Abstracts (complete list) - Wissenschaft Online

Xin Ding, Niklas Beyersdorf, Gregor Blank, Fred Lühder, Kevin Dennehy, Ralf Gold,
Thomas Kerkau, Thomas Hünig
Blockade of CD28-B7 interactions by anti-CD28 antibodies
protects from
immunopathology in vivo
Co-stimulation through CD28 achieved either by interactions of CD28 with B7 molecules
or by agonistic anti-CD28 antibodies is critically involved in the initiation of T cell
responses.
Here we have studied the in vitro and in vivo properties of a novel mouse anti-mouse
CD28 antibody, E18, which recognizes an epitope close to the B7 binding site. In vitro,
both, the intact antibody and its Fab fragment, completely blocked the binding of B7
molecules to CD28 expressed on mouse thymocytes. E18 Fab also inhibited T cell
proliferation after stimulation with anti-CD3 or the superantigen staphylococcal
enterotoxin B (SEB) in vitro, while the intact antibody triggered suboptimal costimulation.
Application of E18 mAb to normal BALB/c mice in vivo or to newborn
thymus organ cultures in vitro selectively reduced the generation of CD25+ FoxP3+
regulatory T cells (Treg cells). In the periphery, a single injection of 250 •g E18 to adult
BALB/c mice led to a gradual loss of CD4+ T cells from secondary lymphoid organs,
while not reducing Treg cell frequencies among CD4 cells. Even after weekly treatment
with 100 •g E18/ mouse for a period of 26 weeks only a two-fold reduction in Treg cell
frequencies among CD4+ cells was observed, which thoroughly rebounded after
cessation of treatment. Preventive application of E18 mAb prior to in vivo stimulation
with SEB strongly reduced the proliferation of responding Vβ8+ CD4+ T cells. The
capacity of mAb E18 to inhibit effector T cell responses in vivo translated into protection
from acute graft versus host disease-associated lethality and provided efficient
treatment for experimental autoimmune encephalomyelitis. This work was supported by
grants from the DFG (Hu295/8), the GHS (1.01.1/06/001) and the Wilhelm Sander-
Stiftung (2005.133.1).