Heat-aggregated immunoglobulins increase in vivo immunogenicity of mouse hapten (TNP)-derivatized macrophages by upregulation of interleukin-12 secretion and expression of B7-1 and B7-2 costimulatory molecules.

摘要

Antigen-antibody complexes (IC) can up or down regulate immune responses by induction of immunoregulatory cells. We have studied the effect of mouse heat-aggregated immunoglobulin (Ig) (HA) which have many biological activities similar to IC on immunogenicity of TNP-substituted macrophages (TNP-Mphi). Our results show that: (1) mouse oil-induced peritoneal macrophages treated with HA produce in vitro significantly higher levels of interleukin (IL-1beta), tumor necrosis factor (TNF)-alpha, IL-6, IL-10 and particularly IL-12 and express more B7-1 and B7-2 and ICAM-1 cell surface costimulatory molecules than Mphi treated with monomeric Ig (MM); (2) Mphi derivatized with TNP, treated or not with MM, induce in vivo antigen-specific unresponsiveness. In contrast TNP-Mphi treated with HA induce significant contact sensitivity reaction even when injected into previously tolerized recipient animals. Treatment of recipients with anti-IL-12 Ab prevents immunization by TNP-Mphi-HA. These results indicate that bypass of tolerance by treatment of TNP-Mphi with HA is a result of an increased production of IL-12 by these cells and an enhanced expression of costimulatory molecules important in T cell-Mphi interactions. We suggest that a similar overcoming of tolerance through the action of IC may be responsible for the generation of autoantibodies of heterologous specificity in pathological conditions in which such complexes are formed.