Cytokines in the Induction and Circumvention of Peripheral Tolerance

Abstract

Injection of deaggregated (monomeric) human gamma globulin (DHGG) into mice induces a state of immunological tolerance to subsequent challenge with immunogenic forms of HGG. Tolerance was shown to be induced in both the Th1 and Th2 CD4+ subsets. These mice fail to demonstrate antibody production, T cell proliferation, cytokine release, or T cell helper function. On the other hand, simultaneous injection of lipopolysaccharide (LPS) as well as interleukin-1 (IL-1) was capable of interfering with the induction of tolerance to DHGG. The purpose of the present study is to extend these investigations to determination of the cellular mechanisms responsible for the interference of tolerance induction in both CD4+ T cell subsets. It was demonstrated that LPS and IL-1 have differential effects on the induction of tolerance in the CD4+ subsets. As evidenced by immunoglobulin G (IgG) subclass, T helper cell function, and lymphokine secretion, coinjection of LPS with tolerogen interfered with the induction of tolerance in both subsets, whereas IL-1 interfered with the induction of tolerance exclusively in the Th1 subset. LPS and IL-1 had differential effects on the interference of the induction of tolerance in LPS-resistant mice where IL-1, but not LPS, was effective. In contrast to IL-1, IL-12 injected along with DHGG failed to interfere with the induction of tolerance in either Th1 or Th2 cells. Previous studies that demonstrated tolerance in the DHGG models induced in both the Th1 and Th2 subsets was further suggested by the demonstrations in the present study that dose-response curves for the induction of tolerance are identical in both subsets. The above findings taken together are compatible with the suggestion that tolerance induction results from the lack of cytokine production, which then prevents the expansion of Th1 and Th2 subsets following activation of the CD4+ precursor T cell. Furthermore, they support the general opinion that the expansion of these two subsets involve different cytokine pathways and that LPS and IL-1 most likely act through different cell receptors.

Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment

“…Thus, tolerance to self proteins present at low levels is not robust 32,33,36,37 , with potentially self-reactive antibody-secreting B cells deleted only at high levels of protein exposure; at lower levels, B cells may be reversibly nonresponsive, and at the extreme low end of abundance, they may be fully reactive 29,30,34,38 . In contrast, T cells are tolerized at much lower levels of protein 32,39,40 , which may be related in part to promiscuous expression of what were once thought to be tissue-restricted antigens in the thymus 41 or to the unique ability of the thymus to present soluble antigens in a highly tolerogenic fashion 42 .…”

Understanding How Lipopolysaccharide Impacts CD4 T-Cell Immunity

“…82 However, whereas LPS generated both IgG1 and IgG2a antibodies, IL-1β only generated IgG1 which is indicative of a Th2-biased response. 83 Therefore, IL-1 can only partially substitute for LPS. This is not surprising considering the complexity of LPS signaling (Fig.…”

Biobetters

“…In contrast, immune responses to therapeutic proteins are expected when the protein is foreign, either because its sequence is derived from a different species or because patients lack the natural analog as a result of genetic deletion or modifi cation, as can be observed in Hemophilia A (lacking FVIII) and Pompe disease (lacking lysosomal acid alpha-glucosidase (GAA) enzyme). The development and phenotype of immune responses to FVIII and GAA, for instance, may depend on several factors which include: (1) the extent of the genetic deletion (minimal, partial, complete), (2) the prevalence of the protein in cells and circulation, and (3) the HLA alleles expressed by the patient (Opdenakker et al 2003 ;Haribhai et al 2003 ;Link et al 2014 ;McLachlan et al 2012 ;Romball and Weigle 1999 ;Bachmann et al 1994 ). For example, in Pompe disease, patients have genetic defi ciencies in GAA that result in accumulation of glycogen in lysosomes of cells throughout the body.…”