Blood. 2003 Aug 21
Theien BE, Vanderlugt CL, Nickerson-Nutter C, Cornebise M, Scott DM, Perper SJ, Whalley ET, Miller SD.
Microbiology-Immunology/Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL, USA.
Interaction of VLA-4 with its ligand VCAM-1 is required for CNS migration of encephalitogenic T cells in relapsing experimental autoimmune encephalomyelitis (R-EAE).
Anti-VLA-4 mAb treatment prior to EAE onset inhibits disease induction, however, treatment initiated after the appearance of clinical symptoms increases relapse rates, augments Th1 responses, and enhances epitope spreading perhaps due to the activation of costimulatory signals.
To negate the potential costimulatory activity of intact anti-VLA-4, we examined the ability of BIO 5192, a small molecule VLA-4 antagonist, to regulate active PLP139-151-induced R-EAE.
BIO 5192 administered one week after peptide priming, i.e. before clinical disease onset, delayed the clinical disease onset, but led to severe disease exacerbation upon treatment removal.
BIO 5192 treatment initiated during disease remission moderately enhanced clinical disease while mice were on treatment and also resulted in post-treatment exacerbation.
Interestingly, BIO 5192 treatment begun at the peak of acute disease accelerated entrance into disease remission and inhibited relapses, but treatment removal again exacerbated disease.
Enhanced disease was caused by the release of encephalitogenic cells from the periphery and the rapid accumulation of T cells in the CNS.
Collectively, these results further demonstrate the complexity of VLA-4/VCAM interactions, particularly in a relapsing-remitting autoimmune disease.