CD25 monoclonal antibody binding to the α‐chain of the Interleukin‐2 (IL‐2) receptor, blocks high‐affinity IL‐2 binding, thereby preventing complete T‐cell activation and being of ample importance in transplantation medicine and potentially the treatment of autoimmune disease. However, CD25 antibodies do not only block T‐cell activation but also prevent activation‐induced cell death (AICD) attributing a dual function to IL‐2. In this study, the modulation of the genomic expression profile of human peripheral blood mononuclear cells (PBMC) with therapeutic concentrations of humanized anti‐CD25 mAb was investigated. PBMC were stimulated with CD3 antibody OKT‐3 together with recombinant IL‐2 in the absence or presence of anti‐CD25 mAb. RNA was extracted and subjected to microarray analysis on U133A microarrays (Affymetrix). Anti‐CD25 treatment inhibited several genes typically expressed during T‐cell activation including granzyme B, signalling lymphocyte activation molecule, family member 1 (SLAMF1), CD40‐Ligand (CD40‐L), IL‐9 and interferon (IFN)‐γ. Interestingly, anti‐CD25 mAb also blocked the expression of several genes important for susceptibility to apoptosis, such as death receptor 6 (DR6) or reversed IL‐2‐mediated repression of anti‐apoptotic genes, such as Fas apoptotic inhibitory molecule 3 (FAIM3)/TOSO. Functional significance of DR6 and TOSO expression in IL‐2‐dependent T‐cell activation was subsequently evaluated by RNA interference in AICD: While siRNA specifically directed against DR6 did not modulate FAS‐L‐mediated apoptosis induction in primary T cells, down‐regulation of TOSO significantly increased susceptibility to apoptosis, emphasizing an important role for TOSO in IL‐2‐mediated AICD.
Since transfection of dendritic cells (DC) plays a key role in DNA vaccination, in vivo expansion of DC might be a tool to increase vaccine efficacy. We asked whether Fms-like tyrosine kinase-3 ligand (Flt-3L), a growth factor for DC, can be used as an adjuvant for DNA vaccination. Betagalactosidase (b-gal) was used as a model antigen in C57BL/6 mice. Mice were immunized i.m. with DNA coding for b-gal with or without additional injection of Flt-3L. In both cases, antigen-specific CD4 þ and CD8 þ T cells were detectable after vaccination. Compared with DNA alone, additional administration of Flt-3L led to a significant increase in the antigen-specific proliferative response. However, increased cytotoxicity by T cells was not observed. The cytokines secreted by splenocytes of immunized mice upon in vitro stimulation with antigen had a TH2 profile. Humoral responses against b-gal preferentially consisted of IgG1 antibodies. Analysis of DC from Flt-3L-treated mice revealed an immature phenotype with low or absent expression levels of CD80, CD86 and CD40. We conclude that Flt-3L does not generally skew immune responses towards a TH1 type. More likely, factors determined by the antigen and/or the vaccination procedure itself are crucial for the resulting type of immune response. Flt-3L -under circumstances such as the one we have investigated -can also lead to suppression of TH1 T cell immunity, possibly by expansion of immature/ unactivated DC.
Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems beneficial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL/6 mice were reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6-9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The difference between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25+CD4+ regulatory T cells since their depletion did not abrogate the therapeutic effect of ICOSL blockade. Microarray analysis revealed IFN-gamma and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction.
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