Blockade of signaling via the very late antigen (VLA-4) and its counterligand vascular cell adhesion molecule-1 (VCAM-1) causes increased T cell apoptosis in experimental autoimmune neuritis.
We characterized the early effects of anti-very late antigen (VLA-4) and its counterligand vascular cell adhesion molecule-1 (VCAM-1) antibody therapy on T cell infiltration and apoptosis in adoptive transfer experimental autoimmune neuritis of female Lewis rats. At the peak of disease, animals were treated with anti-VCAM-1 monoclonal antibody (mAb), anti-VLA-4 mAb, or the respective isotype mAb controls 18, 12, or 6 h before perfusion. Anti-VCAM-1 led to a rapid, significant increase of apoptotic T cells in the sciatic nerve with a maximum after 6 h, preceding the significant decrease of T cell infiltration seen after 18 h. This was accompanied by a significant reduction in mRNA levels for IFN-gamma and inducible nitric oxide synthase. The results for anti-VLA-4 treatment showed a similar trend. The early increase of T cell apoptosis following disruption of VLA-4/VCAM-1 interaction may reflect a novel signaling component of proapoptotic pathways.
Leussink
V I
VI
Department of Neurology, University of Würzburg, Josef-Schneider-Strasse 11, 97080 Würzburg, Germany.
Zettl
U K
UK
Jander
S
S
Pepinsky
R B
RB
Lobb
R R
RR
Stoll
G
G
Toyka
K V
KV
Gold
R
R
D000818:Animals; D018926:Anti-Allergic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D009444:Neuritis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D011917:Rats, Inbred Lew; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology*
D018926:Anti-Allergic Agents; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1