Independent Genetic Control of B‐ and T‐Cell Tolerance in Strains of Mouse Selected for Extreme Phenotypes of Oral Tolerance

Abstract

Two strains of mice were genetically selected for susceptibility (TS-Ab/HetS strain) or resistance (TR-Ab/ HetS strain) to oral tolerance of the humoral response by using ovalbumin (OVA). The progressive interstrain divergence produced by bi-directional selective breeding during 15 generations demonstrated the polygenic nature of oral tolerance. This paper shows the humoral and delayed-type hypersensitivity (DTH) responses, after intragastric administration of OVA and subsequent immunization with that immunogen in complete Freund adjuvant (CFA). Only the TS-Ab/HetS mice were tolerant for immunoglobulin (Ig)G production with its tolerance degree being the same as that obtained when Al (OH) 3 was employed. The DTH reactivity was not correlated to the antibody responsiveness, because both the TS-Ab/ HetS and TR-Ab/HetS strains had their DTH reactions suppressed. The cyclophosphamide (Cy) pretreatment prevented DTH suppression on TR-Ab/HetS but do not in TS-Ab/HetS mice. Interstrain difference was also observed for the splenic index in the Cy-treated groups, although the number of splenocytes was the same. Flux cytometry cell analysis showed the recovery of CD3 1 cell numbers in both strains, but only the TR-Ab/HetS mice had their CD4/CD8 pattern restored. These results suggest: firstly, the independent control of DTH and humoral tolerance responsiveness; secondly no support for the clonal anergy concept; and thirdly the matrix proteins neo-synthesis after Cy treatment may facilitate the tolerance abrogation.

Innate profiles of cytokines implicated on oral tolerance correlate with low‐ or high‐suppression of humoral response

“…3a), as in previous results for delayed-type hypersensitivity reaction and IgE responses. 22,29 This dose-dependent . The mean differences between OVA-gavaged TS and OVAgavaged TR were statistically significant (P < 0Á001) by t-test as were those between OVA-gavaged TS and its respective saline-gavaged control (P < 0Á001), and between OVA-gavaged F 2 and saline-gavaged F 2 (P < 0Á01).…”

“…Immunoglobulin G antibodies of TR and TS mice to OVA and other antigens such as casein (Sigma-Aldrich), fowl gamma globulin (IgY), peanuts and cashew nuts were assessed by enzyme-linked immunosorbent assay (ELISA) as described previously. 22 Tetramethylbenzidine (Zymed Lab., Inc., San Francisco, CA) was used as the substrate for horseradish peroxidase. The yellow colour produced was read at 450-nm wavelength using a multiscan photometer.…”

Oral tolerance induction in humans

“…Furthermore, it has to be kept in mind that even between different mice strains significant differences in the induction of oral tolerance were observed (da Silva et al, 1998(da Silva et al, , 2001, highlighting the importance of basic research in another species like humans.…”

The anti-IRBP IgG1 and IgG2a response does not correlate with susceptibility to experimental autoimmune uveitis

“…The investigation of genes controlling acquired or innate immune mechanisms has demonstrated that major immunobiological functions such as inflammatory responses, quantitative antibody production, immunological tolerance, and T cell-mediated reactivity, in spite of their functional integration are, at least in part, under the additive effect of independent segregating loci (22)(23)(24)(25). The resulting polymorphic regulation of innate and adaptive immunity is the fundamental characteristic ensuring the survival of a genetically heterogeneous natural population.…”