Differential Requirement for CD28/CTLA-4-CD80/CD86 Interactions in Drug-Induced Type 1 and Type 2 Immune Responses to Trinitrophenyl-Ovalbumin

Abstract

The use of mAbs to abrogate costimulatory interactions has attracted much attention with regard to prevention and modulation of adverse (auto)immune-like reactions. However, the role of costimulatory molecules and possible therapeutic use of Ab-treatment in drug-induced immunostimulation is poorly elucidated. In the present studies, we show that CD28/CTLA-4-CD80/CD86 costimulatory interactions differently regulate drug-induced type 1 and type 2 responses to an identical bystander Ag, TNP-OVA, in BALB/c mice using the reporter Ag popliteal lymph node assay. The antirheumatic drug D-Penicillamine, which may induce lupus-like side-effects, stimulated type 2 responses against TNP-OVA, characterized by the production of IL-4 and TNP-specific IgG1 and IgE. These responses were abrogated in CD80/CD86-deficient mice and in wild-type mice that were treated with anti-CD80 and anti-CD86, or CTLA-4-Ig. Anti-CTLA-4 intensively enhanced the D-Penicillamine-induced effects. In contrast, the type 1 response (IFN-γ, TNF-α, IgG2a) to TNP-OVA induced by the diabetogen streptozotocin still developed in the absence of CD80/CD86 costimulatory signaling. In addition, it was demonstrated that coadministration of anti-CD80 and anti-CD86 mAbs slightly enhanced streptozotocin-induced type 1 responses, whereas the CTLA-4-Ig fusion protein completely abrogated this response. In conclusion, different drugs may stimulate distinct types of immune responses against an identical bystander Ag, which are completely dependent on (type 2) or independent of (type 1) the CD28/CTLA-4-CD80/CD86 pathway. Importantly, the effects of treatment with anti-CD80/CD86 mAbs and CTLA-4-Ig may be considerably different in responses induced by distinct drugs.

Impairment of stimulation ability of very-preterm neonatal monocytes in response to lipopolysaccharide

“…Moreover, monocytes of very-preterm neonates show a lack of response to IFN-␥ [11,38], which agrees with the fact that since it is usually synthesized by T h 1 lymphocytes, it generates a monocyte/macrophagelike costimulatory signal that induces or increases the expression of the B7-family receptors [39]. Besides T cell activation, the expression of B7 family molecules has an effect on cytokine production [40], and some authors have described a relationship between the expression of costimulatory molecules and the type of immune response developed [41]. The lack of expression of CD80 molecule, as well as IFN-␥ responses, observed in very-preterm neonates indicates that these infants could have an incomplete T h 1 response when confronted with the pathogen.…”

An intravenous exposure mouse model for prediction of potential drug‐sensitization using reporter antigens popliteal lymph node assay

“…Popliteal lymph node assay (PLNA), a straightforward animal test, has been recognized as a simple tool that is a reliable, fast and reproducible method for IDHR assessment (Carey et al, 2006;Gehrs and Smialowicz, 1999;Gutting et al, 2002b;Kammuller et al, 1989;Lovik et al, 2007;Nierkens et al, 2005a). Since 1976, PLNA has been used to study graft vs host reactions, initially by Gleichmann and Gleichmann, and studies have demonstrated that numerous drugs and chemicals known to induce IDHR in humans, such as penicillin, diclofenac and cadmium, cause PLN reactions following injection into the footpad (Aida et al, 1998;Carey et al, 2006;Gleichmann and Gleichmann, 1976;Gutting et al, 2002b;Samuelsen et al, 2008); the results of these tests showed close correlations.…”