Effects of anti-CD4 antibody treatment on lymphocyte subsets and stimulated tumor necrosis factor alpha production: a study of 29 multiple sclerosis patients entered into a clinical trial of cM-T412.
T lymphocytes may play a central role in MS. The search for more targeted immunosuppression than is currently available has led to recent clinical trials of novel therapeutics. We studied 29 patients in a double-blind placebo-controlled trial of the chimeric monoclonal anti-CD4 antibody, cM-T412 (Centocor, Leiden, Holland) over a period of 18 months. Total and differential WBC counts; T, B, and natural killer lymphocytes; CD4+ and CD8+ T cells; CD4+ and CD4- naive cells; CD4+ and CD4- memory cells; interleukin-2 receptor- and major histocompatibility class II-positive T cells; serum tumor necrosis factor alpha (TNF-alpha); and PHA (phytohemagglutinin)/LPS (lipopolysaccharide)-stimulated whole blood TNF-alpha production were all examined serially in peripheral blood for the duration of the trial. In addition, for the first two treatment cycles, the above variables were tested 1 and 7 days after treatment. The results demonstrated significant long-term reductions, lasting up to 12 months after the last treatment cycle in all CD4+ subsets studied, but with a relative preservation of CD4+ memory cells as opposed to CD4+ naive cells. CD4- subsets also showed significant reductions after treatment but returned to baseline levels within 7 days. Monocyte counts were unaffected by cM-T412. Serum TNF-alpha and 2- and 18-hour PHA/LPS-stimulated TNF-alpha levels were also unchanged in the long term, although significant increases were observed in the 2- and 18-hour PHA/LPS-stimulated TNF-alpha levels the day immediately after treatment. There was no significant correlation between any of the immunologic markers studied and MRI measures of disease activity.
Llewellyn-Smith
N
N
Department of Haematology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Lai
M
M
Miller
D H
DH
Rudge
P
P
Thompson
A J
AJ
Cuzner
M L
ML
D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology*; D002678:Chimera; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D016131:Lymphocyte Subsets / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D012016:Reference Values; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D014409:Tumor Necrosis Factor-alpha