation was elucidated by the method of bidirectional selective breeding of mouse strains for tolerance susceptibility (TS) and resistance (TR) starting from a genetically heterogeneous population achieved by the equilibrated intercrossing of eight inbred mouse strains (A/J, DBA/2J, P/J, SWR/J, SJL/J, CBA/J, BALB/cJ and C57BL/6J). Seven days after intragastric administration of 5 mg OVA or BSA, mice were intraperitoneally immunized with 100 microg of the corresponding antigen. The individual antibody titres were measured by haemagglutination. The phenotypes at the highest and lowest extremes were selected for assortative mating, avoiding consanguinity. The second litter of each mating couple was intraperitoneally immunized only to evaluate the immunocompetence of the corresponding generation and to ascertain the non-selection of non-responder mice. A normal distribution of agglutinin titres ranging from 4 to 14 log2 was observed in the F0 population. In the F12 generation, TR and TS strains showed highly significant differences for agglutinin titres (TR=15.06+/-1.80 and TS=8.35+/-2.44), and IgG responses by ELISA. Up to the F12 generation, the mean realized heritability was 0.14+/-0.02. The response to the selection was 0.43 log2 and the selection differential 3.10 log2/generation. A provisional estimation indicated that oral tolerance may be influenced by eight or nine independent loci.