Anti-tumor necrosis factor antibodies suppress cell-mediated immunity in vivo.
Rabbit anti-murine TNF-alpha antibodies were administered in vivo to mice to evaluate the role of TNF-alpha in T cell-mediated immunity. Anti-TNF suppressed the in vivo development of contact sensitivity to the hapten TNP in a dose-dependent fashion. Similarly anti-TNF suppressed the in vivo priming for TNP-specific CTL. Control antibodies did not suppress cell-mediated immunity, whereas purified murine rTNF-alpha neutralized the antibody activity. Antibody therapy was effective during the afferent or priming limb of immunity, but could not inhibit the response if administered during the efferent limb. FACS for CD2, CD3, CD4, and CD8 T, B, and NK cell surface markers demonstrated no major change in the distribution of splenic lymphoid cell populations in animals pretreated with anti-TNF antibody. These results suggest that anti-TNF antibody may be interfering with soluble cytokines rather than with cell surface TNF causing depletion of cell populations. In vitro analyses also showed that anti-TNF has minimal inhibitory effects on secondary (secondary CTL) or strong primary (primary CTL, alpha CD3, MLR) responses, even though these in vitro cultures produce TNF mRNA as shown by polymerase chain reaction amplification. Although anti-TNF antibody did not affect the above responses, primary interactions are strongly inhibited in vivo. These findings suggest that TNF is important during afferent, priming events in immunity and that inhibition of TNF receptor-ligand interactions may alter immunity early in a response. Conversely such inhibition is ineffective later in a response, perhaps due to the ability of multiple other receptor-ligand pathways to bypass TNF.
Bromberg
J S
JS
Department of Surgery, Medical University of South Carolina, Charleston 29425.
Chavin
K D
KD
Kunkel
S L
SL
D000818:Animals; D003602:Cytotoxicity, Immunologic; D003877:Dermatitis, Contact / Q000276:immunology / Q000473:pathology; D015870:Gene Expression; D007111:Immunity, Cellular; D007156:Immunologic Memory; D051379:Mice; D008815:Mice, Inbred Strains; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014301:Trinitrobenzenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D012333:RNA, Messenger; D014301:Trinitrobenzenes; D014409:Tumor Necrosis Factor-alpha